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

. Erratum in J Appl Biomater Funct Mater. 2013;11(1):e71. Natural polymers, because of their biocompatibility, availability, and physico-chemical properties have been the materials of choice for the fabrication of injectable hydrogels for regenerative medicine. In particular, they are appealing materials for delivery systems and provide sustained and controlled release of drugs, proteins, gene, cells, and other active biomolecules immobilized.In this work, the use of hydrogels obtained from natural source polymers as cell delivery systems is discussed. These materials were investigated for the repair of cartilage, bone, adipose tissue, intervertebral disc, neural, and cardiac tissue. Papers from the last ten years were considered, with a particular focus on the advances of the last five years. A critical discussion is centered on new perspectives and challenges in the regeneration of specific tissues, with the aim of highlighting the limits of current systems and possible future advancements. PMID: 22865572 [PubMed - indexed for MEDLINE] 124. Obes Facts. 2012;5(4):546-60. doi: 10.1159/000341560. Epub 2012 Jul 27. Influence of exclusive resistance training on body composition and cardiovascular risk factors in overweight or obese children: a systematic review. Dietz P(1), Hoffmann S, Lachtermann E, Simon P. Author information: (1)Department of Sports Medicine, Rehabilitation and Disease Prevention, Faculty of Social Science, Media and Sports, Johannes Gutenberg-University Mainz, Germany. pdietz@uni-mainz.de OBJECTIVE: Since the last decade, a significant increase in the prevalence of overweight and obesity among children has been reported. Low aerobic fitness and a low compliance with endurance sports in such children are theoretical reasons to favor the use of resistance training in intervention studies, even though positive effects of resistance training on morbidity without accompanying dietary modifications are a matter of debate. In this review we summarize the studies that have shown the isolated effect of resistance training on body composition and cardiovascular risk factors in overweight and obese children. METHOD: We systematically reviewed interventional studies that exclusively applied resistance training to overweight and obese 3- to 18-year-old children. Outcome measurements were body composition or cardiovascular risk factors. RESULTS: Only six studies passed the inclusion criteria. All studies preferred an individually planned and supervised whole-body resistance training of moderate to submaximal intensity during treatment. The mean compliance was 84%. Four studies reported significant changes in body composition, with an increase in fat free mass and BMI, along with a decrease in fat mass. Three studies analyzed the effect of resistance training on cardiovascular risk factors, and only one study reported a significant decrease in systolic blood pressure. CONCLUSION: An individually planned and supervised whole-body resistance training of moderate to submaximal intensity in children seems to be safe and tends to show positive effects on body composition. Similar to interventions based on endurance exercise alone or in combination with dietary modifications, the effects on cardiovascular risk factors cannot be substantiated. In consequence, we suggest to substantiate the effect of resistance training on cardiovascular risk factors in overweight and obese children in upcoming randomized controlled trials with high case numbers, applying both resistance training only and resistance training in combination with dietary intervention to get knowledge about whether resistance training alone is effectual in the treatment of overweight and obesity in youth or if a combination of resistance training and dietary interventions is actually needed. PMID: 22854678 [PubMed - indexed for MEDLINE] 125. Exp Diabetes Res. 2012;2012:484696. doi: 10.1155/2012/484696. Epub 2012 Jul 18. MicroRNAs in insulin resistance and obesity. Williams MD(1), Mitchell GM. Author information: (1)O'Brien Institute, Melbourne, VIC 3065, Australia. mwilliams.student@gmail.com MicroRNAs (miRNAs) are a class of short, single-stranded non-protein coding gene products which can regulate the gene expression through post-transcriptional inhibition of messenger RNA (mRNA) translation. They are known to be involved in many essential biological processes including development, insulin secretion, and adipocyte differentiation. miRNAs are involved in complex metabolic processes, such as energy and lipid metabolism, which have been studied in the context of diabetes and obesity. Obesity, hyperlipidemia (elevated levels of blood lipids), and insulin resistance are strongly associated with the onset of type 2 diabetes. These conditions are also associated with aberrant expression of multiple essential miRNAs in pancreatic islets of Langerhans and peripheral tissues, including adipose tissue. A thorough understanding of the physiological role these miRNAs play in these tissues, and changes to their expression under pathological conditions, will allow researchers to develop new therapeutics with the potential to correct the aberrant expression of miRNAs in type 2 diabetes and obesity. PMCID: PMC3407629 PMID: 22851965 [PubMed - indexed for MEDLINE] 126. J Bras Nefrol. 2012 Jun;34(2):184-8. [Crosstalk between bone and adipose tissue in chronic kidney disease]. [Article in Portuguese] Marinho SM(1), Moraes C, Mafra D. Author information: (1)Universidade Federal Fluminense, Niterói, RJ, Brazil. sandramaramarinho@ hotmail.com Within the concept that hormones are regulated by a cycle of reciprocity, the fact that osteoblasts and adipocytes are developed from mesenchymal stem cells and that bone remodeling is regulated by leptin brings up the idea of possible bone participation in energy metabolism and vice-versa. Recent studies have shown that the differentiation and function of these bone cells are regulated by leptin, which seems to trigger a bimodal response, via sympathetic nervous system, and a local response, in which leptin acts on the bone. In fact, studies have shown complex interactions between bone, adipose tissue and brain. However, there are few studies on crosstalk in patients with chronic kidney disease (CKD). These patients have a tendency to decreased bone mineral density and high levels of leptin. Then, this article presented a review of potential involvement of adipose tissue and bone mass in patients with CKD. PMID: 22850921 [PubMed - indexed for MEDLINE] 127. Nat Rev Endocrinol. 2012 Dec;8(12):709-16. doi: 10.1038/nrendo.2012.114. Epub 2012 Jul 31. Adaptive immunity in obesity and insulin resistance. Sell H(1), Habich C, Eckel J. Author information: (1)Paul-Langerhans Group, German Diabetes Center, Leibniz Center for Diabetes Research at the Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany. Obesity is the hallmark of the metabolic syndrome and predisposes patients to the development of major chronic metabolic diseases including type 2 diabetes mellitus. Adipose tissue expansion in obesity is characterized by increasing infiltration of proinflammatory immune cells into adipose tissue causing chronic, low-grade inflammation. Phenotypic switching of macrophages is an important mechanism of adipose tissue inflammation, and there is involvement of cells from the adaptive immune system in this process. T-cell phenotype changes and recruitment of B cells and T cells precedes macrophage infiltration. Cytokines and chemokines produced by immune cells influence localized and systemic inflammation, which is a pathogenic link between obesity and insulin resistance. Antigens absorbed from the gut might contribute to T-cell activation and recruitment into visceral adipose tissue in obesity. This Review summarizes, in the context of obesity, the evidence for infiltration of adipose tissue by cells of the adaptive immune system, how adaptive system cells affect innate cell populations and the influence of adaptive immune cells on the development of insulin resistance. PMID: 22847239 [PubMed - indexed for MEDLINE] 128. Int J Obes (Lond). 2013 Jun;37(6):759-64. doi: 10.1038/ijo.2012.124. Epub 2012 Jul 31. Adaptive thermogenesis can make a difference in the ability of obese individuals to lose body weight. Tremblay A(1), Royer MM, Chaput JP, Doucet E. Author information: (1)Department of Kinesiology, PEPS, Laval University, Quebec City, Quebec, Canada. angelo.tremblay@kin.msp.ulaval.ca The decrease in energy expenditure that occurs during weight loss is a process that attenuates over time the impact of a restrictive diet on energy balance up to a point beyond which no further weight loss seems to be possible. For some health professionals, such a diminished energy expenditure is the normal consequence of a progressive decrease in the motivation to exercise over the course of a weight-reducing program. Another explanation of decreased energy needs during weight loss is the decrease in body energy stores (that is, fat mass and muscle mass) and its related obligatory costs of living. Many studies have also documented the existence of adaptive thermogenesis in the context of weight loss, which represents a greater-than-predicted decrease in energy expenditure. In this paper, we pursue the analysis of this phenomenon by demonstrating that an adaptive decrease in thermogenesis can have a major role in the occurrence of resistance to further lose fat in weight-reduced obese individuals. Evidence is also presented to support the idea of greater hunger sensations in individuals displaying more pronounced thermogenic changes. Finally, as the decrease in thermogenesis persists over time, it is also likely associated with a greater predisposition to body-weight regain after weight loss. Globally, these observations suggest that the adaptive reduction in thermogenesis that accompanies a prolonged negative energy balance is a major determinant of the ability to spontaneously lose body fat. PMID: 22846776 [PubMed - indexed for MEDLINE] 129. Exp Gerontol. 2013 Jul;48(7):608-11. doi: 10.1016/j.exger.2012.07.009. Epub 2012 Jul 27. Expression and function of APP and its metabolites outside the central nervous system. Puig KL(1), Combs CK. Author information: (1)Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58203, USA. Amyloid precursor protein (APP) derived amyloid beta (Aβ) peptides have been extensively investigated in Alzheimer's disease pathology of the brain. However, the function of full length APP in the central nervous system remains unclear. Even less is known about the function of this ubiquitously expressed protein and its metabolites outside of the central nervous system. This review summarizes key aspects of the current understanding of the expression and function of APP and its proteolytic fragments in specific non-neuronal tissues. Copyright © 2012 Elsevier Inc. All rights reserved. PMCID: PMC3505247 PMID: 22846461 [PubMed - indexed for MEDLINE] 130. Br J Nutr. 2011 Jul;106(2):196-202. The efficacy of Phaseolus vulgaris as a weight-loss supplement: a systematic review and meta-analysis of randomised clinical trials. Onakpoya I(1), Aldaas S, Terry R, Ernst E. Author information: (1)Complementary Medicine, Peninsula Medical School, University of Exeter, Exeter, UK. igho.onakpoya@pcmd.ac.uk A variety of dietary supplements are presently available as slimming aids, but their efficacy has not been proven. One such slimming aid is the bean extract, Phaseolus vulgaris. The aim of the present systematic review is to evaluate the evidence for or against the efficacy of P. vulgaris. Electronic and non-electronic searches were conducted to identify relevant human randomised clinical trials (RCT). Hand searches of bibliographies were also conducted. No age, time or language restrictions were imposed. The eligibility of studies was determined by two reviewers independently, and the methodological quality of the included studies was assessed. We identified eleven eligible trials, and six were included. All the included RCT had serious methodological flaws. A meta-analysis revealed a statistically non-significant difference in weight loss between P. vulgaris and placebo groups (mean difference (MD) − 1.77 kg, 95 % CI − 3.33, 0.33). A further meta-analysis revealed a statistically significant reduction in body fat favouring P. vulgaris over placebo (MD − 1.86 kg, 95 % CI − 3.39, − 0.32). Heterogeneity was evident in both analyses. The poor quality of the included RCT prevents us from drawing any firm conclusions about the effects of P. vulgaris supplementation on body weight. Larger and more rigorous trials are needed to objectively assess the effects of this herbal supplement. PMID: 22844674 [PubMed - indexed for MEDLINE] 131. Kardiologiia. 2012;52(7):78-83. [The problem of bone marrow fatty transformation]. [Article in Russian] Shishkova VN. PMID: 22839719 [PubMed - indexed for MEDLINE] 132. Clin Rheumatol. 2012 Sep;31(9):1401-2. doi: 10.1007/s10067-012-2034-0. Epub 2012 Jul 27. Improvement in insulin resistance after short-term treatment with abatacept: case report and short review. Ursini F(1), Mauro D, Naty S, Gagliardi D, Grembiale RD. Author information: (1)Program in Molecular Oncology, Experimental Immunology and Development of Innovative Therapies, University of Catanzaro Magna Graecia campus Salvatore Venuta, viale Europa, 88100 Catanzaro, Italy. francesco.ursini@yahoo.it Insulin resistance, a key feature of type 2 diabetes, is an independent risk factor for developing cardiovascular diseases (CVD), and represents the core of metabolic syndrome (MetS). Actually, an intriguing correlation between MetS and inflammation associated with rheumatoid arthritis (RA) is largely accepted but not yet completely clarified in detail. Recently, the therapeutic arsenal against RA has been enriched of abatacept, a fusion protein (CTLA4 immunoglobulin) designed to modulate the T cell co-stimulatory signal mediated through the CD28-CD80/86 pathway. Here, we report a case of dramatic improvement in insulin resistance, estimated with the surrogate measure HOMA-IR, after treatment with abatacept. Lastly, we shortly review the preclinical evidences supporting a possible role of T lymphocytes in rheumatoid arthritis-associated insulin resistance and how abatacept could improve glucose metabolism by suppressing adipose tissue infiltrating cells. PMID: 22837017 [PubMed - indexed for MEDLINE] 133. Dent Clin North Am. 2012 Jul;56(3):549-61. doi: 10.1016/j.cden.2012.05.004. Epub 2012 Jun 23. Dental stem cells and their sources. Sedgley CM(1), Botero TM. Author information: (1)Department of Endodontology, School of Dentistry, Oregon Health and Science University, 611 Southwest Campus Drive, Portland, OR 97239, USA. sedgley@ohsu.edu The search for more accessible mesenchymal stem cells than those found in bone marrow has propelled interest in dental tissues. Human dental stem/progenitor cells (collectively termed dental stem cells [DSCs]) that have been isolated and characterized include dental pulp stem cells, stem cells from exfoliated deciduous teeth, stem cells from apical papilla, periodontal ligament stem cells, and dental follicle progenitor cells. Common characteristics of these cell populations are the capacity for self-renewal and the ability to differentiate into multiple lineages. In vitro and animal studies have shown that DSCs can differentiate into osseous, odontogenic, adipose, endothelial, and neural-like tissues. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22835537 [PubMed - indexed for MEDLINE] 134. Ann Med. 2013 May;45(3):242-53. doi: 10.3109/07853890.2012.705015. Epub 2012 Jul 26. Metabolic inflammation: connecting obesity and insulin resistance. Dali-Youcef N(1), Mecili M, Ricci R, Andrès E. Author information: (1)Laboratoire de Biochimie et de Biologie Moléculaire, Hôpitaux universitaires de Strasbourg, 1 place de l'hôpital 67091 Strasbourg Cedex, France. n.daliyoucef@unistra.fr Insulin resistance is a pathological condition that arises when insulin signaling is impaired, forcing β-cells to produce more insulin in order to cope with body demands and to maintain glucose homeostasis. When the pancreas is no more able to support an appropriate insulin secretion, insulin resistance becomes decompensated and hyperglycemia is detected. One of the mechanisms leading to insulin resistance is low-grade inflammation that involves a number of protagonists such as inflammatory cytokines, lipids and their metabolites, reactive oxygen species (ROS), hypoxia and endoplasmic reticulum stress, and changes in gut microbiota profiles. We review here the molecular aspects of metabolic inflammation converging to insulin resistance and secondarily to type 2 diabetes. We also discuss the place of high-sensitivity C-reactive protein (hsCRP) in the assessment of metabolic inflammation and potential therapeutic interventions aimed to impede inflammation and therefore prevent insulin resistance. PMID: 22834949 [PubMed - indexed for MEDLINE] 135. Crit Rev Oncog. 2012;17(3):263-76. Is tissue cross-talk important in cancer cachexia? Johns N(1), Greig C, Fearon KC. Author information: (1)Department of Clinical Surgery and Geriatrics, School of Clinical Sciences and Community Health, University of Edinburgh, Edinburgh, EH16 4SB, UK. Recent work suggests molecular cross-talk between adipose tissue and muscle that occurs through adipokines and myokines. These molecules act in an endocrine fashion to play an intricate role in regulating body composition in both health and disease. Studies in exercise physiology have focused on the molecular cross-talk between adipose tissue and muscle that occurs through adipokines and myokines and on the role these molecules may play in chronic diseases. Similarly, integrative physiology in obesity and diabetes has long emphasised the importance of chronic inflammation, increased adipocyte lipolysis, and increased levels of circulating free fatty acids in the adipose-muscle cross-talk that contributes to lipotoxicity and insulin resistance in muscle. Cachexia affects the majority of patients with advanced cancer and is associated with a reduction in treatment tolerance, response to therapy, quality of life, and duration of survival. Although cachexia in patients with cancer is characterized by systemic inflammation, increased lipolysis, insulin resistance, and reduced physical activity, there has been little effort to manipulate the integrative physiology of adipose tissue and muscle tissue for therapeutic gain. PMID: 22831157 [PubMed - indexed for MEDLINE] 136. Crit Rev Oncog. 2012;17(3):247-51. Neuroinflammation: a contributing factor to the pathogenesis of cancer cachexia. Laviano A(1), Seelaender M, Rianda S, Silverio R, Rossi Fanelli F. Author information: (1)Department of Clinical Medicine, Sapienza University, Rome, Italy. alessandro.laviano@uniroma1.it The clinical journey of cancer patients is frequently complicated by the development of a complex and multifaceted syndrome, the main features of which are reduced appetite, decreased food intake, progressive weight loss, and wasting of muscle mass and adipose tissue, which is not prevented by the provision of calories and proteins. This syndrome, termed Cachexia, is responsible for increased morbidity, reduced survival, and impinged quality of life of cancer patients. The pathogenesis is complex and involves deranged metabolism of peripheral tissues and profound alterations of brain neurochemistry. Recent studies indicate that brain neurochemistry is perturbed during tumor growth by cancer-induced increased intrahypothalamic expression of proinflammatory cytokines. The attending neurochemical chaos mediates the anorexigenic behavioral responses associated to cancer cachexia, but recent data seem to suggest that neuronal output also may be involved in the metabolic changes occurring at the peripheral level. PMID: 22831155 [PubMed - indexed for MEDLINE] 137. Oxid Med Cell Longev. 2012;2012:349710. doi: 10.1155/2012/349710. Epub 2012 Jul 5. Exercise in the metabolic syndrome. Golbidi S(1), Mesdaghinia A, Laher I. Author information: (1)Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, The University of British Columbia, Vancouver, Canada. The metabolic syndrome is a clustering of obesity, diabetes, hyperlipidemia, and hypertension that is occurring in increasing frequency across the global population. Although there is some controversy about its diagnostic criteria, oxidative stress, which is defined as imbalance between the production and inactivation of reactive oxygen species, has a major pathophysiological role in all the components of this disease. Oxidative stress and consequent inflammation induce insulin resistance, which likely links the various components of this disease. We briefly review the role of oxidative stress as a major component of the metabolic syndrome and then discuss the impact of exercise on these pathophysiological pathways. Included in this paper is the effect of exercise in reducing fat-induced inflammation, blood pressure, and improving muscular metabolism. PMCID: PMC3399489 PMID: 22829955 [PubMed - indexed for MEDLINE] 138. J Mol Endocrinol. 2012 Aug 30;49(2):R79-87. doi: 10.1530/JME-12-0080. Print 2012 Oct. Searching for ways to switch on brown fat: are we getting warmer? Whittle A(1). Author information: (1)Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK. ajw232@medschl.cam.ac.uk Obesity rates are increasing alongside those of its co-morbidities, placing a huge strain on health systems across the globe. Evidence points to inappropriate levels of ectopic lipid accumulation outside of adipose tissue being a major factor in the progression of many of these diseases. Brown adipose tissue (BAT) has a huge capacity to remove lipids from the circulatory system to fuel thermogenesis. Multiple studies have now confirmed the existence of active BAT in adult humans, making strategies aimed at activating it a potential therapeutic option in obese subjects. In recent years, researchers working in murine models have found a wide range of endogenous molecules with specific roles regulating BAT. These findings place BAT firmly within the wider network of physiological regulation covering global metabolism. They also highlight the possibility of targeting thermogenesis in a safe and specific manner to remove potentially harmful lipids released from stressed or failing white adipose tissue in obese states. PMID: 22829654 [PubMed - indexed for MEDLINE] 139. Endocr Rev. 2012 Oct;33(5):812-41. doi: 10.1210/er.2012-1003. Epub 2012 Jul 24. Cardiometabolic aspects of the polycystic ovary syndrome. Randeva HS(1), Tan BK, Weickert MO, Lois K, Nestler JE, Sattar N, Lehnert H. Author information: (1)Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, United Kingdom. Harpal.Randeva@warwick.ac.uk Polycystic ovary syndrome (PCOS) is the most common endocrine disorder amongst women of reproductive age and is associated with various metabolic perturbations, in addition to chronic anovulation and factors related to androgen excess. In general, women live longer than men and develop cardiovascular disease at an older age. However, women with PCOS, as compared with age- and body mass index-matched women without the syndrome, appear to have a higher risk of insulin resistance, hyperinsulinemia, glucose intolerance, dyslipidemia, and an increased prothrombotic state, possibly resulting in a higher rate of type 2 diabetes mellitus, fatty liver disease, subclinical atherosclerosis, vascular dysfunction, and finally cardiovascular disease and mortality. Further alterations in PCOS include an increased prevalence of sleep apnea, as well as various changes in the secretion and/or function of adipokines, adipose tissue-derived proinflammatory factors and gut hormones, all of them with direct or indirect influences on the complex signaling network that regulates metabolism, insulin sensitivity, and energy homeostasis. Reviews on the cardiometabolic aspects of PCOS are rare, and our knowledge from recent studies is expanding rapidly. Therefore, it is the aim of the present review to discuss and to summarize the current knowledge, focusing on the alterations of cardiometabolic factors in women with PCOS. Further insight into this network of factors may facilitate finding therapeutic targets that should ameliorate not only ovarian dysfunction but also the various cardiometabolic alterations related to the syndrome. PMCID: PMC3461136 PMID: 22829562 [PubMed - indexed for MEDLINE] 140. Pathol Int. 2012 Aug;62(8):538-42. doi: 10.1111/j.1440-1827.2012.02831.x. Epub 2012 Jun 12. Mixed angiosarcoma, clear cell adenocarcinoma and mature teratoma elements in an ovarian tumor: a case report and literature review. Takahashi H(1), Chaopotong P, Kajita S, Hashimura M, Yamazaki H, Saegusa M. Author information: (1)Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan. hiroyuki.takahashi36@gmail.com Malignant transformation of a mature teratoma in the ovary is a rare event, with an approximate rate of only 1-2%. Here, we report an ovarian tumor with a unique combination of epithelial and non-epithelial malignant components, including mature teratoma elements. A 59 year-old postmenopusal woman underwent total hysterectomy and bilateral salpingo-oophorectomy to remove a huge solid mass of the right ovary. The ovarian tumor was 16 × 12 × 4.5 cm in dimensions, composed of red-brown and greyish-white tissue with several cystic areas. Microscopically, atypical cells immunopositive for both CD31 and CD34 formed irregular ectatic vascular patterns with a high MIB-1 labeling index in red-brown areas. In contrast, tubule-cystic and papillary structures were lined by HNF-1β-immunopositive atypical cuboidal and hobnail cells with clear cytoplasm in greyish-white areas. In addition, normal-looking epithelial and stromal components, including mature squamous, cuboidal and ciliated epithelial cells, and adipose tissues, were observed in red-brown areas, suggesting an ovarian tumor combining angiosarcoma, clear cell adenocarcinoma, and mature teratoma features. We could demonstrate identical X-chromosome inactivation patterns among all three components by human androgen receptor gene (HUMARA) assays, pointing to complex inter-relationships regarding their pathogenesis. These observations suggest that a malignant tumor composed of two characteristic phenotypes arose in mature teratoma. © 2012 The Authors. Pathology International © 2012 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd. PMID: 22827762 [PubMed - indexed for MEDLINE] 141. Clin Liver Dis. 2012 Aug;16(3):505-24. doi: 10.1016/j.cld.2012.05.005. Mechanisms of simple hepatic steatosis: not so simple after all. Matherly SC(1), Puri P. Author information: (1)Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, 23298, USA. Nonalcoholic fatty liver disease is becoming an epidemic. Fat is typically stored in adipose tissue in the form of triglycerides (TGs). The deposition of TGs in the liver is the result of an imbalance between the amount of energy taken in and the amount used. This balance is maintained by a complex interplay between the dietary intake of nutrients, the hormonal response to the nutrients, and their effect on both the liver and adipose tissue. Disruption of this system is what leads to the development of steatosis and is the focus of this article. Copyright © 2012. Published by Elsevier Inc. PMID: 22824478 [PubMed - indexed for MEDLINE] 142. Endocrine. 2012 Dec;42(3):496-505. doi: 10.1007/s12020-012-9754-4. Epub 2012 Jul 21. Fetuin-A and angiopoietins in obesity and type 2 diabetes mellitus. Rasul S(1), Wagner L, Kautzky-Willer A. Author information: (1)Unit of Gender Medicine, Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. Although type 2 diabetes mellitus (DM) is a chronic metabolic disorder with multiple etiologies, obesity has been constantly linked with insulin resistance and manifestation of type 2 DM. In addition, obesity is associated with hypertension, dyslipidemia, and fatty liver disease and is regarded as a subclinical inflammatory condition characterized by release of pro-inflammatory mediators such as cytokines from adipose tissue. Both, type 2 DM and obesity are considered as major risks for developing micro- and macrovascular diseases. Recent studies showed that impaired circulating levels of fetuin-A, which is involved in propagating insulin resistance as well as circulating levels of angiopoietins, which are growth factors promoting angiogenesis, were observed in patients with obesity, metabolic syndrome, and type 2 DM. However, independent of type 2 DM and obesity, defective regulation of fetuin-A and angiopoietin are playing a critical role in predisposing to coronary and peripheral vascular diseases. Therefore, mechanisms linking type 2 DM and obesity with fetuin-A and angiopoietins seem to be complex and are in need of further exploration. In this review, we aimed to present a summary concerning associations of type 2 diabetes, obesity, and vascular diseases with circulating levels of angiopoietins and fetuin-A. Furthermore, we aimed to focus on roles of fetuin-A and angiopoietins and to highlight the most plausible mechanisms that might explain their associations with type 2 DM and obesity. PMID: 22820893 [PubMed - indexed for MEDLINE] 143. Exp Gerontol. 2013 Jul;48(7):654-60. doi: 10.1016/j.exger.2012.07.005. Epub 2012 Jul 20. Metabolic adaptations to methionine restriction that benefit health and lifespan in rodents. Perrone CE(1), Malloy VL, Orentreich DS, Orentreich N. Author information: (1)Orentreich Foundation for the Advancement of Science, Inc., Cold Spring-on-Hudson, NY 10516, USA. perrone@orentreich.org Restriction of dietary methionine by 80% slows the progression of aged-related diseases and prolongs lifespan in rodents. A salient feature of the methionine restriction phenotype is the significant reduction of adipose tissue mass, which is associated with improvement of insulin sensitivity. These beneficial effects of MR involve a host of metabolic adaptations leading to increased mitochondrial biogenesis and function, elevated energy expenditure, changes of lipid and carbohydrate homeostasis, and decreased oxidative damage and inflammation. This review summarizes observations from MR studies and provides insight about potential mediators of tissue-specific responses associated with MR's favorable metabolic effects that contribute to health and lifespan extension. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22819757 [PubMed - indexed for MEDLINE] 144. Metab Syndr Relat Disord. 2012 Oct;10(5):319-20. Epub 2012 Jul 20. Role of subcutaneous adipose tissue in metabolic complications of obesity. Abate N, Chandalia M. PMID: 22816652 [PubMed - indexed for MEDLINE] 145. Arterioscler Thromb Vasc Biol. 2012 Aug;32(8):1771-6. doi: 10.1161/ATVBAHA.111.241869. Metabolic syndrome, insulin resistance, and roles of inflammation--mechanisms and therapeutic targets. Romeo GR(1), Lee J, Shoelson SE. Author information: (1)Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Obesity and its comorbidities, including type 2 diabetes mellitus and cardiovascular disease, are associated with a state of chronic low-grade inflammation that can be detected both systemically and within specific tissues. Areas of active investigation focus on the molecular bases of metabolic inflammation and potential pathogenic roles in insulin resistance, diabetes, and cardiovascular disease. An increased accumulation of macrophages occurring in obese adipose tissue has emerged as a key process in metabolic inflammation. Recent studies have also begun to unravel the heterogeneity of adipose tissue macrophages, and their physical and functional interactions with adipocytes, endothelial cells, and other immune cells within the adipose tissue microenvironment. Translating the information gathered from experimental models of insulin resistance and diabetes into meaningful therapeutic interventions is a tantalizing goal with long-term global health implications. In this context, ongoing clinical studies are testing the effects of targeting inflammation systemically on metabolic and cardiovascular outcomes. PMID: 22815343 [PubMed - indexed for MEDLINE] 146. Curr Opin Clin Nutr Metab Care. 2012 Sep;15(5):424-9. doi: 10.1097/MCO.0b013e328356b944. Segmental bioelectrical impedance analysis: an update. Ward LC(1). Author information: (1)School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Brisbane, Australia. l.ward@uq.edu.au PURPOSE OF REVIEW: Bioelectrical impedance analysis is a popular, noninvasive and practical method for assessment of body composition. The last decade has seen the development of impedance analyzers designed to assess the composition of body segments as well as the whole body. This review outlines the theoretical basis for segmental impedance analysis, validity and use in practice. RECENT FINDINGS: Segmental impedance analysis tends to underestimate fat-free mass and overestimate fat mass when compared to reference techniques, although the magnitude of these differences can be small. Performance is improved with population-specific prediction equations; algorithms in-built into instrument firmware should not be relied upon. Prediction of whole-body composition from the sum of the individual segments, although theoretically preferable, shows little advantage over whole body wrist to ankle impedance approaches. Prediction of appendicular skeletal muscle mass, although promising, requires further research. The use of measured impedance data directly as indices of composition, rather than for prediction, has not found extensive application in nutritional research despite its success in other fields. SUMMARY: Segmental bioimpedance techniques have advanced substantially in recent years due to availability of simple-to-use analyzers and simplified measurement protocols. The method has been well validated and increasingly adopted in nutritional and clinical practice. Segmental impedance, like conventional whole body impedance approaches, provides indirect prediction of body composition whose accuracy is yet to achieve that of reference techniques such as magnetic reference imaging. This lack of accuracy, however, is outweighed by the method's practicality of use in many settings. PMID: 22814626 [PubMed - indexed for MEDLINE] 147. Annu Rev Nutr. 2012 Aug 21;32:17-33. doi: 10.1146/annurev-nutr-071811-150644. Endoplasmic reticulum stress in nonalcoholic fatty liver disease. Pagliassotti MJ(1). Author information: (1)Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO 80523, USA. pagliasm@cahs.colostate.edu The underlying causes of nonalcoholic fatty liver disease are unclear, although recent evidence has implicated the endoplasmic reticulum in both the development of steatosis and progression to nonalcoholic steatohepatitis. Disruption of endoplasmic reticulum homeostasis, often termed ER stress, has been observed in liver and adipose tissue of humans with nonalcoholic fatty liver disease and/or obesity. Importantly, the signaling pathway activated by disruption of endoplasmic reticulum homeostasis, the unfolded protein response, has been linked to lipid and membrane biosynthesis, insulin action, inflammation, and apoptosis. Therefore, understanding the mechanisms that disrupt endoplasmic reticulum homeostasis in nonalcoholic fatty liver disease and the role of the unfolded protein response in the broader context of chronic, metabolic diseases have become topics of intense investigation. The present review examines the endoplasmic reticulum and the unfolded protein response in the context of nonalcoholic fatty liver disease. PMID: 22809102 [PubMed - indexed for MEDLINE] 148. Swiss Med Wkly. 2012 Jul 16;142:w13622. doi: 10.4414/smw.2012.13622. Stem cells for heart valve regeneration. Weber B(1), Emmert MY, Hoerstrup SP. Author information: (1)Swiss Centre for Regenerative Medicine, University of Zurich, Switzerland. benedikt.weber@access.uzh.ch Heart valve tissue engineering holds the potential to overcome limitations of currently used heart valve prostheses. It involves the isolation and expansion of autologous patient cells, the subsequent seeding of these cells onto an appropriate scaffold material, the in vitro incubation and the in vivo implantation of the derived tissue-engineered construct into the patient from whom the cells were taken. While vascular-derived cells require harvest of intact donor tissue and show limited expansion capacities, the use of stem or progenitor cells may overcome these limitations and expand the versatility of the concept of heart valve tissue engineering. Possible sources include cells isolated from blood, bone marrow, adipose tissue, amniotic fluid, chorionic villi, umbilical cord and induced pluripotent stem cells. Here we review different stem cell sources with particular regard to cellular phenotypes and their suitability for application in heart valve tissue engineering. PMID: 22802212 [PubMed - indexed for MEDLINE] 149. Steroids. 2012 Sep;77(11):1107-12. doi: 10.1016/j.steroids.2012.06.005. Epub 2012 Jul 16. The potential therapeutic benefits of vitamin D in the treatment of estrogen receptor positive breast cancer. Krishnan AV(1), Swami S, Feldman D. Author information: (1)Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, United States. Calcitriol (1,25-dihydroxyvitamin D(3)), the hormonally active form of vitamin D, inhibits the growth of many malignant cells including breast cancer (BCa) cells. The mechanisms of calcitriol anticancer actions include cell cycle arrest, stimulation of apoptosis and inhibition of invasion, metastasis and angiogenesis. In addition we have discovered new pathways of calcitriol action that are especially relevant in inhibiting the growth of estrogen receptor positive (ER+) BCa cells. Calcitriol suppresses COX-2 expression and increases that of 15-PGDH thereby reducing the levels of inflammatory prostaglandins (PGs). Our in vitro and in vivo studies show that calcitriol decreases the expression of aromatase, the enzyme that catalyzes estrogen synthesis selectively in BCa cells and in the mammary adipose tissue surrounding BCa, by a direct repression of aromatase transcription via promoter II as well as an indirect effect due to the reduction in the levels of PGs, which are major stimulator of aromatase transcription through promoter II. Calcitriol down-regulates the expression of ERα and thereby attenuates estrogen signaling in BCa cells including the proliferative stimulus provided by estrogens. Thus the inhibition of estrogen synthesis and signaling by calcitriol and its anti-inflammatory actions will play an important role in inhibiting ER+BCa. We hypothesize that dietary vitamin D would exhibit similar anticancer activity due to the presence of the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) in breast cells ensuring conversion of circulating 25-hydroxyvitamin D to calcitriol locally within the breast micro-environment where it can act in a paracrine manner to inhibit BCa growth. Cell culture and in vivo data in mice strongly suggest that calcitriol and dietary vitamin D would play a beneficial role in the prevention and/or treatment of ER+BCa in women. Copyright © 2012 Elsevier Inc. All rights reserved. PMCID: PMC3429709 PMID: 22801352 [PubMed - indexed for MEDLINE] 150. Biochimie. 2012 Oct;94(10):2143-9. doi: 10.1016/j.biochi.2012.06.030. Epub 2012 Jul 13. Adiponectin: anti-inflammatory and cardioprotective effects. Villarreal-Molina MT(1), Antuna-Puente B. Author information: (1)Instituto Nacional de Medicina Genómica, Mexico City, Mexico. Adipose tissue is an endocrine organ that plays an essential role in regulating several metabolic functions through the secretion of biological mediators called "adipokines". Dysregulation of adipokines plays a crucial role in obesity-related diseases. Adiponectin (APN) is the most abundant adipokine accounting for the 0.01% of total serum protein, and is involved in a wide variety of physiological processes including energy metabolism, inflammation, and vascular physiology. APN plasma levels are reduced in individuals with obesity, type 2 diabetes and coronary artery disease, all traits with low-grade chronic inflammation. It is has been suggested that the absence of APN anti-inflammatory effects may be a contributing factor to this inflammation. APN inhibits the expression of tumor necrosis factor-α-induced endothelial adhesion molecules, macrophage-to-foam cell transformation, tumor necrosis factor-α expression in macrophages and adipose tissue, and smooth muscle cell proliferation. It also has anti-apoptotic and anti-oxidant effects, which play a role in its cardioprotective action. This review will focus on APN as an anti-inflammatory, anti-atherogenic and cardioprotective plasma protein. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMID: 22796520 [PubMed - indexed for MEDLINE] 151. Trends Endocrinol Metab. 2012 Aug;23(8):407-15. doi: 10.1016/j.tem.2012.05.011. Epub 2012 Jul 12. Adipose tissue-resident immune cells: key players in immunometabolism. Schipper HS(1), Prakken B, Kalkhoven E, Boes M. Author information: (1)Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht and Center for Molecular and Cellular Intervention, Wilhelmina Children's Hospital, Utrecht, The Netherlands. Adipose tissue (AT) plays a pivotal role in whole-body lipid and glucose homeostasis. AT exerts metabolic control through various immunological mechanisms that instigated a new research field termed immunometabolism. Here, we review AT-resident immune cells and their role as key players in immunometabolism. In lean subjects, AT-resident immune cells have housekeeping functions ranging from apoptotic cell clearance to extracellular matrix remodeling and angiogenesis. However, obesity provides bacterial and metabolic danger signals that mimic bacterial infection, and drives a shift in immune-cell phenotypes and numbers, classified as a prototypic T helper 1 (Th1) inflammatory response. The resulting AT inflammation and insulin resistance link obesity to its metabolic sequel, and suggests that targeted immunomodulatory interventions may be beneficial for obese patients. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22795937 [PubMed - indexed for MEDLINE] 152. Cell Metab. 2012 Aug 8;16(2):153-66. doi: 10.1016/j.cmet.2012.06.011. Epub 2012 Jul 12. Cancer cachexia: mediators, signaling, and metabolic pathways. Fearon KC(1), Glass DJ, Guttridge DC. Author information: (1)Clinical Surgery, School of Clinical Sciences and Community Health, University of Edinburgh, Royal Infirmary, Edinburgh EH16 4SA, UK. k.fearon@ed.ac.uk Cancer cachexia is characterized by a significant reduction in body weight resulting predominantly from loss of adipose tissue and skeletal muscle. Cachexia causes reduced cancer treatment tolerance and reduced quality and length of life, and remains an unmet medical need. Therapeutic progress has been impeded, in part, by the marked heterogeneity of mediators, signaling, and metabolic pathways both within and between model systems and the clinical syndrome. Recent progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22795476 [PubMed - indexed for MEDLINE] 153. Cell Transplant. 2012;21(2-3):387-99. doi: 10.3727/096368911X605286. Regenerative cells for transplantation in hepatic failure. Ishikawa T(1), Banas A, Teratani T, Iwaguro H, Ochiya T. Author information: (1)Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan. Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells have an enormous potential; however, their potential clinical application is being arrested due to various limitations such as teratoma formation followed by tumorigenesis, emergent usage, and the quality control of cells, as well as safety issues regarding long-term culture are also delaying their clinical application. In addition, human ES cells have two crucial issues: immunogenicity and ethical issues associated with their clinical application. The efficient generation of human iPS cells requires gene transfer, yet the mechanism underlying pluripotent stem cell induction has not yet been fully elucidated. Otherwise, although human adult regenerative cells including mesenchymal stem cells have a limited capacity for differentiation, they are nevertheless promising candidates for tissue regeneration in a clinical setting. This review highlights the use of regenerative cells for transplantation in hepatic failure. PMID: 22793046 [PubMed - indexed for MEDLINE] 154. Arq Bras Endocrinol Metabol. 2012 Jun;56(4):215-25. The role of the uncoupling protein 1 (UCP1) on the development of obesity and type 2 diabetes mellitus. Brondani LA(1), Assmann TS, Duarte GC, Gross JL, Canani LH, Crispim D. Author information: (1)Endocrinology Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, RS, Brazil. It is well established that genetic factors play an important role in the development of both type 2 diabetes mellitus (DM2) and obesity, and that genetically susceptible subjects can develop these metabolic diseases after being exposed to environmental risk factors. Therefore, great efforts have been made to identify genes associated with DM2 and/or obesity. Uncoupling protein 1 (UCP1) is mainly expressed in brown adipose tissue, and acts in thermogenesis, regulation of energy expenditure, and protection against oxidative stress. All these mechanisms are associated with the pathogenesis of DM2 and obesity. Hence, UCP1 is a candidate gene for the development of these disorders. Indeed, several studies have reported that polymorphisms -3826A/G, -1766A/G and -112A/C in the promoter region, Ala64Thr in exon 2 and Met299Leu in exon 5 of UCP1 gene are possibly associated with obesity and/or DM2. However, results are still controversial in different populations. Thus, the aim of this study was to review the role of UCP1 in the development of these metabolic diseases. PMID: 22790465 [PubMed - indexed for MEDLINE] 155. Adv Biol Regul. 2012 May;52(2):340-50. doi: 10.1016/j.jbior.2012.03.001. Epub 2012 Mar 30. Secretomics for skeletal muscle cells: a discovery of novel regulators? Yoon JH(1), Kim J, Song P, Lee TG, Suh PG, Ryu SH. Author information: (1)Division of Molecular and Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk 790-784, Republic of Korea. Metabolic tissues, including skeletal muscle, adipose tissue and the digestive system, dynamically secrete various factors depending on the metabolic state, communicate with each other and orchestrate functions to maintain body homeostasis. Skeletal muscle secretes cytokines such as interleukin-6 (IL-6), IL-15, fibroblast growth factor-21 (FGF21) and IL-8. These compounds, myokines, play important roles in biological homeostasis such as energy metabolism, angiogenesis and myogenesis. New technological advances have allowed secretomics - analysis of the secretome - to be performed. The application of highly sensitive mass spectrometry makes qualitative and quantitative analysis of the secretome of skeletal muscle possible. Secretory proteins derived from skeletal muscle cells under various conditions were analyzed, and many important factors were suggested. In-depth studies of the secretome from metabolic cells in various conditions are strongly recommended. This study will provide information on methods of novel communication between metabolic tissues. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22781747 [PubMed - indexed for MEDLINE] 156. Nihon Eiseigaku Zasshi. 2012 May;67(3):363-74. [Associations of exposure to dioxins and polychlorinated biphenyls with diabetes: based on epidemiological findings]. [Article in Japanese] Uemura H(1). Author information: (1)Department of Preventive Medicine, the University of Tokushima Graduate School, Japan. uemura@basic.med.tokushima-u.ac.jp Persistent organic pollutants (POPs) are a group of chemical substances that have the common properties of resistance to biodegradation, wide-range transportation, high lipophilicity, bioaccumulation in fat, and biomagnification in the food chain. POPs are persistent in the environment worldwide and have potential adverse impacts on human health and the environment. Polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) are well known chemicals that are considered as POPs. The association between high-level exposure to dioxins and type 2 diabetes among U.S. Air Force veterans who had been exposed to Agent Orange contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during the Vietnam War was reported in the late 1990s. This association has been supported by similar epidemiologic studies, whose subjects were exposed to high doses of dioxins in their places of work involving phenoxyacid herbicide production and spraying, and in the industrial accident in Seveso, Italy. Recently, low-level exposure to dioxins and PCBs has been reported to be linked to type 2 diabetes. Cross-sectional studies in the U.S. general population and Japanese general population showed that body burden levels of some dioxins and PCBs were strongly associated with the prevalence of type 2 diabetes. Very recently, following these cross-sectional studies, several prospective studies have suggested that low-level exposure to some PCBs predicted the future risk of type 2 diabetes in the general population. Environmental exposure to some dioxins and PCBs, which mainly accumulate in adipose tissue, may play a role in the development of type 2 diabetes. PMID: 22781010 [PubMed - indexed for MEDLINE] 157. J Biol Chem. 2012 Sep 14;287(38):31658-65. doi: 10.1074/jbc.R112.356485. Epub 2012 Jul 9. Calcium/calmodulin-dependent protein kinase kinase 2: roles in signaling and pathophysiology. Racioppi L(1), Means AR. Author information: (1)Department of Pharmacology and Cancer Biology, Duke University Medical Center, Duke University, Durham, North Carolina 27710, USA. luigi.racioppi@duke.edu Many cellular Ca(2+)-dependent signaling cascades utilize calmodulin (CaM) as the intracellular Ca(2+) receptor. Ca(2+)/CaM binds and activates a plethora of enzymes, including CaM kinases (CaMKs). CaMKK2 is one of the most versatile of the CaMKs and will phosphorylate and activate CaMKI, CaMKIV, and AMP-activated protein kinase. Cell expression of CaMKK2 is limited, yet CaMKK2 is involved in regulating many important physiological and pathophysiological processes, including energy balance, adiposity, glucose homeostasis, hematopoiesis, inflammation, and cancer. Here, we explore known functions of CaMKK2 and discuss its potential as a target for therapeutic intervention. PMCID: PMC3442500 PMID: 22778263 [PubMed - indexed for MEDLINE] 158. Curr Opin Lipidol. 2012 Aug;23(4):290-302. doi: 10.1097/MOL.0b013e328354fcf4. Lysophospholipid acyltransferases: 1-acylglycerol-3-phosphate O-acyltransferases. From discovery to disease. Agarwal AK(1). Author information: (1)Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. Anil.Agarwal@UTSouthwestern.edu PURPOSE OF REVIEW: Over the past several years, many more isoforms for the same enzymes, specifically for 1-acylglycerol-3-phosphate O-acyltransferases (AGPATs), have been cloned and studied. In this review, we summarize their biochemical features and discuss their functional role. RECENT FINDINGS: The most significant role of these AGPATs appeared from our observation of AGPAT2 in the biology of adipose tissue (adipocytes) in humans and mice. Other isoforms are shown to be implicated in lung, reproductive and cardiac muscle function and in the cause of cancer. In-vitro substrate specificities of these AGPATs also suggest the in-vivo role of these AGPATs in remodeling of several of the glycerophospholipids. SUMMARY: Despite significant progress in understanding the role of these AGPATs, much is still to be discovered in terms of how each of these AGPATs function in the presence or absence of other AGPATs and what their functional role might be. PMID: 22777291 [PubMed - indexed for MEDLINE] 159. Trends Endocrinol Metab. 2012 Aug;23(8):381-90. doi: 10.1016/j.tem.2012.06.003. Epub 2012 Jul 4. New insights into ER stress-induced insulin resistance. Flamment M(1), Hajduch E, Ferré P, Foufelle F. Author information: (1)Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers, Unité Mixte de Recherche en Santé (UMR-S) 872, Paris, F-75006 France. Insulin resistance is a major characteristic of obesity and type 2 diabetes (T2DM). During the last decade, endoplasmic reticulum (ER) stress has emerged as a new player in this field and a considerable number of recent studies have pointed out its role in the onset of insulin resistance (IR). ER stress appears to act directly as a negative modulator of the insulin signaling pathway but also indirectly by promoting lipid accumulation. This review aims to summarize and decipher the abundant new literature concerning the emerging and multifaceted involvement of ER stress in the development of metabolic dysfunctions in insulin target tissues. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22770719 [PubMed - indexed for MEDLINE] 160. Rev Med Inst Mex Seguro Soc. 2012 Jan-Feb;50(1):39-45. [New trends in macrophages, inflammation and adipose tissue]. [Article in Spanish] Rico-Rosillo MG(1), Vega-Robledo GB. Author information: (1)Universidad Nacional Autónoma de México, Distrito Federal, México, Mexico. gricor12@yahoo.com.mx Obesity is considered a low-inflammatory condition. An increasing number of reports suggest that the adipose tissue itself might be a source of proinflammatory factors and a target of inflammatory processes. Accumulating evidence suggest the involvement of adipose tissue derived proteins, collectively known as adipokines as well as other factors produced in this tissue by cells besides to adipocytes, like fibroblasts, lymphocytes and macrophages. The burden of obesity on health extends across multiple organs systems and diseases (atherosclerosis, coronary heart diseases, osteoarthritis, diabetes, hypertension, dyslipidemia). The high incidence and its chronic inflammatory condition have had a wide impact. The chronic nature of obesity produces a tonic low-grade activation of the innate immune system that affects steady-state measures of metabolic homeostasis over time. In this review we highlight the macrophage participation in the generation of obesity-induced inflammation. PMID: 22768816 [PubMed - indexed for MEDLINE] 161. J Pediatr Endocrinol Metab. 2012;25(3-4):233-7. Brown adipose tissue: distribution and influencing factors on FDG PET/CT scan. Hao R(1), Yuan L, Zhang N, Li C, Yang J. Author information: (1)Healthcare Center of Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, 100050 Beijing, China. Brown adipose tissue (BAT) functions as a thermogenic organ by producing heat to maintain body temperature in many mammals, especially in the young. BAT is generally found in deep cervical, supraclavicular, interscapular, and paravertebral regions, as well as areas near large vessels. If not recognized, BAT activity can considerably interfere with 18F-fluorodeoxyglucose position emission tomography (PET)/computed tomography (CT) image interpretation. BAT activation can be influenced by several factors and reduced by different methods. In this paper, we review BAT distribution and factors influencing BAT activity on FDG PET/CT scan. The purpose of this review is to enhance the recognition of pediatric-related physician of BAT on FDG PET/CT scan. PMID: 22768649 [PubMed - indexed for MEDLINE] 162. Biomed Mater Eng. 2012;22(1-3):105-11. doi: 10.3233/BME-2012-0695. Research on stem cells as candidates to be differentiated into hepatocytes. Zhang L(1), Ye JS, Decot V, Stoltz JF, de Isla N. Author information: (1)BRC, First Hospital of Kun Ming (affiliated Calmette Hospital of Kun Ming Medical College), Kun Ming, China. zlei01@hotmail.com Liver diseases have become one of the most important causes of morbidity and mortality in the world. Cell therapy and liver transplantation are though to be two treatment options well accepted. However, the shortage of cells sources in cytotherapy and the lack of liver donor in liver transplantation are the major obstacles for the performance of these treatment methods. It urged us to find new origins of extra-hepatic cells. A number of recent studies show that extra-hepatic mesenchymal stem cells (MSC) from different tissues can be differentiated into hepatocytes like cells (HLC). Several hepatic differentiation protocols of MSC have been published in recent years, based on cellular stimulation with exogenous cytokines/growth factors, co-culture with fetal or adult hepatocytes, 2- or 3-dimensional (2D, 3D) matrices to favor differentiation. Independently from the starting stem cells population used, some minimal criteria must be fulfilled to ensure therapeutic success: in vitro expandability, expression of hepatic like surface markers, with hepatic cell functions, and minimal or absent immunogenicity in the recipient host. In this review, we focused on stem cells originated from bone marrow, umbilical cord and adipose tissue which are widely investigated in recent years and have been proved to have liver regenerative potential, the factors used to differentiate stem cells to hepatocyte-like cells and the methods used to investigate these cells. PMID: 22766708 [PubMed - indexed for MEDLINE] 163. Trends Endocrinol Metab. 2012 Aug;23(8):372-80. doi: 10.1016/j.tem.2012.05.003. Epub 2012 Jul 4. Novel links between HIFs, type 2 diabetes, and metabolic syndrome. Girgis CM(1), Cheng K, Scott CH, Gunton JE. Author information: (1)Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia. Hypoxia inducible factors (HIFs) are master-regulators of cellular responses to hypoxia, and thus are crucial for survival. HIFs also play a role in regulating cellular processes in β-cells, liver, muscle, and adipose tissue, have effects on the regulation of weight, and play a role in type 2 diabetes (T2D). Indeed, in people with T2D the HIF pathway is dyregulated in major metabolic tissues involved in the pathogenesis of diabetes. This review covers the contrasting, complementary and conflicting effects of decreasing and increasing HIFs in various tissues, and shows that a delicate balance exists between HIF levels and optimal metabolic function. We propose that increasing the activity of HIFs might be a potential therapeutic strategy for treating T2D. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22766319 [PubMed - indexed for MEDLINE] 164. Expert Opin Ther Targets. 2012 Aug;16(8):819-32. doi: 10.1517/14728222.2012.703656. Epub 2012 Jul 5. Can targeting SIRT-1 to treat type 2 diabetes be a good strategy? A review. Pulla VK(1), Battu MB, Alvala M, Sriram D, Yogeeswari P. Author information: (1)Birla Institute of Technology & Science- Pilani, Hyderabad Campus, Department of Pharmacy, Drug Discovery Research Laboratory, R.R. District-500078, Andhra Pradesh, India. INTRODUCTION: Dysregulation of metabolic pathways, caused by imbalances in energy homeostasis, leads to type 2 diabetes characterized by high glucose concentration in the blood due to insulin resistance which is a major disorder in developed countries. AREAS COVERED: One of the recent treatment strategies is using activators of SIRT1, which has been in clinical trials. Many of the cellular processes including insulin secretion, cell cycle, and apoptosis are imperatively regulated by a family of mediators called sirtuins. First known mammalian sirtuin, SIRT1 is a positive regulator of insulin secretion, which triggers glucose uptake and utilization. Since the past decade, a major outstanding question is whether SIRT1 activation is a safe therapy for human diseases such as type 2 diabetes? This review summarizes and discusses the advances of the past decade and the challenges that will brazen out perplexity about homeostasis and metabolic pathways linked to SIRT1 and type 2 diabetes. Furthermore, we described the interlink between SIRT1 metabolic pathways of various tissues such as pancreas, skeletal muscle, adipose tissue and liver. EXPERT OPINION: However be the complexity of the pathways involved, T2DM regulated by SIRT1 affected metabolism is dropping down progressively due to profound research. In the context of interlinking all the SIRT1 pathways in T2DM we found various crucial intermediaries in metabolic tissues, which can also be targeted for future prospects. PMID: 22762724 [PubMed - indexed for MEDLINE] 165. Mol Nutr Food Res. 2012 Jul;56(7):1173-84. doi: 10.1002/mnfr.201100785. Nutritional status, genetic susceptibility, and insulin resistance--important precedents to atherosclerosis. McGillicuddy FC(1), Roche HM. Author information: (1)UCD Conway Institute, School of Public Health & Population Science, University College Dublin, Dublin, Ireland. Atherosclerosis is a progressive disease that starts early in life and is manifested clinically as coronary artery disease (CAD), cerebrovascular disease, or peripheral artery disease. CAD remains the leading cause of morbidity and mortality in Western society despite the great advances made in understanding its underlying pathophysiology. The key risk factors associated with CAD include hypercholesterolemia, hypertension, poor diet, obesity, age, male gender, smoking, and physical inactivity. Genetics also play an important role that may interact with environmental factors, including diet, nutritional status, and physiological parameters. Furthermore, certain chronic inflammatory conditions also predispose to the development of CAD. The spiraling increase in obesity rates worldwide has made it more pertinent than ever before to understand the metabolic perturbations that link over nutrition to enhanced cardiovascular risk. Great breakthroughs have been made at the pharmacological level to manage CAD; statins and aspirin have revolutionized treatment of CAD and prolonged lifespan. Nonetheless, lifestyle intervention prior to clinical presentation of CAD symptoms would negate/delay the need for chronic pharmacotherapy in at-risk individuals which in turn would relieve healthcare systems of a costly burden. Throughout this review, we debate the relative impact of nutrition versus genetics in driving CAD. We will investigate how overnutrition affects adipose tissue biology and drives IR and will discuss the subsequent implications for the cardiovascular system. Furthermore, we will discuss how lifestyle interventions including diet modification and weight loss can improve both IR and metabolic dyslipidemia that is associated with obesity. We will conclude by delving into the concept that nutritional status interacts with genetic susceptibility, such that perhaps a more personalized nutrition approach may be more effective in determining diet-related risk as well as response to nutritional interventions. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. PMID: 22760984 [PubMed - indexed for MEDLINE] 166. Sleep Breath. 2013 May;17(2):505-10. doi: 10.1007/s11325-012-0729-8. Epub 2012 Jun 20. Does physical exercise reduce excessive daytime sleepiness by improving inflammatory profiles in obstructive sleep apnea patients? Alves Eda S(1), Ackel-D'Elia C, Luz GP, Cunha TC, Carneiro G, Tufik S, Bittencourt LR, de Mello MT. Author information: (1)Disciplina de Medicina e Biologia do Sono, Departamento de Psicobiologia, Universidade Federal de São Paulo-UNIFESP, São Paulo, CEP: 04020-050, Brazil. INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is associated with a variety of long-term consequences such as high rates of morbidity and mortality, due to excessive diurnal somnolence as well as cardiovascular and metabolic diseases. Obesity, recurrent episodes of upper airway obstruction, progressive hypoxemia, and sleep fragmentation during sleep cause neural, cardiovascular, and metabolic changes. These changes include activation of peripheral sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, insulin sensitivity, and inflammatory cytokines alterations, which predispose an individual to vascular damage. DISCUSSION: Previous studies proposed that OSAS modulated the expression and secretion of inflammatory cytokines from fat and other tissues. Independent of obesity, patients with OSAS exhibited elevated levels of C-reactive protein, tumor necrosis factor-α and interleukin-6, which are associated with sleepiness, fatigue, and the development of a variety of metabolic and cardiovascular diseases. OSAS and obesity are strongly associated with each other and share many common pathways that induce chronic inflammation. Previous studies suggested that the protective effect of exercise may be partially attributed to the anti-inflammatory effect of regular exercise, and this effect was observed in obese patients. Although some studies assessed the effects of physical exercise on objective and subjective sleep parameters, the quality of life, and mood in patients with OSAS, no study has evaluated the effects of this treatment on inflammatory profiles. In this review, we cited some studies that directed our opinion to believe that since OSAS causes increased inflammation and has excessive daytime sleepiness as a symptom and being that physical exercise improves inflammatory profiles and possibly OSAS symptoms, it must be that physical exercise improves excessive daytime sleepiness due to its improvement in inflammatory profiles. PMID: 22760814 [PubMed - indexed for MEDLINE] 167. J Eur Acad Dermatol Venereol. 2013 Mar;27(3):273-8. doi: 10.1111/j.1468-3083.2012.04622.x. Epub 2012 Jul 3. Cellulite's aetiology: a review. de la Casa Almeida M(1), Suarez Serrano C, Rebollo Roldán J, Jiménez Rejano JJ. Author information: (1)Physiotherapy, University of Seville, Seville, Spain. Cellulite, highly prevalent among women, represents a serious problem for many of them, and one of their main aesthetic concerns. It is difficult to pinpoint its aetiology and physiology/pathophysiology, as there are many factors that are involved in it, affect it, and many processes that are taking place simultaneously and sequentially. Our objective is therefore, to review the scientific scholarship on cellulite to explore the causes of its origin. We carried out a preliminary search of the Medline, Cochrane, and Web of Knowledge databases covering the period from 1978 to April 2011. As there is no specific key word for the phenomenon at hand, we used the following descriptors: adipose tissue, subcutaneous fat, subcutaneous tissue, connective tissue, skin, skin disease and dermis. This resulted in a retrieval of 26 articles contributing to relevant information on the aetiology of cellulite. As a result of our first research, we concluded that cellulite is a physiological phenomenon or at least, that it has a physiological origin, which is characteristic of women, and multi-causal, with the coexistence of a number of factors that trigger, perpetuate, or exacerbate it. The outstanding factors include, among others, connective tissue architecture, oestrogen action, microvascular alterations and certain genetic and hormonal characteristics. All of them provide us with future and novel clues to cellulite treatment, and is necessary to take some or all of these factors into account in developing an effective therapy. However, we are aware of the necessity of further investigation in this field. © 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology. PMID: 22758934 [PubMed - indexed for MEDLINE] 168. Anticancer Res. 2012 Jul;32(7):2585-90. A significant role of lipogenic enzymes in colorectal cancer. Notarnicola M(1), Messa C, Caruso MG. Author information: (1)Laboratory of Nutritional Biochemistry, National Institute for Digestive Diseases, Via Turi, 27, 70013 Castellana Grotte (Bari), Italy. In this review, we summarize recent progress regarding the study of the main enzymes of lipid metabolism involved in colorectal cancer development, namely of a) farnesyltransferase (Ftase), a cytosolic enzyme that catalyzes the first step in the protein farnesylation; b) farnesyl diphosphate synthase (FPPS, which yields FPP, a substrate for Ftase; c) fatty acid synthase (FAS), an enzyme required for the conversion of acetyl-CoA and malonyl-CoA to palmitate; and d) lipoprotein lipase (LPL), the crucial enzyme for intravascular catabolism of triglyceride-rich lipoproteins. Alterations in the levels of these enzymes may contribute to a cell growth advantage acquired during the carcinogenic process and to the development of malignancy. We have demonstrated an elevated Ftase activity in human colorectal cancer (CRC), with differences in Ftase activity related to histological grading, tumor location and KRAS mutation status. Moreover, the first evidence of FPPS activity in human CRC was demonstrated by our study, where a higher FPPS activity and mRNA expression was present in cancer rather than in normal mucosa. We also detected a hyperactivation of FAS in colon cancer, related to tumor location, sex and, p53 mutation status. Our data reinforce the role of lipid metabolism in the regulation of cellular metabolic processes and in carcinogenesis. Moreover, our findings suggest that biological factors including sex, gene mutation status, as well as the stratification of patients with colorectal cancer into right- and left-sided subsets may be important in patient selection for targeted therapies. Our studies in vitro demonstrated that FAS might also be a molecular target for the antiproliferative activity of olive oil polyphenols in a metabolically defined subset of patients with colon cancer. Moreover, we detected that the serum levels of FAS in patients with colorectal cancer are associated with tumor stage. Recently, we found a significant reduction in the levels of FAS and another lipogenic enzyme, LPL, in adipose tissue adjacent to tumor lesions, compared to the levels of FAS detected in paired tissue distant from neoplasia in patients with colorectal cancer. The study of metabolic changes in lipogenic enzyme pathways, as well as the determination of the distribution of individual roles within each biochemical pathway provide a rationale for selecting a particular reaction step suitable for therapeutic intervention. PMID: 22753716 [PubMed - indexed for MEDLINE] 169. Mol Cell Endocrinol. 2013 Sep 25;378(1-2):1-14. doi: 10.1016/j.mce.2012.06.021. Epub 2012 Jun 29. Adipose tissue renin-angiotensin-aldosterone system (RAAS) and progression of insulin resistance. Marcus Y(1), Shefer G, Stern N. Author information: (1)Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel. This review focuses on the expression of the key components of the renin-angiotensin-aldosterone axis in fat tissue. At the center of this report is the role of RAAS in normal and excessive fat mass enlargement, the leading etiology of insulin resistance. Understanding the expression and regulation of RAAS components in various fat depots allows insight not only into the processes by which these complex patterns are modified by the enlargement of adipose tissue, but also into their impact on local and systemic response to insulin. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved. PMID: 22750719 [PubMed - indexed for MEDLINE] 170. Biochimie. 2012 Oct;94(10):2104-10. doi: 10.1016/j.biochi.2012.06.017. Epub 2012 Jun 29. Is there NO help for leptin? Joffin N(1), Niang F, Forest C, Jaubert AM. Author information: (1)Institut National de la Santé et de la Recherche Médicale UMR-S 747, Université Paris Descartes, Pharmacologie Toxicologie et Signalisation Cellulaire, 45 rue des Saints Pères, 75006 Paris, France. Since the initial identification of leptin as the product of the ob gene in 1994, the signaling pathways by which this hormone alters cell physiology have been the subject of extensive investigations. The fact that leptin can induce nitric oxide (NO) production was first demonstrated in studies of the pituitary gland and pancreatic islets. A large number of additional studies further showed that this adipokine stimulates NO synthesis in multiple tissues. This review article discusses the role of leptin in NO production and its pathophysiological consequences. The role of this gaseous messenger in cell physiology depends on the cell type, the concentration of NO and the duration of exposure. It can be either a potent oxidant or a protector of cell integrity against the formation of reactive oxygen species. Leptin plays two opposing roles on arterial pressure. It exerts a hypertensive effect due to sympathetic activation and a vasorelaxant effect due to NO production. This adipokine acts via NO to produce pro-inflammatory factors in cartilage pathology, potentially contributing to an increased risk for osteoarthritis. Another well-documented role of leptin-induced NO, acting either directly or via the hypothalamus, concerns lipid metabolism in muscle and adipose tissue. In adipocytes, the direct and rapid action of leptin is to activate the nitric oxide synthase III, which favors lipolysis. In contrast, in the long-term, leptin reduces lipolysis. However, both in the short-term and in the long-term, glyceroneogenesis and its key enzyme, the cytosolic phosphoenolpyruvatecarboxykinase (PEPCK-C), are down-regulated by the adipokine, thus favoring fatty acid release. Hence, leptin-induced NO production plays a crucial role in fatty acid metabolism in adipose tissue. The resulting effects are to prevent lipid storage and to improve energy expenditure, with possible improvements of the obese state and its associated diseases. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMID: 22750650 [PubMed - indexed for MEDLINE] 171. Pulm Pharmacol Ther. 2013 Aug;26(4):420-6. doi: 10.1016/j.pupt.2012.06.006. Epub 2012 Jun 26. Fat, fire and muscle--the role of adiponectin in pulmonary vascular inflammation and remodeling. Medoff BD(1). Author information: (1)Pulmonary and Critical Care Unit and the Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. bmedoff@partners.org Pulmonary hypertension is a life-threatening condition that results from a heterogeneous group of diseases, many of which demonstrate characteristic pathologic changes of pulmonary vascular inflammation and remodeling. Recent clinical studies indicate obesity to be a risk factor for the development of pulmonary hypertension; however, the mechanisms leading to this association are unknown. Adipocytes secrete multiple bioactive mediators that can influence inflammation and tissue remodeling, suggesting that adipose tissue may directly influence the pathogenesis of pulmonary hypertension. One of these mediators is adiponectin, a protein with a wide range of metabolic, anti-inflammatory, and anti-proliferative activities. Paradoxically, adiponectin is present in high concentration in the serum of lean healthy individuals, but decreases in obesity. Studies suggest that relative adiponectin-deficiency may contribute to the development of inflammatory diseases in obesity, and recent animal studies implicate adiponectin in the pathogenesis of pulmonary hypertension. Most notably, experimental studies show that adiponectin can reduce lung vascular remodeling in response to inflammation and hypoxia. Moreover, mice deficient in adiponectin develop a spontaneous lung vascular phenotype characterized by age-dependent increases in peri-vascular inflammatory cells and elevated pulmonary artery pressures. Emerging evidence indicates adiponectin's effects are mediated through anti-inflammatory and anti-proliferative actions on cells in the lung. This review aims to synthesize the existing data related to adiponectin's effects on the pulmonary vasculature and to discuss how changes in adiponectin levels might contribute to the development of pulmonary hypertension. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22750271 [PubMed - indexed for MEDLINE] 172. Biochimie. 2012 Oct;94(10):2082-8. doi: 10.1016/j.biochi.2012.05.018. Epub 2012 Jun 26. Immunological functions of leptin and adiponectin. Carbone F(1), La Rocca C, Matarese G. Author information: (1)Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli 80131, Italy c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Napoli 80131, Italy. Recent years have seen several advances in our understanding of the functions of adipose tissue regarding not only the energy storage, but also the regulation of complex metabolic and endocrine functions. In this context, leptin and adiponectin, the two most abundant adipocyte products, represent one of the best example of adipocytokines involved in the control of energy expenditure, lipid and carbohydrate metabolism as well as in the regulation of immune responses. Leptin and adiponectin secretion is counter-regulated in vivo, in relation to degree of adiposity, since plasma leptin concentrations are significantly elevated in obese subjects in proportion to body mass index while adiponectin secretion decreases in relation to the amount of adipose tissue. In this review we focus on the main biological activities of leptin and adiponectin on the lipid and carbohydrate metabolism and on their contribute in regulation of innate and adaptive immune responses. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMID: 22750129 [PubMed - indexed for MEDLINE] 173. Mol Cell Endocrinol. 2013 Feb 25;366(2):194-203. doi: 10.1016/j.mce.2012.06.014. Epub 2012 Jun 28. The role of AMP-activated protein kinase in regulating white adipose tissue metabolism. Ceddia RB(1). Author information: (1)School of Kinesiology and Health Science, York University, Toronto, ON, Canada. roceddia@yorku.ca AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that plays a major role in the maintenance of energy homeostasis in various organs and tissues. When activated, AMPK can induce substrate catabolism and shut down energy-consuming anabolic pathways to increase intracellular ATP availability. Even though most of these effects have been described in muscle and liver, several studies have provided compelling evidence that AMPK also plays an important role in the regulation of white adipose tissue (WAT) glucose and lipid metabolism. In fact, the effects of acute and chronic AMPK activation in the WAT induce profound changes in adiposity with important implications for the treatment of obesity and its related metabolic disorders. This review discusses the role of AMPK in the regulation of white adipocyte metabolism with respect to energy storage and release, gene expression, mitochondrial biogenesis, oxidative capacity, cell differentiation, and the potential impact on whole-body adiposity and energy homeostasis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved. PMID: 22750051 [PubMed - indexed for MEDLINE] 174. J Nutr Biochem. 2012 Sep;23(9):1027-40. doi: 10.1016/j.jnutbio.2012.03.004. Epub 2012 Jun 27. The role of dietary fatty acids in the pathology of metabolic syndrome. Lottenberg AM(1), Afonso Mda S, Lavrador MS, Machado RM, Nakandakare ER. Author information: (1)Faculty of Medical Sciences of the University of Sao Paulo, Sao Paulo, Brazil. amlottenberg@uol.com.br Dysfunctional lipid metabolism is a key component in the development of metabolic syndrome, a very frequent condition characterized by dyslipidemia, insulin resistance, abdominal obesity and hypertension, which are related to an elevated risk for type 2 diabetes mellitus. The prevalence of metabolic syndrome is strongly associated with the severity of obesity; its physiopathology is related to both genetics and food intake habits, especially the consumption of a high-caloric, high-fat and high-carbohydrate diet. With the progress of scientific knowledge in the field of nutrigenomics, it was possible to elucidate how the majority of dietary fatty acids influence plasma lipid metabolism and also the genes expression involved in lipolysis and lipogenesis within hepatocytes and adipocytes. The aim of this review is to examine the relevant mechanistic aspects of dietary fatty acids related to blood lipids, adipose tissue metabolism, hepatic fat storage and inflammatory process, all of them closely related to the genesis of metabolic syndrome. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22749135 [PubMed - indexed for MEDLINE] 175. Ann Endocrinol (Paris). 2012 Jun;73(3):170-89. doi: 10.1016/j.ando.2012.04.010. Epub 2012 Jun 28. How to diagnose a lipodystrophy syndrome. Vantyghem MC(1), Balavoine AS, Douillard C, Defrance F, Dieudonne L, Mouton F, Lemaire C, Bertrand-Escouflaire N, Bourdelle-Hego MF, Devemy F, Evrard A, Gheerbrand D, Girardot C, Gumuche S, Hober C, Topolinski H, Lamblin B, Mycinski B, Ryndak A, Karrouz W, Duvivier E, Merlen E, Cortet C, Weill J, Lacroix D, Wémeau JL. Author information: (1)Inserm U859, service d'endocrinologie et maladies métaboliques, hôpital Huriez, CHRU de Lille, 1, rue Polonovski, 59000 Lille, France. mc-vantyghem@chru-lille.fr The spectrum of adipose tissue diseases ranges from obesity to lipodystrophy, and is accompanied by insulin resistance syndrome, which promotes the occurrence of type 2 diabetes, dyslipidemia and cardiovascular complications. Lipodystrophy refers to a group of rare diseases characterized by the generalized or partial absence of adipose tissue, and occurs with or without hypertrophy of adipose tissue in other sites. They are classified as being familial or acquired, and generalized or partial. The genetically determined partial forms usually occur as Dunnigan syndrome, which is a type of laminopathy that can also manifest as muscle, cardiac, neuropathic or progeroid involvement. Gene mutations encoding for PPAR-gamma, Akt2, CIDEC, perilipin and the ZMPSTE 24 enzyme are much more rare. The genetically determined generalized forms are also very rare and are linked to mutations of seipin AGPAT2, FBN1, which is accompanied by Marfan syndrome, or of BANF1, which is characterized by a progeroid syndrome without insulin resistance and with early bone complications. Glycosylation disorders are sometimes involved. Some genetically determined forms have recently been found to be due to autoinflammatory syndromes linked to a proteasome anomaly (PSMB8). They result in a lipodystrophy syndrome that occurs secondarily with fever, dermatosis and panniculitis. Then there are forms that are considered to be acquired. They may be iatrogenic (protease inhibitors in HIV patients, glucocorticosteroids, insulin, graft-versus-host disease, etc.), related to an immune system disease (sequelae of dermatopolymyositis, autoimmune polyendocrine syndromes, particularly associated with type 1 diabetes, Barraquer-Simons and Lawrence syndromes), which are promoted by anomalies of the complement system. Finally, lipomatosis is currently classified as a painful form (adiposis dolorosa or Dercum's disease) or benign symmetric multiple form, also known as Launois-Bensaude syndrome or Madelung's disease, which are sometimes related to mitochondrial DNA mutations, but are usually promoted by alcohol. In addition to the medical management of metabolic syndrome and the sometimes surgical treatment of lipodystrophy, recombinant leptin provides hope for genetically determined lipodystrophy syndromes, whereas modifications in antiretroviral treatment and tesamorelin, a GHRH analog, is effective in the metabolic syndrome of HIV patients. Other therapeutic options will undoubtedly be developed, dependent on pathophysiological advances, which today tend to classify genetically determined lipodystrophy as being related to laminopathy or to lipid droplet disorders. Copyright © 2012. Published by Elsevier Masson SAS. PMID: 22748602 [PubMed - indexed for MEDLINE] 176. BMC Physiol. 2012 Jun 27;12:8. doi: 10.1186/1472-6793-12-8. Interleukin-1 beta: a potential link between stress and the development of visceral obesity. Speaker KJ(1), Fleshner M. Author information: (1)Department of Integrative Physiology, University of Colorado at Boulder, 80309, USA. BACKGROUND: A disproportionate amount of body fat within the abdominal cavity, otherwise known as visceral obesity, best predicts the negative health outcomes associated with high levels body fat. Growing evidence suggests that repeated activation of the stress response can favor visceral fat deposition and that visceral obesity may induce low-grade, systemic inflammation which is etiologically linked to the pathogenesis of obesity related diseases such as cardiovascular disease and type 2 diabetes. While the obesity epidemic has fueled considerable interest in these obesity-related inflammatory diseases, surprisingly little research is currently focused on understanding the functions of inflammatory proteins in healthy, non-obese white adipose tissue (WAT) and their possible role in modulating stress-induced shifts in body fat distribution. HYPOTHESIS: The current review presents evidence in support the novel hypothesis that stress-evoked interleukin-1 beta (IL-1β) signaling within subcutaneous adipose tissue, when repeatedly induced, contributes toward the development of visceral obesity. It is suggested that because acute stressor exposure differentially increases IL-1β levels within subcutaneous adipose relative to visceral adipose tissue in otherwise healthy, non-obese rats, repeated induction of this response may impair the ability of subcutaneous adipose tissue to uptake energy substrates, synthesize and retain triglycerides, and/or adapt to positive energy balance via hyperplasia. Consequently, circulating energy substrates may be disproportionately shunted to visceral adipose tissue for storage, thus driving the development of visceral obesity. CONCLUSIONS: This review establishes the following key points: 1) body fat distribution outweighs the importance of total body fat when predicting obesity-related disease risk; 2) repeated exposure to stress can drive the development of visceral obesity independent of changes in body weight; 3) because of the heterogeneity of WAT composition and function, an accurate understanding of WAT responses requires sampling multiple WAT depots; 4) acute, non-pathogenic stressor exposure increases WAT IL-1β concentrations in a depot specific manner suggesting an adaptive, metabolic role for this cytokine; however, when repeated, stress-induced IL-1β in non-visceral WAT may result in functional impairments that drive the development of stress-induced visceral obesity. PMCID: PMC3404929 PMID: 22738239 [PubMed - indexed for MEDLINE] 177. Diabetologia. 2012 Oct;55(10):2583-92. doi: 10.1007/s00125-012-2607-0. Epub 2012 Jun 26. Lymphocytes in obesity-related adipose tissue inflammation. Chatzigeorgiou A(1), Karalis KP, Bornstein SR, Chavakis T. Author information: (1)Department of Internal Medicine III, Division of Vascular Inflammation, Diabetes and Kidney, University Clinic Carl-Gustav-Carus, University of Dresden, Fetscherstrasse 74, 01307 Dresden, Germany. Antonios.Chatzigeorgiou@uniklinikum-dresden.de Inflammation in the white adipose tissue (WAT) is considered a major player in the development of insulin resistance. The role of macrophages accumulating in the WAT during obesity, promoting WAT inflammation and insulin resistance is well established. In contrast, less is known about the role of lymphocytes. Recent studies have implicated different lymphocyte subsets in WAT inflammation. For instance, cytotoxic CD8(+) T cells infiltrating the WAT may contribute to the recruitment, differentiation and activation of macrophages. On the other hand, a differential role for CD4(+) Th1 and CD4(+) Th2 cells has been suggested. Levels of WAT regulatory T cells decrease during the course of obesity and may represent a crucial factor for the maintenance of insulin sensitivity. Moreover, activation of natural killer T cells, an innate-like T cell population, which recognises lipid antigens, promotes insulin resistance and WAT inflammation. Finally, B cells may infiltrate WAT very early in response to high-fat feeding and worsen glucose metabolism through modulation of T cells and the production of pathogenic antibodies. These interesting new findings however bear controversies and introduce novel, yet unanswered, questions. Here, we review and discuss the impact of the different lymphocyte subsets in obesity-related WAT inflammation and attempt to identify the open questions to be answered by future studies. PMID: 22733483 [PubMed - indexed for MEDLINE] 178. Curr Opin Pediatr. 2012 Aug;24(4):523-9. doi: 10.1097/MOP.0b013e3283557d22. Metabolic actions of fibroblast growth factor 21. Cuevas-Ramos D(1), Aguilar-Salinas CA, Gómez-Pérez FJ. Author information: (1)Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico. PURPOSE OF REVIEW: FGF21 has emerged as a hormone involved in energy homeostasis. A large number of recent reports have expanded the role of FGF21 from a response factor to prolonged fasting to a key hormone that regulates free fatty acid (FFAs) levels. The therapeutic role of recombinant human FGF21 for type 2 diabetes and dyslipidemia is under study. RECENT FINDINGS: Recent evidence suggests that supraphysiological concentrations of FFAs induce FGF21 secretion (i.e., starvation and intense physical activity) through the peroxisome proliferator-activated receptor alpha (PPARα) pathway. The rise in FGF21 levels is aimed at improving energy production (ketogenesis) and utilization (oxidation) of FFAs. FGF21 increment may protect against chronic exposure to high concentrations of FFAs, which causes lipotoxicity in muscle, pancreas, and liver. In addition, FGF21 induces appetite and inhibits growth, probably as part of the adaptive starvation response. The autocrine function of FGF21 in adipose tissue increases PPARγ activity and glucose uptake. Increased plasma FGF21 levels have been found in insulin resistance states in humans. However, the reason for this rise in FGF21 values is still under study. SUMMARY: We propose that FGF21 serves as a defense mechanism against supraphysiological concentrations of FFAs. In addition, FGF21 might have a therapeutic indication in humans. PMID: 22732636 [PubMed - indexed for MEDLINE] 179. Clin Plast Surg. 2012 Jul;39(3):281-92. doi: 10.1016/j.cps.2012.04.005. Epub 2012 May 22. Early experiences with stem cells in treating chronic wounds. Akita S(1), Yoshimoto H, Akino K, Ohtsuru A, Hayashida K, Hirano A, Suzuki K, Yamashita S. Author information: (1)Department of Plastic and Reconstructive Surgery, Nagasaki University Hospital, Japan. akitas@hf.rim.or.jp This review provides a thorough and clear discussion on the outcomes of stem cells in treating chronic wounds. With recent technological developments that now allow isolation and culture of stem cells, researchers are able to perform vigorous studies on somatic or adult stem cells. Human and animal stem cell studies are discussed with a focus on the basic process of stem cells in wound healing and the authors' first-hand clinical experience with stem cells used for chronic wound healing. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22732376 [PubMed - indexed for MEDLINE] 180. Rev Prat. 2012 May;62(5):621-4. [Osteoarthritis and obesity]. [Article in French] Sellam J(1), Berenbaum F. Author information: (1)Service de rhumatologie, hôpital Saint-Antoine, AP-HP, 75012 Paris. jeremie.sellam@sat.aphp.fr Obesity is one of the risk factors for hip or knee osteoarthritis (OA), since mechanical overload on weight-bearing joints activates chondrocytes and accelerates cartilage degeneration. Surprisingly, obesity and overweight also contribute to hand OA due to a systemic effect involving the pro-inflammatory and -degenerative role of some adipokines, secreted by adipose tissue, as well as some joint cells. Obesity-induced OA is now included in a larger phenotype termed "metabolic GA", since OA is associated with various parameters of the metabolic Ssyndrome (including type-2 diabetes) and excess cardiovascular mortality related to this disease. Early-onset OA should lead to suspect a potential metabolic syndrome. Weight loss strategies remain a valuable therapeutic approach to prevent OA and reduce its symptoms, and must be associated with physical activity to allow for optimal outcomes. PMID: 22730785 [PubMed - indexed for MEDLINE] 181. Protein Cell. 2012 Sep;3(9):648-60. doi: 10.1007/s13238-012-2043-4. Epub 2012 Jun 22. Mitochondria in the pathogenesis of diabetes: a proteomic view. Chen X(1), Wei S, Yang F. Author information: (1)Key Laboratory of Protein and Peptide Pharmaceuticals and Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. Diabetes mellitus is a complex metabolic disorder characterized by chronic hyperglycemia due to absolute or relative lack of insulin. Though great efforts have been made to investigate the pathogenesis of diabetes, the underlying mechanism behind the development of diabetes and its complications remains unexplored. Cumulative evidence has linked mitochondrial modification to the pathogenesis of diabetes and its complications and they are also observed in various tissues affected by diabetes. Proteomics is an attractive tool for the study of diabetes since it allows researchers to compare normal and diabetic samples by identifying and quantifying the differentially expressed proteins in tissues, cells or organelles. Great progress has already been made in mitochondrial proteomics to elucidate the role of mitochondria in the pathogenesis of diabetes and its complications. Further studies on the changes of mitochondrial protein specifically post-translational modifications during the diabetic state using proteomic tools, would provide more information to better understand diabetes. PMID: 22729395 [PubMed - indexed for MEDLINE] 182. Dig Dis. 2012;30(2):154-7. doi: 10.1159/000336668. Epub 2012 Jun 20. The role of obesity in gastroesophageal reflux disease and Barrett's esophagus. Eusebi LH(1), Fuccio L, Bazzoli F. Author information: (1)Department of Internal Medicine and Gastroenterology, University of Bologna, Italy. The prevalence of gastroesophageal reflux disease (GERD) and related disorders has been increasing worldwide, particularly in Western populations where a parallel rise in obesity prevalence has been reported. As weight gain often overlaps with the GERD-related symptoms, several recent studies investigated the significance of this correlation, mainly using meta-analyses. Here, we discuss the large amount of evidence linking obesity and GERD-related symptoms, providing potential mechanisms for their co-occurrence. Particular attention is given also to the association between obesity, Barrett's esophagus and esophageal adenocarcinoma development. Copyright © 2012 S. Karger AG, Basel. PMID: 22722430 [PubMed - indexed for MEDLINE] 183. Dig Dis. 2012;30(2):148-53. doi: 10.1159/000336664. Epub 2012 Jun 20. Obesity and metabolic syndrome: an inflammatory condition. Scarpellini E(1), Tack J. Author information: (1)Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Belgium. Obesity causes chronic low-grade inflammation that contributes to systemic metabolic dysfunction associated with obesity-linked disorders that fall under the definition of metabolic syndrome. Adipose tissue is a key endocrine organ as it releases multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have proinflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this emerging context, the gut microbiota-metabolism interactions play an increasingly important role in the understanding and hopefully future treatment of complex metabolic unbalances responsible for insulin resistance and cardiovascular high-risk diseases. Copyright © 2012 S. Karger AG, Basel. PMID: 22722429 [PubMed - indexed for MEDLINE] 184. Crit Rev Biochem Mol Biol. 2012 Jul-Aug;47(4):379-90. doi: 10.3109/10409238.2012.694843. The adipose tissue renin-angiotensin system and metabolic disorders: a review of molecular mechanisms. Kalupahana NS(1), Moustaid-Moussa N. Author information: (1)Obesity Research Center, The University of Tennessee (UT), Knoxville, TN, USA. The renin-angiotensin system (RAS) is classically known for its role in regulation of blood pressure, fluid and electrolyte balance. In this system, angiotensinogen (Agt), the obligate precursor of all bioactive angiotensin peptides, undergoes two enzymatic cleavages by renin and angiotensin converting enzyme (ACE) to produce angiotensin I (Ang I) and angiotensin II (Ang II), respectively. The contemporary view of RAS has become more complex with the discovery of additional angiotensin degradation pathways such as ACE2. All components of the RAS are expressed in and have independent regulation of adipose tissue. This local adipose RAS exerts important auto/paracrine functions in modulating lipogenesis, lipolysis, adipogenesis as well as systemic and adipose tissue inflammation. Mice with adipose-specific Agt overproduction have a 30% increase in plasma Agt levels and develop hypertension and insulin resistance, while mice with adipose-specific Agt knockout have a 25% reduction in Agt plasma levels, demonstrating endocrine actions of adipose RAS. Emerging evidence also points towards a role of RAS in regulation of energy balance. Because adipose RAS is overactivated in many obesity conditions, it is considered a potential candidate linking obesity to hypertension, insulin resistance and other metabolic derangements. PMID: 22720713 [PubMed - indexed for MEDLINE] 185. J Gastrointestin Liver Dis. 2012 Jun;21(2):205-8. Is visceral fat reduction necessary to favour metabolic changes in the liver? Finelli C(1), Tarantino G. Author information: (1)Center of Obesity and Eating Disorder, Stella Maris Mediterraneo Foundation Chiaromonte, Potenza, Italy. As excess body weight constitutes a major health problem, it is now important for hepatologists to weigh risk factors that lead to insulin resistance and hepatic steatosis. This mini-review focuses on the type of bodily fat distribution that determines the ectopic fat storage into the liver in overweight or obese people. Although obesity is closely associated with non-alcoholic fatty liver disease, the excess of visceral fat storage is reckoned to be just as or even more important. PMID: 22720311 [PubMed - indexed for MEDLINE] 186. Ann Med. 2012 Jun;44 Suppl 1:S74-84. doi: 10.3109/07853890.2012.663928. Obesity-related hypertension: epidemiology, pathophysiology, treatments, and the contribution of perivascular adipose tissue. Aghamohammadzadeh R(1), Heagerty AM. Author information: (1)Cardiovascular Research Group, University of Manchester, UK. The advent of the obesity epidemic has highlighted the need to re-assess more closely the pathophysiology of obesity-related hypertension with the aim of identifying new therapies. In this article, we review the role of the renin-angiotensin-aldosterone system, sympathetic nervous system, and inflammation in relation to the pathophysiology of this condition. We also discuss the potential role of the perivascular adipose tissue in the context of obesity-related hypertension. PMID: 22713152 [PubMed - indexed for MEDLINE] 187. Adv Exp Med Biol. 2012;984:287-98. doi: 10.1007/978-94-007-4315-1_15. Immune response and Coxiella burnetii invasion. Amara AB(1), Bechah Y, Mege JL. Author information: (1)Unité de Recherche sur les Maladies Infectieuses Transmissibles et Emergentes, CNRS-IRD UMR 6236, Institut Fédératif de Recherche 48, Faculté de Médecine, Université de la Méditerranée, Marseille, France. Coxiella burnetii, the causative agent of Q fever, has evolved a wealth of mechanisms in order to persist within hosts. Two tissues, namely adipose tissue and placenta, are candidates to house C. burnetii, but the mechanisms governing C. burnetii survival in these tissues are still unknown. In contrast, monocytes and macrophages are well-known targets of C. burnetii. First, C. burnetii has developed a specific strategy of phagocytosis subversion that consists of the inhibition of integrin interplay. Second, C. burnetii persistence is associated with macrophage activation profiles. Indeed, monocytes (in which C. burnetii survives without replication) exhibit a proinflammatory M1-type response, whereas macrophages (in which C. burnetii slowly replicates) are polarized towards an M2-type. Third, interleukin-10 produced by monocytes is a main factor of the chronic development of Q fever, and murine models confirm the key role of interleukin-10 in C. burnetii persistence. Fourth, apoptotic cells may play a key role in chronic Q fever. The uptake of apoptotic cells by circulating monocytes increases C. burnetii replication by redirecting monocytes toward a non-protective M2 profile. In the presence of interferon-γ, apoptotic cell engulfment is inhibited and monocytes polarized toward an M1 program are able to kill C. burnetii; this is the situation observed in patients with uncomplicated acute Q fever. Finally, we cannot exclude that regulatory T cells may play a role in C. burnetii persistence because their number is increased in patients with chronic Q fever. PMID: 22711638 [PubMed - indexed for MEDLINE] 188. Int J Obes (Lond). 2012 Oct;36(10):1261-9. doi: 10.1038/ijo.2012.95. Epub 2012 Jun 19. Ethnic and sex differences in body fat and visceral and subcutaneous adiposity in children and adolescents. Staiano AE(1), Katzmarzyk PT. Author information: (1)Population Science, Pennington Biomedical Research Center, Baton Rouge, LA, USA. Body fat and the specific depot where adipose tissue (AT) is stored can contribute to cardiometabolic health risks in children and adolescents. Imaging procedures including magnetic resonance imaging and computed tomography allow for the exploration of individual and group differences in pediatric adiposity. This review examines the variation in pediatric total body fat (TBF), visceral AT (VAT) and subcutaneous AT (SAT) due to age, sex, maturational status and ethnicity. TBF, VAT and SAT typically increase as a child ages, though different trends emerge. Girls tend to accumulate more TBF and SAT during and after puberty, depositing fat preferentially in the gynoid and extremity regions. In contrast, pubertal and postpubertal boys tend to deposit more fat in the abdominal region, particularly in the VAT depot. Sexual maturation significantly influences TBF, VAT and SAT. Ethnic differences in TBF are mixed. VAT tends to be higher in white and Hispanic youth, whereas SAT is typically higher in African American youth. Asian youth typically have less gynoid fat but more VAT than whites. Obesity per se may attenuate sex and ethnic differences. Particular health risks are associated with high amounts of TBF, VAT and SAT, including insulin resistance, hepatic steatosis, metabolic syndrome and hypertension. These risks are affected by genetic, biological and lifestyle factors including physical activity, nutrition and stress. Synthesizing evidence is difficult as there is no consistent methodology or definition to estimate and define depot-specific adiposity, and many analyses compare SAT and VAT without controlling for TBF. Future research should include longitudinal examinations of adiposity changes over time in representative samples of youth to make generalizations to the entire pediatric population and examine variation in organ-specific body fat. PMCID: PMC4129655 PMID: 22710928 [PubMed - indexed for MEDLINE] 189. Int J Cardiol. 2013 Jul 15;167(1):22-5. doi: 10.1016/j.ijcard.2012.05.082. Epub 2012 Jun 17. Cardiac adipose tissue: a new frontier for cardiac regeneration? Bayes-Genis A(1), Gálvez-Montón C, Prat-Vidal C, Soler-Botija C. Author information: (1)ICREC, Heart Failure and Cardiac Regeneration, Research Program, Health Sciences Research Institute Germans Trias i Pujol, Cardiology Service, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain. abayes.germanstrias@gencat.cat The human heart has limited regenerative capacity. We focused on cardiac adipose tissue as a source of progenitor cells and biological matrix material for salvaging injured myocardium. First, a population of human adult mesenchymal-like progenitors derived from cardiac adipose tissue, with inherent cardiac and endothelial cell potential, was identified and characterized. Next, a salvage strategy was tested, where a pericardial-derived, vascularized, adipose flap was used to cover oxygen-deprived myocardium in a porcine model. The fat flap reduced the myocardial scar size, in both acute and chronic infarcts. A human clinical trial to examine this novel intervention is currently underway. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved. PMID: 22709728 [PubMed - indexed for MEDLINE] 190. Obes Rev. 2012 Oct;13(10):848-57. doi: 10.1111/j.1467-789X.2012.01013.x. Epub 2012 Jun 19. Effect of calcium intake on fat oxidation in adults: a meta-analysis of randomized, controlled trials. Gonzalez JT(1), Rumbold PL, Stevenson EJ. Author information: (1)Brain, Performance and Nutrition Research Centre, School of Life Sciences, Northumbria University, Newcastle upon Tyne, UK. janvier.gonzalex@northumbria.ac.uk Calcium intake is likely to increase body fat loss during energy restriction. Part of this effect may be explained by increased fat oxidation in the presence of a similar energy balance, yet studies have not provided a conclusive answer. Therefore a meta-analysis was performed to determine whether chronic or acute high calcium intake increases fat oxidation. Randomized controlled trials of high calcium intake in human adults where measures of fat oxidation were taken were included. A random-effects meta-analysis was performed on outcomes expressed as standardized mean differences. Chronic high calcium intake increased fat oxidation by a standardized mean difference of 0.42 (95% confidence intervals: 0.14, 0.69; P= 0.003; estimated to correspond to an 11% increase), displaying low heterogeneity (I(2) = 18%), which was more prominent when habitual calcium intake was low (<700 mg d(-1) ). Acute high calcium intake increased fat oxidation by a standardized mean difference of 0.41 (0.04, 0.77; P = 0.03), with low heterogeneity (I(2) = 19%), yet sensitivity analysis revealed that this effect was relatively weak. In conclusion, chronic high calcium intake is likely to increase rates of fat oxidation. The effects of acute high calcium intake appear to point in the same direction, but further work is needed to permit a greater degree of certainty. © 2012 The Authors. obesity reviews © 2012 International Association for the Study of Obesity. PMID: 22708505 [PubMed - indexed for MEDLINE] 191. Postepy Hig Med Dosw (Online). 2012 May 23;66:267-74. [Leptin as a mediator between obesity and cardiac dysfunction]. [Article in Polish] Karbowska J(1), Kochan Z. Author information: (1)Katedra Biochemii, Gdański Uniwersytet Medyczny, Gdańsk. Obesity is now recognised as one of the most important risk factors for heart disease. Obese individuals have high circulating levels of leptin, a hormone secreted by adipose tissue and involved in energy homeostasis. Growing evidence suggests that leptin may contribute to the development of cardiac dysfunction. In a large prospective study leptin has been shown to be an independent risk factor for coronary heart disease. An independent positive association has also been found between plasma leptin levels and heart rate in hypertensive patients and heart transplant recipients. In animal studies chronic leptin infusion increased heart rate and blood pressure. It has also been demonstrated that circulating leptin levels are elevated in patients with heart failure. The level of plasma leptin was associated with increased myocardial wall thickness and correlated with left ventricular mass, suggesting a role for this hormone in mediating left ventricular hypertrophy in humans. Moreover, leptin directly induced hypertrophy and hyperplasia in human and rodent cardiomyocytes, accompanied by cardiac extracellular matrix remodelling. Leptin may also influence energy substrate utilisation in cardiac tissue. These findings suggest that leptin acting directly or through the sympathetic nervous system may have adverse effects on cardiac structure and function, and that chronic hyperleptinaemia may greatly increase the risk of cardiac disorders. Additional studies are needed to define the role of leptin in cardiac physiology and pathophysiology, nevertheless the reduction in plasma leptin levels with caloric restriction and weight loss may prevent cardiac dysfunction in obese patients. PMID: 22706112 [PubMed - indexed for MEDLINE] 192. Trends Endocrinol Metab. 2012 Jul;23(7):351-63. doi: 10.1016/j.tem.2012.05.001. Epub 2012 Jun 14. PPARs at the crossroads of lipid signaling and inflammation. Wahli W(1), Michalik L. Author information: (1)Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland. walter.wahli@unil.ch Nuclear receptors (NRs) are ligand-dependent transcription factors whose activation affects genes controlling vital processes. Among them, the peroxisome proliferator-activated receptors (PPARs) have emerged as links between lipids, metabolic diseases, and innate immunity. PPARs are activated by fatty acids and their derivatives, many of which also signal through membrane receptors, thereby creating a lipid signaling network between the cell surface and the nucleus. Tissues that play a role in whole-body metabolic homeostasis, such as adipose tissue, liver, skeletal muscle, intestines, and blood vessel walls, are prone to inflammation when metabolism is disturbed, a complication that promotes type 2 diabetes and cardiovascular disease. This review discusses the protective roles of PPARs in inflammatory conditions and the therapeutic anti-inflammatory potential of PPAR ligands. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22704720 [PubMed - indexed for MEDLINE] 193. Proc Nutr Soc. 2012 Aug;71(3):363-70. doi: 10.1017/S0029665112000584. Epub 2012 Jun 18. Adipose tissue development during early life: novel insights into energy balance from small and large mammals. Symonds ME(1), Pope M, Budge H. Author information: (1)The Early Life Nutrition Research Unit, Academic Child Health, School of Clinical Sciences, University Hospital, Nottingham NG7 2UH, UK. michael.symonds@nottingham.ac.uk Since the rediscovery of brown adipose tissue (BAT) in adult human subjects in 2007, there has been a dramatic resurgence in research interest in its role in heat production and energy balance. This has coincided with a reassessment of the origins of BAT and the suggestion that brown preadipocytes could share a common lineage with skeletal myoblasts. In precocial newborns, such as sheep, the onset of non-shivering thermogenesis through activation of the BAT-specific uncoupling protein 1 (UCP1) is essential for effective adaptation to the cold exposure of the extra-uterine environment. This is mediated by a combination of endocrine adaptations which accompany normal parturition at birth and further endocrine stimulation from the mother's milk. Three distinct adipose depots have been identified in all species studied to date. These contain either primarily white, primarily brown or a mix of brown and white adipocytes. The latter tissue type is present, at least, in the fetus and, thereafter, appears to take on the characteristics of white adipose tissue during postnatal development. It is becoming apparent that a range of organ-specific mechanisms can promote UCP1 expression. They include the liver, heart and skeletal muscle, and involve unique endocrine systems that are stimulated by cold exposure and/or exercise. These multiple pathways that promote BAT function vary with age and between species that may determine the potential to be manipulated in early life. Such interventions could modify, or reverse, the normal ontogenic pathway by which BAT disappears after birth, thereby facilitating BAT thermogenesis through the life cycle. PMID: 22704581 [PubMed - indexed for MEDLINE] 194. J Intern Med. 2012 Oct;272(4):317-29. doi: 10.1111/j.1365-2796.2012.02564.x. Epub 2012 Jul 29. New insights into osteoporosis: the bone-fat connection. Kawai M(1), de Paula FJ, Rosen CJ. Author information: (1)Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan. Osteoporosis and obesity are chronic disorders that are both increasing in prevalence. The pathophysiology of these conditions is multifactorial and includes genetic, environmental and hormonal determinants. Although it has long been considered that these are distinct disorders rarely found in the same individual, emerging evidence from basic and clinical studies support an important interaction between adipose tissue and the skeleton. It is proposed that adiposity may influence bone remodelling through three mechanisms: (i) secretion of cytokines that directly target bone, (ii) production of adipokines that influence the central nervous system thereby changing sympathetic impulses to bone and (iii) paracrine influences on adjacent skeletal cells. Here we focus on the current understanding of bone-fat interactions and the clinical implications of recent studies linking obesity to osteoporosis. © 2012 The Association for the Publication of the Journal of Internal Medicine. PMCID: PMC3634716 PMID: 22702419 [PubMed - indexed for MEDLINE] 195. Exp Diabetes Res. 2012;2012:789174. doi: 10.1155/2012/789174. Epub 2012 Jun 4. Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms. Arcidiacono B(1), Iiritano S, Nocera A, Possidente K, Nevolo MT, Ventura V, Foti D, Chiefari E, Brunetti A. Author information: (1)Department of Health Sciences, Magna Græcia University of Catanzaro, Viale Europa (Località Germaneto), 88100 Catanzaro, Italy. Insulin resistance is common in individuals with obesity or type 2 diabetes (T2D), in which circulating insulin levels are frequently increased. Recent epidemiological and clinical evidence points to a link between insulin resistance and cancer. The mechanisms for this association are unknown, but hyperinsulinaemia (a hallmark of insulin resistance) and the increase in bioavailable insulin-like growth factor I (IGF-I) appear to have a role in tumor initiation and progression in insulin-resistant patients. Insulin and IGF-I inhibit the hepatic synthesis of sex-hormone binding globulin (SHBG), whereas both hormones stimulate the ovarian synthesis of sex steroids, whose effects, in breast epithelium and endometrium, can promote cellular proliferation and inhibit apoptosis. Furthermore, an increased risk of cancer among insulin-resistant patients can be due to overproduction of reactive oxygen species (ROS) that can damage DNA contributing to mutagenesis and carcinogenesis. On the other hand, it is possible that the abundance of inflammatory cells in adipose tissue of obese and diabetic patients may promote systemic inflammation which can result in a protumorigenic environment. Here, we summarize recent progress on insulin resistance and cancer, focusing on various implicated mechanisms that have been described recently, and discuss how these mechanisms may contribute to cancer initiation and progression. PMCID: PMC3372318 PMID: 22701472 [PubMed - indexed for MEDLINE] 196. Ann Hepatol. 2012 Jul-Aug;11(4):440-9.  Gut microbiota and nonalcoholic fatty liver disease. Machado MV(1), Cortez-Pinto H. Author information: (1)Departamento de Gastrenterologia, Hospital Santa Maria, CHLN, Lisbon, Portugal. Comment in Ann Hepatol. 2013 Jan-Feb;12(1):161-3.  Recent evidence has linked obesity and the metabolic syndrome with gut dysbiota. The precise mechanisms underlying that association are not entirely understood; however, microbiota can enhance the extraction of energy from diet and regulate whole-body metabolism towards increased fatty acids uptake from adipose tissue and shift lipids metabolism from oxidation to de novo production. Obesity and high fat diet relate to a specific gut microbiota, which is enriched in Firmicutes and with less Bacterioidetes. Microbiota can also play a role in the development of hepatic steatosis, necroinflammation and fibrosis. In fact, some studies have shown an association between small intestinal bacterial overgrowth, increased intestinal permeability and nonalcoholic steatohepatitis (NASH). That association is, in part, due to increased endotoxinaemia and activation of the Toll-like receptor-4 signaling cascade. Preliminary data on probiotics suggest a potential role in NASH treatment, however randomized controlled clinical trials are still lacking. PMID: 22700625 [PubMed - indexed for MEDLINE] 197. J Mal Vasc. 2012 Jul;37(4):213-8. doi: 10.1016/j.jmv.2012.05.002. Epub 2012 Jun 13. [Lipedema: a misdiagnosed entity]. [Article in French] Vignes S(1). Author information: (1)Unité de lymphologie, centre national de référence des maladies vasculaires rares (lymphœdèmes primaires), hôpital Cognacq-Jay, 15, rue Eugène-Millon, 75015 Paris, France. stephane.vignes@cognacq-jay.fr Lipedema is a clinical entity frequently misdiagnosed or confound with primary lymphedema. Lipedema is a disorder of adipose tissue that occurs almost exclusively in obese women. It is characterized by bilateral enlargement from hip to ankle due to abnormal depositions of subcutaneous fat associated with often mild edema, usually sparing the feet. Disease onset is usually at or soon after puberty. Lipedema results in considerable frustration and distress resulting from the cosmetic appearance. Patients may complain of pain, tenderness, easy bruising of the affected areas with moderate to severe sensitivity to digital pressure or pinching. Imaging studies using computed tomography, magnetic resonance imaging, ultrasound, lymphoscintigraphy are not indicated, except if the diagnosis is atypic or doubtful. Long-term evolution may alter lymphatic system and lead to a lipo-lymphedema with specific complications such as cellulitis. Lipedema management is not codified and included weight loss (poorly improving leg appearance or discomfort), psychological counselling and compression therapy. Liposuction, especially using tumescent local anaesthesia, may reduce edema, spontaneous pain, sensitivity to pressure, bruising and improve appearance resulting in a important increase in quality of life. Copyright © 2012. Published by Elsevier Masson SAS. PMID: 22698628 [PubMed - indexed for MEDLINE] 198. J Laryngol Otol. 2012 Jul;126(7):725-8. doi: 10.1017/S0022215112000783. Case of progressive facial hemiatrophy with cervical sympathetic hyperactivity as underlying aetiology. Monobe H(1), Miyano K, Kagoya R, Tojima H. Author information: (1)Department of Otolaryngology, Hitachi General Hospital, Ibaraki, Japan. h-monobe@chime.ocn.ne.jp OBJECTIVE: We report a case of progressive facial hemiatrophy with cervical sympathetic hyperactivity as a possible underlying aetiology, based on clinical findings, three-dimensional computed tomography and thermographic imaging. METHODS: We present a case report in which we describe the investigation and clinical course of progressive facial hemiatrophy, and we also review the world literature on this condition. RESULTS: To our knowledge, this is the first report in the world literature of progressive facial hemiatrophy with cervical sympathetic hyperactivity indicated as a possible underlying aetiology, based on clinical findings, three-dimensional computed tomography and thermographic imaging. CONCLUSION: This syndrome may lead to atrophy of the subcutaneous adipose tissue with hyperfunction of the vegetative system. Although this is a rare syndrome, otolaryngologists should be aware of its symptoms, aetiology and treatment. PMID: 22697810 [PubMed - indexed for MEDLINE] 199. Stomatologiia (Mosk). 2012;91(1):71-5. [Stem cells and possibilities of their application in parodontology]. [Article in Russian] Grudianov AI, Sysoeva VIu, Ternovoĭ IuV. PMID: 22696797 [PubMed - indexed for MEDLINE] 200. Am J Physiol Regul Integr Comp Physiol. 2012 Aug 1;303(3):R247-58. doi: 10.1152/ajpregu.00167.2012. Epub 2012 Jun 13. Potential clinical translation of juvenile rodent inactivity models to study the onset of childhood obesity. Roberts MD(1), Company JM, Brown JD, Toedebusch RG, Padilla J, Jenkins NT, Laughlin MH, Booth FW. Author information: (1)Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, 65211, USA. According to the latest data from the Center for Disease Control and Prevention 17%, or 12.5 million, of children and adolescents aged 2-19 years in the United States are obese. Physical inactivity is designated as one of the actual causes of US deaths and undoubtedly contributes to the obesity epidemic in children and adults. Examining the effects of inactivity on physiological homeostasis during youth is crucial given that 58% of children between the ages 6-11 yr old fail to obtain the recommended 60 min/day of physical activity and 92% of adolescents fail to achieve this goal [Troiano et al. Med Sci Sports Exerc. 40, 2008]. Nonetheless, invasive mechanistic studies in children linking diminished physical activity with metabolic maladies are lacking for obvious ethical reasons. The rodent wheel lock (WL) model was adopted by our laboratory and others to study how different organ systems of juvenile rats respond to a cessation of daily physical activity. Our WL model houses rats in cages equipped with voluntary running wheels starting at 28 days of age. After a certain period of voluntary running (3 to 6 wk), the wheels are locked, thus preventing the rats' primary source of physical activity. The studies discussed herein suggest that obesity-associated maladies including skeletal muscle insulin resistance, hypothalamic leptin resistance, fatty acid oxidation impairments in skeletal muscle and adipose tissue, nonalcoholic fatty liver disease, and endothelial dysfunction are initiated in juvenile animals that are restrained from voluntary exercise via WL. The use of the juvenile rodent WL or other inactivity models will continue to provide a powerful clinical translational tool that can be used for primordial prevention of human childhood obesity. PMCID: PMC3423989 PMID: 22696577 [PubMed - indexed for MEDLINE] 201. Magn Reson Med. 2012 Aug;68(2):378-88. doi: 10.1002/mrm.24369. Epub 2012 Jun 12. ISMRM workshop on fat-water separation: insights, applications and progress in MRI. Hu HH(1), Börnert P, Hernando D, Kellman P, Ma J, Reeder S, Sirlin C. Author information: (1)Departments of Radiology and Electrical Engineering, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027, USA. houchunh@usc.edu Approximately 130 attendees convened on February 19-22, 2012 for the first ISMRM-sponsored workshop on water-fat imaging. The motivation to host this meeting was driven by the increasing number of research publications on this topic over the past decade. The scientific program included an historical perspective and a discussion of the clinical relevance of water-fat MRI, a technical description of multiecho pulse sequences, a review of data acquisition and reconstruction algorithms, a summary of the confounding factors that influence quantitative fat measurements and the importance of MRI-based biomarkers, a description of applications in the heart, liver, pancreas, abdomen, spine, pelvis, and muscles, an overview of the implications of fat in diabetes and obesity, a discussion on MR spectroscopy, a review of childhood obesity, the efficacy of lifestyle interventional studies, and the role of brown adipose tissue, and an outlook on federal funding opportunities from the National Institutes of Health. Copyright © 2012 Wiley Periodicals, Inc. PMCID: PMC3575097 PMID: 22693111 [PubMed - indexed for MEDLINE] 202. Physiology (Bethesda). 2012 Jun;27(3):156-66. doi: 10.1152/physiol.00007.2012. Orphan nuclear receptors and the regulation of nutrient metabolism: understanding obesity. Pearen MA(1), Muscat GE. Author information: (1)Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia. m.pearen@uq.edu.au Nuclear hormone receptors (NRs) are a superfamily of eukaryotic ligand-dependent transcription factors that translate endocrine, metabolic, nutritional, developmental, and pathophysiological signals into gene regulation. Members of the NR superfamily (on the basis of sequence homology) that lack identified natural and/or synthetic ligands are/were classified as "orphan" NRs. These members of the NR superfamily are abundantly expressed in tissues associated with major metabolic activity, such as skeletal muscle, adipose, and liver. Subsequently, in vivo genetic studies on these orphan NRs and exploitation of novel natural and synthetic agonists has revealed that orphan NRs regulate 1) carbohydrate, lipid, and energy homeostasis in a tissue-specific manner, and 2) the pathophysiology of dyslipidemia, obesity, Type 2 diabetes, and cardiovascular disease. This review discusses key studies that have implicated the orphan NRs as organ-specific regulators of metabolism and mediators of adverse pathophysiological effects. The emerging discovery of novel endogenous orphan NR ligands and synthetic agonists has provided the foundation for therapeutic exploitation of the orphans in the treatment of metabolic disease. PMID: 22689791 [PubMed - indexed for MEDLINE] 203. Diabetologia. 2012 Sep;55(9):2319-26. doi: 10.1007/s00125-012-2598-x. Epub 2012 Jun 12. Adiponectin: mechanistic insights and clinical implications. Turer AT(1), Scherer PE. Author information: (1)Department of Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8521, USA. Aslan.Turer@UTSouthwestern.edu Adiponectin is an adipocyte-derived secretory protein that has been very widely studied over the past 15 years. A multitude of different functions have been attributed to this adipokine. It has been characterised in vitro at the level of tissue culture systems and in vivo through genetic manipulation of rodent models. It is also widely accepted as a biomarker in clinical studies. Originating in adipose tissue, generally positive metabolic effects have been attributed to adiponectin. In this review, we briefly discuss the key characteristics of this interesting but very complex molecule, highlight recent results in the context of its mechanism of action and summarise some of the key epidemiological data that helped establish adiponectin as a robust biomarker for insulin sensitivity, cardiovascular disease and many additional disease phenomena. PMID: 22688349 [PubMed - indexed for MEDLINE] 204. Yakugaku Zasshi. 2012;132(6):721-5. [Pivotal role of skeletal tissues in the regulation mechanisms for physiological functions mediated by multiple organ networks]. Hinoi E(1). Author information: (1)Laboratory of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan. hinoi@p.kanazawa-u.ac.jp Bone formation and maintenance are sophisticatedly orchestrated through a well-organized and highly regulated mechanism by two distinct cell types; bone-forming osteoblast and bone-resorbing osteoclast. It has been previously established that the adipocyte-derived hormone leptin regulates bone metabolism through the central nervous system and the sympathetic nervous system. We recently identified the osteoblast as the principal cell type in which the sympathetic tone could signal to regulate bone mass by generating and analyzing the cell specific adrenergic receptor deletion mice. The fact that adipocyte-derived hormone regulates bone metabolism implies that the skeleton might exert a feedback control of glucose metabolism. We then revealed that the skeleton acts as an endocrine regulator of energy metabolism through the osteoblast-specific secreted molecule osteocalcin that activates insulin secretion by pancreatic β-cells, insulin sensitivity in fat, liver, and muscle. Moreover, we have recently reported that the sympathetic tone into osteoblast is a pivotal mediator of leptin regulation of insulin secretion by regulating osteocalcin bioactivity. This unexpected functional cross talk between fat, nervous systems, and skeleton illustrates the importance of the skeleton for the regulation of major physiological functions such as glucose homeostasis in vertebrates. PMID: 22687731 [PubMed - indexed for MEDLINE] 205. Int J Radiat Oncol Biol Phys. 2013 Feb 1;85(2):406-14. doi: 10.1016/j.ijrobp.2012.04.044. Epub 2012 Jun 9. Prospective study of functional bone marrow-sparing intensity modulated radiation therapy with concurrent chemotherapy for pelvic malignancies. Liang Y(1), Bydder M, Yashar CM, Rose BS, Cornell M, Hoh CK, Lawson JD, Einck J, Saenz C, Fanta P, Mundt AJ, Bydder GM, Mell LK. Author information: (1)Department of Radiation Oncology, and Center for Advanced Radiotherapy Technologies, University of California, San Diego, La Jolla, California 92093, USA. PURPOSE: To test the hypothesis that intensity modulated radiation therapy (IMRT) can reduce radiation dose to functional bone marrow (BM) in patients with pelvic malignancies (phase IA) and estimate the clinical feasibility and acute toxicity associated with this technique (phase IB). METHODS AND MATERIALS: We enrolled 31 subjects (19 with gynecologic cancer and 12 with anal cancer) in an institutional review board-approved prospective trial (6 in the pilot study, 10 in phase IA, and 15 in phase IB). The mean age was 52 years; 8 of 31 patients (26%) were men. Twenty-one subjects completed (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) simulation and magnetic resonance imaging by use of quantitative IDEAL (IDEAL IQ; GE Healthcare, Waukesha, WI). The PET/CT and IDEAL IQ were registered, and BM subvolumes were segmented above the mean standardized uptake value and below the mean fat fraction within the pelvis and lumbar spine; their intersection was designated as functional BM for IMRT planning. Functional BM-sparing vs total BM-sparing IMRT plans were compared in 12 subjects; 10 were treated with functional BM-sparing pelvic IMRT per protocol. RESULTS: In gynecologic cancer patients, the mean functional BM V(10) (volume receiving ≥10 Gy) and V(20) (volume receiving ≥20 Gy) were 85% vs 94% (P<.0001) and 70% vs 82% (P<.0001), respectively, for functional BM-sparing IMRT vs total BM-sparing IMRT. In anal cancer patients, the corresponding values were 75% vs 77% (P=.06) and 62% vs 67% (P=.002), respectively. Of 10 subjects treated with functional BM-sparing pelvic IMRT, 3 (30%) had acute grade 3 hematologic toxicity or greater. CONCLUSIONS: IMRT can reduce dose to BM subregions identified by (18)F-fluorodeoxyglucose-PET/CT and IDEAL IQ. The efficacy of BM-sparing IMRT is being tested in a phase II trial. Copyright © 2013 Elsevier Inc. All rights reserved. PMID: 22687195 [PubMed - indexed for MEDLINE] 206. J Biomed Biotechnol. 2012;2012:871272. doi: 10.1155/2012/871272. Epub 2012 May 22. Role of pigment epithelium-derived factor in stem/progenitor cell-associated neovascularization. Liu JT(1), Chen YL, Chen WC, Chen HY, Lin YW, Wang SH, Man KM, Wan HM, Yin WH, Liu PL, Chen YH. Author information: (1)Department of Neurosurgery, School of Medicine, Chung-Shan Medical University and Hospital, Taichung 402, Taiwan. Pigment epithelium-derived factor (PEDF) was first identified in retinal pigment epithelium cells. It is an endogenously produced protein that is widely expressed throughout the human body such as in the eyes, liver, heart, and adipose tissue; it exhibits multiple and varied biological activities. PEDF is a multifunctional protein with antiangiogenic, antitumorigenic, antioxidant, anti-inflammatory, antithrombotic, neurotrophic, and neuroprotective properties. More recently, PEDF has been shown to be the most potent inhibitor of stem/progenitor cell-associated neovascularization. Neovascularization is a complex process regulated by a large, interacting network of molecules from stem/progenitor cells. PEDF is also involved in the pathogenesis of angiogenic eye disease, tumor growth, and cardiovascular disease. Novel antiangiogenic agents with tolerable side effects are desired for the treatment of patients with various diseases. Here, we review the value of PEDF as an important endogenous antiangiogenic molecule; we focus on the recently identified role of PEDF as a possible new target molecule to influence stem/progenitor cell-related neovascularization. PMCID: PMC3364713 PMID: 22685380 [PubMed - indexed for MEDLINE] 207. J Lipid Res. 2012 Sep;53(9):1738-54. doi: 10.1194/jlr.R024505. Epub 2012 Jun 8. PPAR-γ as a therapeutic target in cardiovascular disease: evidence and uncertainty. Huang JV(1), Greyson CR, Schwartz GG. Author information: (1)Cardiology Section, Denver VA Medical Center, US Department of Veterans Affairs, Denver, CO, USA. Peroxisome proliferator-activated receptor γ (PPAR-γ) is a key regulator of fatty acid metabolism, promoting its storage in adipose tissue and reducing circulating concentrations of free fatty acids. Activation of PPAR-γ has favorable effects on measures of adipocyte function, insulin sensitivity, lipoprotein metabolism, and vascular structure and function. Despite these effects, clinical trials of thiazolidinedione PPAR-γ activators have not provided conclusive evidence that they reduce cardiovascular morbidity and mortality. The apparent disparity between effects on laboratory measurements and clinical outcomes may be related to limitations of clinical trials, adverse effects of PPAR-γ activation, or off-target effects of thiazolidinedione agents. This review addresses these issues from a clinician's perspective and highlights several ongoing clinical trials that may help to clarify the therapeutic role of PPAR-γ activators in cardiovascular disease. PMCID: PMC3413217 PMID: 22685322 [PubMed - indexed for MEDLINE] 208. J Burn Care Res. 2012 Jul-Aug;33(4):463-70. doi: 10.1097/BCR.0b013e31825af547. Heterotopic ossification following burn injury: the role of stem cells. Nelson ER(1), Wong VW, Krebsbach PH, Wang SC, Levi B. Author information: (1)Department of Surgery, Plastic and Reconstructive Surgery Division, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA. Heterotopic ossification (HO), or the abnormal development of bone tissue in soft-tissue locations, can be physically debilitating and clinically devastating. For unclear reasons, HO is highly associated with burn injury. The objective of this review is to summarize 1) cells that are responsible for HO, 2) in vitro and in vivo models of HO and how they have contributed to our current knowledge of the disease process, 3) the effects of the adipose compartment on HO, 4) the effects of inflammation on HO, and 5) the effects of mesenchymal stem cells (MSCs) on HO. Preclinical models of HO suggest several possible mechanisms for the development of this pathologic process, including progenitor cell differentiation and paracrine modulation of local inflammatory responses. Further studies are needed to elucidate the molecular mechanisms driving HO so that targeted therapies can be developed. Current literature supports a role for MSCs in modulating heterotopic bone formation, and direct manipulation of MSCs might one day be used to prevent and treat HO. PMID: 22683987 [PubMed - indexed for MEDLINE] 209. Endocrinol Metab Clin North Am. 2012 Jun;41(2):283-95, v-vi. doi: 10.1016/j.ecl.2012.04.011. The insulin-like growth factors in adipogenesis and obesity. Garten A(1), Schuster S, Kiess W. Author information: (1)Department of Women and Child Health, Hospital for Children and Adolescents, Center for Pediatric Research Leipzig, University Hospitals, Liebigstraße 20a, 04103 Leipzig, Germany. Adipose tissue has been recognized as a major target of growth hormone (GH) action. GH was shown to inhibit adipocyte differentiation but stimulated preadipocyte proliferation in vitro. GH acts directly via its receptor or via upregulating insulin-like growth factor (IGF)-I, which is a critical mediator of preadipocyte proliferation, differentiation, and survival. Results from clinical studies on GH treatment in patients with GH deficiency or GH insensitivity syndrome can be used to dissect GH and IGF as well as IGF-binding protein (IGFBP) actions in vivo. In this article, changes of the GH/IGF system during adipocyte differentiation in vitro as well as related signaling pathways and their impact on adipose tissue growth and function are discussed. Clinical considerations include the effects of GH and IGF-I on adipose tissue during treatment of GH deficiency, differences in the IGF system between visceral and subcutaneous adipose tissue depots as well as the recently emerging role for adipose tissue in the regulation of glucose homeostasis. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22682631 [PubMed - indexed for MEDLINE] 210. Cell Mol Life Sci. 2012 Jun 8. [Epub ahead of print] Studying non-alcoholic fatty liver disease with zebrafish: a confluence of optics, genetics, and physiology. Schlegel A(1). Author information: (1)University of Utah Molecular Medicine (U2M2) Program, University of Utah School of Medicine, 15 North 2030 East, Building 533, Room 3240B, Salt Lake City, UT, 84124, USA, amnons@u2m2.utah.edu. Obesity is a public health crisis. New methods for amelioration of its consequences are required because it is very unlikely that the social and economic factors driving it will be reversed. The pathological accumulation of neutral lipids in the liver (hepatic steatosis) is an obesity-related problem whose molecular underpinnings are unknown and whose effective treatment is lacking. Here I review how zebrafish, a powerful model organism long-used for studying vertebrate developmental programs, is being harnessed to uncover new factors that contribute to normal liver lipid handling. Attention is given to dietary models and individual mutants. I speculate on the possible roles of non-hepatocyte residents of the liver, the adipose tissue, and gut microbiome on the development of hepatic steatosis. The highlighted work and future directions may lead to fresh insights into the pathogenesis and treatment of excess liver lipid states. PMCID: PMC3492697 PMID: 22678663 [PubMed - as supplied by publisher] 211. Bioessays. 2012 Aug;34(8):681-91. doi: 10.1002/bies.201200031. Epub 2012 Jun 5. New vistas for treatment of obesity and diabetes? Endocannabinoid signalling and metabolism in the modulation of energy balance. Lipina C(1), Rastedt W, Irving AJ, Hundal HS. Author information: (1)Division of Cell Signalling and Immunology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, Scotland. Growing evidence suggests that pathological overactivation of the endocannabinoid system (ECS) is associated with dyslipidemia, obesity and diabetes. Indeed, this signalling system acting through cannabinoid receptors has been shown to function both centrally and peripherally to regulate feeding behaviour as well as energy expenditure and metabolism. Consequently, modulation of these receptors can promote significant alterations in body weight and associated metabolic profile. Importantly, blocking cannabinoid receptor type 1 function has been found to prevent obesity and metabolic dysfunction in various murine models and in humans. Here we provide a detailed account of the known physiological role of the ECS in energy balance, and explore how recent studies have delivered novel insights into the potential targeting of this system as a therapeutic means for treating obesity and related metabolic disorders. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. PMID: 22674489 [PubMed - indexed for MEDLINE] 212. Acta Physiol (Oxf). 2012 Aug;205(4):456-71. doi: 10.1111/j.1748-1716.2012.02455.x. Exercise training, genetics and type 2 diabetes-related phenotypes. Hagberg JM(1), Jenkins NT, Spangenburg E. Author information: (1)Department of Kinesiology, School of Public Health, University of Maryland, College Park, MD 20742, USA. hagberg@umd.edu Type 2 diabetes mellitus (T2DM) is at virtually pandemic levels world-wide. Diabetes has been referred to as 'a geneticist's nightmare'. However, dramatic advances in our understanding of the genetics of T2DM have occurred in the past 5 years. While endurance exercise training and increased habitual physical activity levels have consistently been shown to improve or be associated with improved T2DM-related phenotypes, there is substantial interindividual variation in these responses. There is some evidence that T2DM-related phenotype responses to exercise training are heritable, indicating that they might have a genetic basis. Genome-wide linkage studies have not identified specific chromosomal loci that could account for these differences, and no genome-wide association studies have been performed relative to T2DM-related phenotype responses to exercise training. From candidate gene studies, there are relatively strong and replicated data supporting a role for the PPARγ Pro12Ala variant in the interindividual differences in T2DM-related phenotype responses to training. This is a potentially important candidate locus because it affects T2DM susceptibility, has high biological plausibility and is the target for the primary pharmaceutical method for treating T2DM. Is it time to conduct a hypothesis-driven large-scale exercise training intervention trial based on PPARγ Pro12Ala genotype with T2DM-related phenotypes as the primary outcome measures, while also assessing potential mechanistic changes in skeletal muscle and adipose tissue? Or would it be more appropriate to propose a smaller trial to address the specific skeletal muscle and adipose tissue mechanisms affected by the interaction between the PPARγ Pro12Ala genotype and exercise training? © 2012 The Authors Acta Physiologica © 2012 Scandinavian Physiological Society. PMID: 22672138 [PubMed - indexed for MEDLINE] 213. Clin Microbiol Infect. 2012 Jul;18 Suppl 4:50-3. doi: 10.1111/j.1469-0691.2012.03866.x. Crosstalk between the gut microbiota and the endocannabinoid system: impact on the gut barrier function and the adipose tissue. Cani PD(1). Author information: (1)Louvain Drug Research Institute, Metabolism and Nutrition Research Group, Université Catholique de Louvain, Brussels, Belgium. patrice.cani@uclouvain.be Obesity is associated with type 2 diabetes, insulin resistance and low grade inflammation. The gut microbiota is now considered as one of the most important environmental factors impacting on host physiology and metabolism. We have recently pointed out the role of this 'organ' on the onset of insulin resistance and the low grade inflammatory tone characterizing obesity. Among the mechanisms, we have introduced the novel concept of metabolic endotoxaemia as factor triggering low grade inflammation and associated disorders. More recently, two novel mechanisms involved in the development of gut permeability and adipose tissue plasticity have been identified. Specific attention has been paid to the role of the glucagon-like peptide 2 and the endocannabinoid system. This review briefly discusses the role of prebiotics as a key tool to modulate the gut microbiota, the gut barrier function, inflammation and the insulin resistance associated with obesity. © 2012 The Author. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases. PMID: 22647050 [PubMed - indexed for MEDLINE] 214. J Pregnancy. 2012;2012:681306. doi: 10.1155/2012/681306. Epub 2012 May 14. Adrenocortical and adipose responses to high-altitude-induced, long-term hypoxia in the ovine fetus. Myers DA(1), Ducsay CA. Author information: (1)Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. dean-myers@ouhsc.edu By late gestation, the maturing hypothalamo-pituitary-adrenal (HPA) axis aids the fetus in responding to stress. Hypoxia represents a significant threat to the fetus accompanying situations such as preeclampsia, smoking, high altitude, and preterm labor. We developed a model of high-altitude (3,820 m), long-term hypoxia (LTH) in pregnant sheep. We describe the impact of LTH on the fetal HPA axis at the level of the hypothalamic paraventricular nucleus (PVN), anterior pituitary corticotrope, and adrenal cortex. At the PVN and anterior pituitary, the responses to LTH are consistent with hypoxia being a potent activator of the HPA axis and potentially maladaptive, while the adrenocortical response to LTH appears to be primarily adaptive. We discuss mechanisms involved in the delicate balance between these seemingly opposing responses that preserve the normal ontogenic rise in fetal plasma cortisol essential for organ maturation and in this species, birth. Further, we examine the response to, and ramifications of, an acute secondary stressor in the LTH fetus. We provide an integrative model on the potential role of adipose in modulating these responses to LTH. Integration of these adaptive responses to LTH plays a key role in promoting normal fetal growth and development under conditions of a chronic stress. PMCID: PMC3361245 PMID: 22666594 [PubMed - indexed for MEDLINE] 215. Circulation. 2012 Jun 5;125(22):2782-91. doi: 10.1161/CIRCULATIONAHA.111.042929. Brown adipose tissue: mechanisms and potential therapeutic targets. Tam CS(1), Lecoultre V, Ravussin E. Author information: (1)Human Physiology, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. PMID: 22665886 [PubMed - indexed for MEDLINE] 216. Front Endocrinol (Lausanne). 2012 Feb 6;3:14. doi: 10.3389/fendo.2012.00014. eCollection 2012. Recruitment of brown adipose tissue as a therapy for obesity-associated diseases. Boss O(1), Farmer SR. Author information: (1)Energesis Pharmaceuticals, Inc. Cambridge, MA, USA. Brown adipose tissue (BAT) has been recognized for more than 20 years to play a key role in cold-induced non-shivering thermogenesis (CIT, NST), and body weight homeostasis in animals. BAT is a flexible tissue that can be recruited by stimuli (including small molecules in animals), and atrophies in the absence of a stimulus. In fact, the contribution of BAT (and UCP1) to resting metabolic rate and healthy body weight homeostasis in animals (rodents) is now well established. Many investigations have shown that resistance to obesity and associated disorders in various rodent models is due to increased BAT mass and the number of brown adipocytes or UCP1 expression in various depots. The recent discovery of active BAT in adult humans has rekindled the notion that BAT is a therapeutic target for combating obesity-related metabolic disorders. In this review, we highlight investigations performed in rodents that support the contention that activation of BAT formation and/or function in obese individuals is therapeutically powerful. We also propose that enhancement of brown adipocyte functions in white adipose tissue (WAT) will also regulate energy balance as well as reduce insulin resistance in obesity-associated inflammation in WAT. PMCID: PMC3356088 PMID: 22654854 [PubMed] 217. Minerva Cardioangiol. 2012 Jun;60(3):299-304. Epicardial and pericardial adipose tissue: physiological importance and role of imaging techniques. Arepalli CD(1), Vrettoy RA, Lamanna JJ, Ebert EL, Kremastinos DT, Lerakis S. Author information: (1)Department of Radiology, Emory University School of Medicine, Atlanta, GA, USA. Epicardial adipose tissue (EAT) is becoming a cardiovascular risk factor. Multiple imaging techniques are used to measure it, each one with its prons and cons. We will review the literature realizing that there is still a lot of work that needs to be done. PMID: 22653044 [PubMed - indexed for MEDLINE] 218. Front Biosci (Schol Ed). 2012 Jun 1;4:1275-94. Cell sources for cartilage repair; contribution of the mesenchymal perivascular niche. Diaz-Flores L Jr(1), Gutierrez R, Madrid JF, Acosta E, Avila J, Diaz-Flores L, Martin-Vasallo P. Author information: (1)Department of Pathology, Histology and Radiology, School of Medicine, La Laguna University, Canary Islands, Spain. Tissue and cell sources for cartilage repair are revised, including: 1) cartilage and subchondral bone (auto and allografts; single or multiple/mosaicplasty grafts), 2) cultured chondrocytes (autologous/ACI, characterized/CCI, matrix assisted/MAC, or allogenic), 3) adult mesenchymal stem cells (MSCs), 4) progenitor cells from perichondrium and periosteum, 5) embryonic and prenatal stem cells, 6) induced pluripotent stem cells, and 7) genetically modified cells. We consider the biological mechanisms that explain usage and possible complications, advantages and limitations, emerging technologies and possible modulations on extracellular matrix properties and on migration, proliferation, de-differentiation, re-differentiation, morphology, function and integration of the cells. The study of MSC role involve: a) identification, b) location (perivascular niche hypothesis, pericytes as progenitor cells), c) lineage (myoadipofibrogenic system: transit amplifying cells, fibroblast/myofibroblasts, chondrocytes, osteoblasts, odontoblasts, vascular smooth muscle cells and adipocytes), and d) use in cartilage repair, comprising: 1) MSCs recruited from neighbouring tissues (bone marrow stimulation, MSCs based "in situ" cartilage repair, microfracture) and 2) MSCs cultured and expanded from bone marrow, adipose tissue, synovial membrane or granulation tissue. PMID: 22652871 [PubMed - indexed for MEDLINE] 219. Front Biosci (Landmark Ed). 2012 Jun 1;17:2550-8. Association between obesity and gallbladder cancer. Wang F(1), Wang B, Qiao L. Author information: (1)Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China. wangby@medmail.com.cn Obesity has become a global health issue because of its increased morbidity and mortality, and a close association with at least 20 different cancers. Clinical and epidemiological studies have suggested that obesity and overweight are positively related with the risk of GBC. Gallbladder cancer (GBC) is a relatively infrequent but highly lethal neoplasm. Obesity may disturb lipid and endogenous hormones metabolism, affect gallbladder motility, increase the risk of gallstones, and thus plays a role in GBC. Control of obesity through measures such as lifestyle modification, healthy diet, and regular exercise may prove useful in the prevention of GBC. PMID: 22652797 [PubMed - indexed for MEDLINE] 220. Front Biosci (Landmark Ed). 2012 Jun 1;17:2356-70. Obesity-related hepatocellular carcinoma: roles of risk factors altered in obesity. Shen C(1), Zhao CY, Zhang R, Qiao L. Author information: (1)Department of Infectious Disease, the Third Hospital of Hebei Medical University, Shijiazhuang, China. Epidemiological data have demonstrated that the prevalence of either obesity or hepatocellular carcinoma (HCC) is increasing worldwide during past decades, and obesity has been unequivocally shown to be a risk factor for HCC. It has been reported that a significant proportion of HCC in obesity develops in cryptogenic cirrhosis, which is largely associated with the progression of nonalcoholic fatty liver disease, especially nonalcoholic steatohepatitis. Since the HCC is a highly malignant tumor with a poor prognosis, a better understanding of the molecular mechanisms may help researchers to explore new approaches for preventing and treating the obesity-related HCC, and thereby facilitating a substantial reduction of morbidity and mortality. In this article, we reviewed the mechanisms underlying the relationship between obesity and HCC, with an emphasis on the roles of insulin/insulin-like growth factor axis, adipose tissue derived hormones, oxidative stress, and liver stem cells. In addition, we will discuss the impact of life-style modification on obesity-related HCC. PMID: 22652784 [PubMed - indexed for MEDLINE] 221. Front Biosci (Landmark Ed). 2012 Jun 1;17:2237-46. Regulatory roles for L-arginine in reducing white adipose tissue. Tan B(1), Li X, Yin Y, Wu Z, Liu C, Tekwe CD, Wu G. Author information: (1)Research Center of Healthy Breeding of Livestock and Poultry and Key Laboratory for Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, the Chinese Academy of Sciences, Changsha, Hunan, China. As the nitrogenous precursor of nitric oxide, L-arginine regulates multiple metabolic pathways involved in the metabolism of fatty acids, glucose, amino acids, and proteins through cell signaling and gene expression. Specifically, arginine stimulates lipolysis and the expression of key genes responsible for activation of fatty acid oxidation to CO2 and water. The underlying mechanisms involve increases in the expression of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), mitochondrial biogenesis, and the growth of brown adipose tissue growth. Furthermore, arginine regulates adipocyte-muscle crosstalk and energy partitioning via the secretion of cytokines and hormones. In addition, arginine enhances AMP-activated protein kinase (AMPK) expression and activity, thereby modulating lipid metabolism and energy balance toward the loss of triacylglycerols. Growing evidence shows that dietary supplementation with arginine effectively reduces white adipose tissue in Zucker diabetic fatty rats, diet-induced obese rats, growing-finishing pigs, and obese patients with type II diabetes. Thus, arginine can be used to prevent and treat adiposity and the associated metabolic syndrome. PMCID: PMC3422877 PMID: 22652774 [PubMed - indexed for MEDLINE] 222. Metabolism. 2013 Jan;62(1):21-33. doi: 10.1016/j.metabol.2012.05.002. Epub 2012 May 30. 11beta-Hydroxysteroid dehydrogenase type 1 inhibitors: novel agents for the treatment of metabolic syndrome and obesity-related disorders? Anagnostis P(1), Katsiki N, Adamidou F, Athyros VG, Karagiannis A, Kita M, Mikhailidis DP. Author information: (1)Department of Endocrinology, Hippokration Hospital, 49 Konstantinoupoleos Str, Thessaloniki, 54 642, Greece. anagnwstis.pan@yahoo.gr OBJECTIVE: Metabolic syndrome (MetS) and Cushing's syndrome share common features. It has been proposed that increased glucocorticoid activity at peripheral tissues may play a role in the pathogenesis of MetS and obesity-related disorders. It is well-known that intracellular cortisol concentrations are determined not only by plasma levels but also by the activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which catalyzes the conversion of inactive cortisone to active cortisol, especially in the liver and adipose tissue. Another isoenzyme exists, the 11β-hydroxysteroid dehydrogenase type 2, which acts in the opposite direction inactivating cortisol to cortisone in the kidney. This review considers the significance of the 11β-HSD1 inhibition in the treatment of several features of MetS and provides current data about the development of 11β-HSD1 inhibitors, as new agents for this purpose. MATERIALS/METHODS: Using PubMed, we searched for publications during the last 20years regarding the development of 11β-HSD1 inhibitors. RESULTS: Emerging data from animal and human studies indicate an association of 11β-HSD1 over-expression with obesity and disorders in glucose and lipid metabolism. This has led to the hypothesis that selective inhibition of 11β-HSD1 could be used to treat MetS and diabetes. Indeed, natural products and older agents such as thiazolidinediones and fibrates seem to exert an inhibitory effect on 11β-HSD1, ameliorating the cardiometabolic profile. In view of this concept, novel compounds, such as adamantyltriazoles, arylsulfonamidothiazoles, anilinothiazolones, BVT2733, INCB-13739, MK-0916 and MK-0736, are currently under investigation and the preliminary findings from both experimental and human studies show a favourable effect on glucose and lipid metabolism, weight reduction and adipokine levels. CONCLUSIONS: Many compounds inhibiting 11β-ΗSD1 are under development and preliminary data about their impact on glucose metabolism and obesity-related disorders are encouraging. Copyright © 2013 Elsevier Inc. All rights reserved. PMID: 22652056 [PubMed - indexed for MEDLINE] 223. Acta Naturae. 2011 Oct;3(4):30-7. Mesenchymal stem cells in tissue growth and repair. Kalinina NI(1), Sysoeva VY, Rubina KA, Parfenova YV, Tkachuk VA. Author information: (1)Department of Fundamental Medicine, Lomonosov Moscow State University. It has been established in the recent several decades that stem cells play a crucial role in tissue renewal and regeneration. Mesenchymal stem cells (MSCs) are part of the most important population of adult stem cells. These cells have hereby been identified for the very first time and subsequently isolated from bone marrow stroma. Bone marrow-derived MSCs have been believed to play the role of a source of cells for the renewal and repair of connective tissues, including bone, cartilage and adipose tissues. Cells similar to bone marrow-derived MSCs have now been identified in all postnatal tissues. Data on the distribution and function of MSCsin vivocollected using novel approaches pertaining to the identification of MSCsin situ, to their isolation from tissues, and finally to the determination of their biological properties have enabled successful revision of the role of MSCs in various organs and tissues. This review summarizes our own, as well as others', data concerning the role of MSCs in the regulation processes of tissue repair and regeneration. In our opinion, MSCs provide the connection between the blood-vascular, immune, endocrine, and nervous systems and tissue-specific stem cells in the body. PMCID: PMC3347612 PMID: 22649702 [PubMed] 224. Can J Physiol Pharmacol. 2012 Aug;90(8):1029-59. doi: 10.1139/y2012-053. Epub 2012 May 30. Adipokines and the cardiovascular system: mechanisms mediating health and disease. Northcott JM(1), Yeganeh A, Taylor CG, Zahradka P, Wigle JT. Author information: (1)Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada. This review focuses on the role of adipokines in the maintenance of a healthy cardiovascular system, and the mechanisms by which these factors mediate the development of cardiovascular disease in obesity. Adipocytes are the major cell type comprising the adipose tissue. These cells secrete numerous factors, termed adipokines, into the blood, including adiponectin, leptin, resistin, chemerin, omentin, vaspin, and visfatin. Adipose tissue is a highly vascularised endocrine organ, and different adipose depots have distinct adipokine secretion profiles, which are altered with obesity. The ability of many adipokines to stimulate angiogenesis is crucial for adipose tissue expansion; however, excessive blood vessel growth is deleterious. As well, some adipokines induce inflammation, which promotes cardiovascular disease progression. We discuss how these 7 aforementioned adipokines act upon the various cardiovascular cell types (endothelial progenitor cells, endothelial cells, vascular smooth muscle cells, pericytes, cardiomyocytes, and cardiac fibroblasts), the direct effects of these actions, and their overall impact on the cardiovascular system. These were chosen, as these adipokines are secreted predominantly from adipocytes and have known effects on cardiovascular cells. PMID: 22646022 [PubMed - indexed for MEDLINE] 225. Int Arch Allergy Immunol. 2012;158 Suppl 1:87-91. doi: 10.1159/000337799. Epub 2012 May 15. Obesity and eosinophilic inflammation: does leptin play a role. Takeda M(1), Ueki S, Kato H, Konno Y, Chihara M, Itoga M, Kobayashi Y, Moritoki Y, Ito W, Kayaba H, Chihara J. Author information: (1)Department of Infection, Allergy, Clinical Immunology and Laboratory Medicine, Akita University Graduate School of Medicine, Akita, Japan. It has been pointed out that obesity is a risk factor for, and is involved in the exacerbation of asthma. Mounting evidence about adipose tissue-derived proteins (adipokines) gave rise to the current understanding of obesity as a systemic inflammatory disorder. In this review, we summarized the involvement of leptin, focusing on eosinophil functions. Several studies have indicated that leptin can restrain eosinophil apoptosis, enhance migration, increase adhesion molecules and induce cytokine production. Since leptin also acts on a variety of immune cells related to allergic response, increased leptin in obese individuals potentially explains the mechanism by which obesity leads to an exacerbation of asthma. Further studies targeting adipokines will delineate the association between obesity and eosinophil-associated diseases. Copyright © 2012 S. Karger AG, Basel. PMID: 22627373 [PubMed - indexed for MEDLINE] 226. Curr Osteoporos Rep. 2012 Sep;10(3):208-16. doi: 10.1007/s11914-012-0106-3. Body composition and skeletal health: too heavy? Too thin? Faje A(1), Klibanski A. Author information: (1)BUL 457, Neuroendocrine Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. afaje@partners.org The relationship between body composition and skeletal metabolism has received growing recognition. Low body weight is an established risk factor for fracture. The effect of obesity on skeletal health is less well defined. Extensive studies in patients with anorexia nervosa and obesity have illuminated many of the underlying biologic mechanisms by which body composition modulates bone mass. This review examines the relationship between body composition and bone mass through data from recent research studies throughout the weight spectrum ranging from anorexia nervosa to obesity. PMCID: PMC3583521 PMID: 22644889 [PubMed - indexed for MEDLINE] 227. Cancer Lett. 2012 Nov 28;324(2):142-51. doi: 10.1016/j.canlet.2012.05.019. Epub 2012 May 27. Adipose tissue and breast epithelial cells: a dangerous dynamic duo in breast cancer. Wang YY(1), Lehuédé C, Laurent V, Dirat B, Dauvillier S, Bochet L, Le Gonidec S, Escourrou G, Valet P, Muller C. Author information: (1)Université de Toulouse, UPS, IPBS, F-31077 Toulouse, France. Among the many different cell types surrounding breast cancer cells, the most abundant are those that compose mammary adipose tissue, mainly mature adipocytes and progenitors. New accumulating recent evidences bring the tumor-surrounding adipose tissue into the light as a key component of breast cancer progression. The purpose of this review is to emphasize the role that adipose tissue might play by locally affecting breast cancer cell behavior and subsequent clinical consequences arising from this dialog. Two particular clinical aspects are addressed: obesity that was identified as an independent negative prognostic factor in breast cancer and the oncological safety of autologous fat transfer used in reconstructive surgery for breast cancer patients. This is preceded by the overall description of adipose tissue composition and function with special emphasis on the specificity of adipose depots and the species differences, key experimental aspects that need to be taken in account when cancer is considered. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved. PMID: 22643115 [PubMed - indexed for MEDLINE] 228. Int J Obes (Lond). 2013 May;37(5):640-50. doi: 10.1038/ijo.2012.80. Epub 2012 May 29. Adaptation of human adipose tissue to hypocaloric diet. Rossmeislová L(1), Mališová L, Kračmerová J, Štich V. Author information: (1)Department of Sport Medicine, Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. Hypocaloric diet is a key component of the weight-reducing treatment of obesity and obesity-related disorders. Hypocaloric diets and the associated weight reduction promote improvement of metabolic profile of obese individuals. Among the mechanisms that underlie this beneficial metabolic outcome, the diet-induced modifications of morphological and functional characteristics of human adipose tissue (AT) are believed to have an important role. Prospective studies of hypocaloric weight-reducing dietary intervention demonstrate effects on adipocyte metabolism, namely lipolysis and lipogenesis, and associated changes of the adipocyte size. The endocrine function of AT, which involves cytokine and adipokine production by adipocytes, as well as by cells of stromavascular fraction, is also regulated by dietary intervention. Related inflammatory status of AT is modulated also as a consequence of the changes in recruitment of immune cells, mainly macrophages, in AT. Here, we give an overview of metabolic and endocrine modifications in human AT induced by a variety of hypocaloric diets. PMID: 22641066 [PubMed - indexed for MEDLINE] 229. Nat Rev Endocrinol. 2012 Oct;8(10):579-87. doi: 10.1038/nrendo.2012.75. Epub 2012 May 29. The role of Klotho in energy metabolism. Razzaque MS(1). Author information: (1)Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Research and Education Building, Room 304, 190 Longwood Avenue, Boston, MA 02115, USA. mrazzaque@hms.harvard.edu A disproportionate expansion of white adipose tissue and abnormal recruitment of adipogenic precursor cells can not only lead to obesity but also impair glucose metabolism, which are both common causes of insulin resistance and diabetes mellitus. The development of novel and effective therapeutic strategies to slow the progression of obesity, diabetes mellitus and their associated complications will require improved understanding of adipogenesis and glucose metabolism. Klotho might have a role in adipocyte maturation and systemic glucose metabolism. Klotho increases adipocyte differentiation in vitro, and mice that lack Klotho activity are lean owing to reduced white adipose tissue accumulation; moreover, mice that lack the Kl gene (which encodes Klotho) are resistant to obesity induced by a high-fat diet. Knockout of Kl in leptin-deficient Lep(ob/ob) mice reduces obesity and increases insulin sensitivity, which lowers blood glucose levels. Energy metabolism might also be influenced by Klotho. However, further studies are needed to explore the possibility that Klotho could be a novel therapeutic target to reduce obesity and related complications, and to determine whether and how Klotho might influence the regulation and function of a related protein, β-Klotho, which is also involved in energy metabolism. PMCID: PMC3704949 PMID: 22641000 [PubMed - indexed for MEDLINE] 230. Curr Pharm Des. 2012;18(31):4749-54. The growth hormone secretagogue receptor (Ghs-R). Laviano A(1), Molfino A, Rianda S, Rossi Fanelli F. Author information: (1)Department of Clinical Medicine, Sapienza University, viale dell'Università 37, 00185 Rome, Italy. alessandro.laviano@uniroma1.it The growth hormone secretagogue receptor (GHS-R) is a component of the ghrelin signaling pathway and is involved in mediating the pleiotropic effects of ghrelin. Two isoforms have been identified, but only GHS-R1a binds with acyl ghrelin and transduces its message. However, the inactive variant of GHS-R, GHS-R1b, appears to play a critical role in modulating the activity of GHS-R1a by forming heterodimeric complexes which attenuates trafficking of the active variant to the cell surface. The molecular mechanisms of signal transduction are complex and are specific of the tissues where GHS-R1a is expressed. The potent induction of GH secretion and the stimulation of appetite are the most intensively studied functions of GHS-R1a. However, the tissue distribution of GHS-R1a extends beyond the pituitary and the hypothalamus, and reflects the different biological functions of the ghrelin/GHS-R system. GHS-R1a is also expressed in other brain areas, in the pancreas, adipose tissue, immune cells and cardiovascular system, and modulates learning and memory, glucose and lipid metabolism, inflammatory response and cardiac performance. The pleiotropic effects of the ghrelin/GHS-R system suggest their exploitation to prevent and treat a number of clinical conditions. Among many other syndromes and diseases, cancer cachexia, aging related cognitive decline, obesity and diabetes may significantly benefit from the use of GHS-R1a agonists or antagonists. PMID: 22632856 [PubMed - indexed for MEDLINE] 231. Drug Discov Today. 2013 Jun;18(11-12):567-73. doi: 10.1016/j.drudis.2012.05.008. Epub 2012 May 22. Treatment of obesity as a potential complementary approach to cancer therapy. Sirin O(1), Kolonin MG. Author information: (1)Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX, USA. Obesity has long been recognized as a risk factor for diabetes and cardiovascular disease. Recent epidemiological data also associate obesity with cancer risk and progression. For this reason, a combination treatment of obesity along with treatment of the cancer itself may improve patient survival and well-being. As the molecular pathways linking obesity and cancer become better understood, new potential therapy targets are surfacing. In this article, we summarize the mechanisms proposed to account for the obesity-cancer association and discuss approaches to manipulation of adipose tissue as potential interventions aimed at cancer prevention or supplemental therapy. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22627005 [PubMed - indexed for MEDLINE] 232. Nutr Res Rev. 2012 Jun;25(1):150-61. doi: 10.1017/S0954422412000054. Epub 2012 May 25. Excess body fat in obese and normal-weight subjects. Thomas EL(1), Frost G, Taylor-Robinson SD, Bell JD. Author information: (1)Metabolic and Molecular Imaging Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. louise.thomas@csc.mrc.ac.uk Excess body adiposity, especially abdominal obesity and ectopic fat accumulation, are key risk factors in the development of a number of chronic diseases. The advent of in vivo imaging methodologies that allow direct assessment of total body fat and its distribution have been pivotal in this process. They have helped to identify a number of sub-phenotypes in the general population whose metabolic risk factors are not commensurate with their BMI. At least two such sub-phenotypes have been identified: subjects with normal BMI, but excess intra-abdominal (visceral) fat (with or without increased ectopic fat) and subjects with elevated BMI (> 25 kg/m(2)) but low visceral and ectopic fat. The former sub-phenotype is associated with adverse metabolic profiles, while the latter is associated with a metabolically normal phenotype, despite a high BMI. Here, examples of these phenotypes are presented and the value of carrying out enhanced phenotypical characterisation of subjects in interventional studies discussed. PMID: 22625426 [PubMed - indexed for MEDLINE] 233. Radiology. 2012 Jun;263(3):836-42. doi: 10.1148/radiol.12100683. Brown fat at PET/CT: correlation with patient characteristics. Cronin CG(1), Prakash P, Daniels GH, Boland GW, Kalra MK, Halpern EF, Palmer EL, Blake MA. Author information: (1)Department of Abdominal Imaging and Interventional Radiology, Massachusetts General Hospital, 55 Fruit St, White 270, Boston, MA 02114, USA. cgcronin@partners.org PURPOSES: To assess the prevalence of brown fat in patients with cancer, compare demographic characteristics of those with and those without brown fat, and correlate these characteristics with the mean and maximum standardized uptake values of brown fat. MATERIALS AND METHODS: This case-control study was institutional review board approved and HIPAA compliant. Informed consent was waived. Reports of 12 195 consecutive positron emission tomography/computed tomography examinations performed in 6867 patients between January 2004 and November 2008 were reviewed for documented fluorodeoxyglucose (FDG) uptake in brown fat (n = 298). Control patients (n = 298) without brown fat were chosen and matched for age, sex, and month and year of examination. Age, sex, weight, body mass index, ethnicity, and examination stage (initial vs restaging) were compared between groups. Paired Student t test, χ(2) test, Pearson correlation coefficient, and analysis of variance were used for statistical analysis. RESULTS: Uptake of FDG in brown fat was demonstrated in 298 of 6867 (4.33%) patients. Prevalence of brown fat was significantly higher in female (5.9% [211 of 3587]) than in male patients (2.65% [87 of 3280]; P < .001). Those with brown fat had significantly lower body weight (147.5 lb ± 3.8 vs 168.61 lb ± 5.0; P < .001) and body mass index (24.3 ± 0.54 vs 27.6 ± 0.77; P < .001) than control patients. There was no significant difference in the prevalence of brown fat among ethnic groups. The maximum standardized uptake value of brown fat had a significant inverse correlation with age (r = -0.3, P < .001). CONCLUSION: Patients with brown fat were more likely to be female and thinner than those without brown fat. Younger patients were more likely to have higher maximum standardized uptake values of brown fat. PMID: 22623697 [PubMed - indexed for MEDLINE] 234. Br J Nutr. 2012 Jun;107 Suppl 2:S64-76. doi: 10.1017/S000711451200147X. Dietary methods and biomarkers of omega 3 fatty acids: a systematic review. Serra-Majem L(1), Nissensohn M, Øverby NC, Fekete K. Author information: (1)Department of Clinical Sciences, University of Las Palmas de Gran Canaria, PO Box 550 35080, Las Palmas de Gran Canaria, Spain. lserra@dcc.ulpgc.es The aims of the present study were to review the validity of dietary methods used to measure the usual long chain (LC) omega-3 polyunsaturated fatty acid (n-3 PUFA) intake of a population and to assess the usefulness of different biomarkers of n-3 PUFA in healthy humans. Two systematic literature searches were conducted until May 2011 to update previous systematic reviews. The first literature search aimed to find studies validating the methodology used for measuring the dietary intake of n-3 PUFA. The second search aimed to find human intervention studies in which n-3 PUFA status changed after 2 weeks of n-3 PUFA supplementation. Sixteen studies were identified for inclusion in the first review. Correlation coefficients between fatty acids in subcutaneous fat or blood lipids and dietary intake of n-3 PUFA from different questionnaires were similar. Subcutaneous fat has been reported as the best reference method for some authors, and these studies showed moderate correlation coefficients with no dietary intake method being superior to any other. As for the evaluation of biomarkers of docosahexaenoic acid (DHA, 22 : 6 n-3) and eicosapentaenoic acid (EPA, 20 : 5n-3) status in response to supplementation, the new search reaffirmed and reinforced the evidence supporting that plasma phospholipid DHA, erythrocyte DHA, and platelet DHA were all effective and robust biomarkers of DHA status. Our findings only confirmed earlier studies and did not provide evidence for reaching new conclusions. PMID: 22591904 [PubMed - indexed for MEDLINE] 235. Br J Nutr. 2012 Jun;107 Suppl 2:S53-63. doi: 10.1017/S0007114512001468. Novel methodologies for assessing omega-3 fatty acid status - a systematic review. Klingler M(1), Koletzko B. Author information: (1)University of Munich Medical Center, Dr. von Hauner Children's Hospital, Div. Metabolic and Nutritional Medicine, München, Germany. Over the last few decades n-3 long chain polyunsaturated fatty acid status became of special interest for scientists. Biochemical measures on the n-3 fatty acid status vary depending on body compartment assessed and measures chosen. Plasma phospholipids and red blood cell membrane phospholipids are mainly used as n-3 fatty acid status marker. The conventional analysis of phospholipid fatty acids involves lipid extraction and consecutive chromatographic separation of phospholipids from other lipid fractions, which is time-consuming and costly. In recent years, different investigators have tried to overcome these limitations by using other biological markers or by modifying the analytical procedures used to assess n-3 fatty acid status. The aim of this systematic review was to provide an overview on these novel analytical methods developed for the fatty acid quantification by gas chromatography, highlights the methodological limitations, and discusses advantages or disadvantages of the biological markers used. Seventeen papers were identified that fulfilled the inclusion criteria. New opportunities arise from sensitive and precise high-throughput methodologies for assessment of plasma total lipid and plasma glycerophospholipid fatty acids, as well as cheek cell fatty acid composition. PMID: 22591903 [PubMed - indexed for MEDLINE] 236. Mar Drugs. 2012 Mar;10(3):604-16. doi: 10.3390/md10030604. Epub 2012 Mar 7. Fucoxantin: a treasure from the sea. D'Orazio N(1), Gemello E, Gammone MA, de Girolamo M, Ficoneri C, Riccioni G. Author information: (1)Human and Clinical Nutrition Unit, Department of Biomedical Science, Via Dei Vestini, University G. D'Annunzio, Chieti, 66013, Italy. ndorazio@unich.it The World Health Organization (WHO) estimates that 2.3 billion people will be overweight and 700 million obese in 2015. The reasons for this disastrous trend are attributed to the global tendency toward the reduced magnitude of exercise and physical activity and the increased dietary intake of fats, sugars and calories with reduced amount of vitamins and minerals. To prevent life-style-related diseases, like Metabolic Syndrome (MS), researchers' attention is increasingly focusing on some of the so called "functional foods" which may be useful for their prevention and treatment. One of these functional ingredients is fucoxanthin (FX), a characteristic carotenoid present in edible brown seaweeds, such as Undaria pinnatifida (Wakame), Hijikia fusiformis (Hijiki), Laminaria japonica (Ma-Kombu) and Sargassum fulvellum. The increasing popularity of this molecule is certainly due to its anti-obesity effect, primarily detected by murine studies. These works revealed FX mediated induction of uncoupling protein-1 (UCP-1) in abdominal white adipose tissue (WAT) mitochondria, leading to the oxidation of fatty acids and heat production in WAT. Beyond this important role, in recent studies FX has shown a great antioxidant activity, anti-cancer, anti-diabetic and anti-photoaging properties. The aim of this review is to highlight the main effects of FX on human health. PMCID: PMC3347018 PMID: 22611357 [PubMed - indexed for MEDLINE] 237. Mol Nutr Food Res. 2012 Jul;56(7):1160-72. doi: 10.1002/mnfr.201100685. Epub 2012 May 18. Gene expression of peripheral blood mononuclear cells as a tool in dietary intervention studies: What do we know so far? de Mello VD(1), Kolehmanien M, Schwab U, Pulkkinen L, Uusitupa M. Author information: (1)Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland. Vanessa.Laaksonen@uef.fi Peripheral blood mononuclear cells (PBMCs) generally refer to monocytes and lymphocytes, representing cells of the innate and adaptive immune systems. PBMCs are a promising target tissue in the field of nutrigenomics because they seem to reflect the effects of dietary modifications at the level of gene expression. In this review, we describe and discuss the scientific literature concerning the use of gene expression at the mRNA level measured from PBMCs in dietary interventions studies conducted in humans. A search of literature was undertaken using PubMed (last assessed November 24, 2011) and 20 articles were selected for discussion. Currently, results from these studies showed that PBMCs seem to reflect liver environment and complement adipose tissue findings in transcriptomics. PBMC gene expression after dietary intervention studies can be used for studying the response of certain genes related to fatty acid and cholesterol metabolism, and to explore the response of dietary interventions in relation to inflammation. However, PBMC transcriptomics from dietary intervention studies have not resulted yet in clear confirmation of candidate genes related to disease risk. Use of microarray technology in larger well-designed dietary intervention studies is still needed for exploring PBMC potential in the field of nutrigenomics. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. PMID: 22610960 [PubMed - indexed for MEDLINE] 238. Rev Environ Contam Toxicol. 2012;219:1-114. doi: 10.1007/978-1-4614-3281-4_1. Parameters for pyrethroid insecticide QSAR and PBPK/PD models for human risk assessment. Knaak JB(1), Dary CC, Zhang X, Gerlach RW, Tornero-Velez R, Chang DT, Goldsmith R, Blancato JN. Author information: (1)Department of Pharmacology and Toxicology, SUNY at Buffalo, Buffalo, NY 14214, USA. jbknaak@aol.com In this review we have examined the status of parameters required by pyrethroid QSAR-PBPK/PD models for assessing health risks. In lieu of the chemical,biological, biochemical, and toxicological information developed on the pyrethroids since 1968, the finding of suitable parameters for QSAR and PBPK/PD model development was a monumental task. The most useful information obtained came from rat toxicokinetic studies (i.e., absorption, distribution, and excretion), metabolism studies with 14C-cyclopropane- and alcohol-labeled pyrethroids, the use of known chiral isomers in the metabolism studies and their relation to commercial products. In this review we identify the individual chiralisomers that have been used in published studies and the chiral HPLC columns available for separating them. Chiral HPLC columns are necessary for isomer identification and for developing kinetic values (Vm,, and Kin) for pyrethroid hydroxylation. Early investigators synthesized analytical standards for key pyrethroid metabolites, and these were used to confirm the identity of urinary etabolites, by using TLC. These analytical standards no longer exist, and muste resynthesized if further studies on the kinetics of the metabolism of pyrethroids are to be undertaken.In an attempt to circumvent the availability of analytical standards, several CYP450 studies were carried out using the substrate depletion method. This approach does not provide information on the products formed downstream, and may be of limited use in developing human environmental exposure PBPK/PD models that require extensive urinary metabolite data. Hydrolytic standards (i.e., alcohols and acids) were available to investigators who studied the carboxylesterase-catalyzed hydrolysis of several pyrethroid insecticides. The data generated in these studies are suitable for use in developing human exposure PBPK/PD models.Tissue:blood partition coefficients were developed for the parent pyrethroids and their metabolites, by using a published mechanistic model introduced by Poulin and Thiele (2002a; b) and log DpH 7.4 values. The estimated coefficients, especially those of adipose tissue, were too high and had to be corrected by using a procedure in which the proportion of parent or metabolite residues that are unbound to plasma albumin is considered, as described in the GastroPlus model (Simulations Plus, Inc.,Lancaster, CA). The literature suggested that Km values be adjusted by multiplying Km by the substrate (decimal amount) that is unbound to microsomal or CYPprotein. Mirfazaelian et al. (2006) used flow- and diffusion-limited compartments in their deltamethrin model. The addition of permeability areas (PA) having diffusion limits, such as the fat and slowly perfused compartments, enabled the investigators to bring model predictions in line with in vivo data.There appears to be large differences in the manner and rate of absorption of the pyrethroids from the gastrointestinal tract, implying that GI advanced compartmental transit models (ACAT) need to be included in PBPK models. This is especially true of the absorption of an oral dose of tefluthrin in male rats, in which 3.0-6.9%,41.3-46.3%, and 5.2-15.5% of the dose is eliminated in urine, feces, and bile,respectively (0-48 h after administration). Several percutaneous studies with the pyrethroids strongly support the belief that these insecticides are not readily absorbed, but remain on the surface of the skin until they are washed off. In one articular study (Sidon et al. 1988) the high levels of permethrin absorption through the forehead skin (24-28%) of the monkey was reported over a 7- to 14-days period.Wester et al. (1994) reported an absorption of 1.9% of pyrethrin that had been applied to the forearm of human volunteers over a 7-days period.SAR models capable of predicting the binding of the pyrethroids to plasma and hepatic proteins were developed by Yamazaki and Kanaoka (2004), Saiakhov et al. (2000), Colmenarejo et al. (2001), and Colmenarejo (2003). QikProp(Schrodinger, LLC) was used to obtain Fu values for calculating partition coefficients and for calculating permeation constants (Caco-2, MDCK, and logBBB). ADMET Predictor (Simulations Plus Inc.) provided Vm~,x and Km values for the hydroxylation of drugs/pyrethroids by human liver recombinant cytochrome P450 enzymes making the values available for possible use in PBPK/PD models.The Caco-2 permeability constants and CYP3A4 Vmax and Km values are needed in PBPK/PD models with GI ACAT sub models. Modeling work by Chang et al.(2009) produced rate constants (kcat) for the hydrolysis of pyrethroids by rat serumcarboxylesterases. The skin permeation model of Potts and Guy (1992) was used topredict K, values for the dermal absorption of the 15 pyrethroids.The electrophysiological studies by Narahashi (1971) and others (Breckenridgeet al. 2009; Shafer et al. 2005; Soderlund et al. 2002; Wolansky and Harrill 2008)demonstrated that the mode of action of pyrethroids on nerves is to interfere with the changes in sodium and potassium ion currents. The pyrethroids, being highly lipid soluble, are bound or distributed in lipid bilayers of the nerve cell membrane and exert their action on sodium channel proteins. The rising phase of the action potential is caused by sodium influx (sodium activation), while the falling phase is caused by sodium activation being turned off, and an increase in potassium efflux(potassium activation). The action of allethrin and other pyrethroids is caused by an inhibition or block of the normal currents. An equation by Tatebayashi and Narahashi (1994) that describes the action of pyrethroids on sodium channels was found in the literature. This equation, or some variation of it, may be suitable for use in the PD portion of pyrethroid PBPK models. PMID: 22610175 [PubMed - indexed for MEDLINE] 239. Vascul Pharmacol. 2012 Sep-Oct;57(2-4):91-7. doi: 10.1016/j.vph.2012.05.003. Epub 2012 May 15. From excess adiposity to insulin resistance: the role of free fatty acids. Capurso C(1), Capurso A. Author information: (1)University of Foggia, Department of Internal Medicine and Geriatrics, Foggia, Italy. a.capurso@alice.it With a positive caloric balance, adipocytes undergo excessive hypertrophy, which causes adipocyte dysfunction, as well as adipose tissue endocrine and immune responses. A preferential site of fat accumulation is the abdominal-perivisceral region, due to peculiar factors of the adipose tissue in such sites, namely an excess of glucocorticoid activity, which promotes the accumulation of fat; and the greater metabolic activity and sensitivity to lipolysis, due to increased number and activity of β3-adrenoceptors and, partly, to reduced activity of α2-adrenoceptors. As a consequence, more free fatty acids (FFA) are released into the portal system. Hypertrophic adipocytes begin to secrete low levels of TNF-α, which stimulate preadipocytes and endothelial cells to produce MCP-1, in turn responsible for attracting macrophages to the adipose tissue, thus developing a state of chronic low-grade inflammation which is causally linked to insulin resistance. Excess of circulating FFA, TNF-α and other factors induces insulin resistance. FFA cause insulin resistance by inhibiting insulin signaling through the activation of serin-kinases, i.e. protein kinase C-Θ, and the kinases JNK and IKK, which promote a mechanism of serine phosphorylation of Insulin Receptor Substrates (IRS), leading to interruption of the downstream insulin receptor (IR) signaling. TNF-α, secreted by hypertrophic adipocytes and adipose tissue macrophages, also inhibits IR signaling by a double mechanism of serine-phosphorylation and tyrosine-dephosphorylation of IRS-1, causing inactivation and degradation of IRS-1 and a consequent stop of IR signaling. Such mechanisms explain the transition from excess adiposity to insulin resistance, key to the further development of type 2 diabetes. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22609131 [PubMed - indexed for MEDLINE] 240. Int J Stroke. 2012 Aug;7(6):491-8. doi: 10.1111/j.1747-4949.2012.00824.x. Epub 2012 May 18. Changes in fat mass in stroke survivors: a systematic review. English C(1), Thoirs K, Coates A, Ryan A, Bernhardt J. Author information: (1)International Centre for Allied Health Evidence, School of Health Sciences, University of South Australia, Adelaide, South Australia, Australia. coralie.english@unisa.edu.au BACKGROUND: Stroke survivors have less muscle mass in their paretic limbs compared with nonparetic limbs, which may or may not be accompanied by changes in regional and/or whole body fat mass. AIM: To examine the current evidence regarding differences in regional fat mass between paretic and nonparetic limbs and changes in whole body fat mass over time in stroke survivors. METHODS: A systematic search of relevant databases. Studies measuring whole body or regional fat mass using dual-energy X-ray absorpiometry, computed tomography, or magnetic resonance imaging were included. RESULTS: Eleven trials were identified. Fat mass differences between paretic and nonparetic limbs and change in fat mass over time were not consistent. Meta-analyses were conducted using dual-energy X-ray absorpiometry-derived data from 10 trials (n = 324). There were no differences in fat mass between paretic and nonparetic legs (pooled mean difference 31·4 g, 95% confidence interval -33·9 to 96·6, P = 0·35), and slightly greater fat mass in the paretic arms compared with nonparetic arms (pooled mean difference 84·0 g, 95% confidence interval 30·7 to 137·3, P = 0·002). Whole body fat mass did not increase significantly between one-month and six-months poststroke (pooled mean difference 282·3 g, 95% confidence interval -824·4 to 1389, P = 0·62), but there was an increase between six- and 12 months poststroke (pooled mean difference 1935 g, 95% confidence interval 1031 to 2839, P < 0·001). CONCLUSIONS: There were inconsistent findings regarding changes in fat mass after stroke. Large, well-designed studies are required to further investigate the impact of body composition changes on the health of stroke survivors. © 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization. PMCID: PMC3399979 PMID: 22594664 [PubMed - indexed for MEDLINE] 241. ScientificWorldJournal. 2012;2012:793039. doi: 10.1100/2012/793039. Epub 2012 Apr 19. Review analysis of the association between the prevalence of activated brown adipose tissue and outdoor temperature. Huang YC(1), Hsu CC, Wang PW, Chang YH, Chen TB, Lee BF, Chiu NT. Author information: (1)Department of Nuclear Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. Brown adipose tissue (BAT) is important for regulating body weight. Environmental temperature influences BAT activation. Activated BAT is identifiable using (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT). (18)F-FDG PET/CT scans done between June 2005 and May 2009 in our institution in tropical southern Taiwan and BAT studies from PubMed (2002-2011) were reviewed, and the average outdoor temperatures during the study periods were obtained. A simple linear regression was used to analyze the association between the prevalence of activated BAT (P) and the average outdoor temperature (T). The review analysis for 9 BAT studies (n = 16, 765) showed a significant negative correlation (r = -0.741, P = 0.022) between the prevalence of activated BAT and the average outdoor temperature. The equation of the regression line is P(%) = 6.99 - 0.20 × T (°C). The prevalence of activated BAT decreased by 1% for each 5°C increase in average outdoor temperature. In a neutral ambient temperature, the prevalence of activated BAT is low and especially rare in the tropics. There is a significant linear negative correlation between the prevalence of activated BAT and the average outdoor temperature. PMCID: PMC3349155 PMID: 22593707 [PubMed - indexed for MEDLINE] 242. Pol Merkur Lekarski. 2012 Feb;32(188):143-6. [Resveratrol--phytophenol with wide activity]. [Article in Polish] Fraczek M(1), Szumiło J, Podlodowska J, Burdan F. Author information: (1)Department of Ophthalmology, Medical University of Lublin, Poland. Resveratrol (3,5,4'-trihydroxystilbene) is a natural phytophenol. It is found in many plants, but the highest concentration was detected in different grape-derived products, especially in red wine. The substance is also an active ingredient of some over-the-counter diet supplements. High resveratrol popularity is a consequence of wide biological properties. Numbers of epidemiological and experimental studies have proved a complex chemiopreventive activity of resveratrol against various cardio-vascular disorders and cancer. Furthermore, the compound possesses anti-inflammatory activity and positively regulates glucose level and metabolism of adipose tissue. Diet rich in resveratrol promotes longevity and attenuates neurodegenerative diseases. PMID: 22590921 [PubMed - indexed for MEDLINE] 243. J Infect Dis. 2012 Jun;205 Suppl 3:S383-90. doi: 10.1093/infdis/jis205. Body composition and metabolic changes in HIV-infected patients. Stanley TL(1), Grinspoon SK. Author information: (1)Program in Nutritional Metabolism, Neuroendocrine Unit, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114, USA. As antiretroviral therapy has decreased human immunodeficiency virus (HIV)-associated mortality, cardiometabolic abnormalities have become increasingly apparent in HIV-infected individuals. Many patients treated for HIV infection exhibit body composition changes, including peripheral fat atrophy and visceral lipohypertrophy. In addition, HIV-infected individuals demonstrate a higher prevalence of dyslipidemia, insulin resistance and diabetes, and cardiovascular risk, compared with the general population. Although antiretroviral therapy appears to contribute to some of the cardiometabolic abnormalities in HIV infection, HIV itself, immunologic factors, and lifestyle factors are also important mediators of cardiovascular risk. Treatment strategies for body composition changes and cardiometabolic abnormalities in HIV infection include lifestyle modification, lipid-lowering agents, insulin sensitizers, and treatments to reverse endocrine abnormalities in HIV, including growth hormone-releasing hormone. None of these strategies has comprehensively addressed the abnormalities experienced by this population, however, and further research is needed into combined strategies to improve body composition and ameliorate cardiovascular risk. PMCID: PMC3349298 PMID: 22577212 [PubMed - indexed for MEDLINE] 244. Am J Manag Care. 2012 Jan;18(1 Suppl):S4-10. Examining the mechanisms of glucose regulation. Triplitt CL(1). Author information: (1)Department of Medicine, Division of Diabetes, University of Texas Health Science Center at San Antonio, TX, USA. Curtis.Triplitt@uhs-sa.com The prevalence of diabetes mellitus (DM) increased by 49% between 1990 and 2000, reaching nearly epidemic proportions. In 2010, DM (type 1 or 2) was estimated to affect nearly 30% (10.9 million) of people 65 years and older and 215,000 of those younger than 20 years. Macrovascular and microvascular complications can occur; DM is a major cause of heart disease and stroke, and is the seventh leading cause of death in the United States. Based on 2007 data, the economic impact of DM is considerable, with total costs, direct medical costs, and indirect costs estimated at $174 billion, $116 billion, and $58 billion, respectively. Normal glucose regulation is maintained by an intricate interaction between pancreatic β-cells (insulin/amylin), pancreatic α-cells (glucagon), and associated organs (eg, intestines, liver, skeletal muscle, adipose tissue). Newly elucidated mechanisms include the involvement of the kidneys in glucose regulation, as well as central glucose regulation by the brain. The central defects in type 2 diabetes mellitus (T2DM) are decreased insulin secretion, glucoregulatory hormone deficiency/resistance, and insulin resistance, resulting in abnormal glucose homeostasis. This article provides an extensive review of mechanisms involved in physiologic blood glucose regulation and imbalances in glucose homeostasis. PMID: 22559855 [PubMed - indexed for MEDLINE] 245. Nutr Res Rev. 2012 Jun;25(1):130-41. doi: 10.1017/S0954422412000029. Epub 2012 May 16. Calcium and vitamin D in obesity. Song Q(1), Sergeev IN. Author information: (1)Department of Health and Nutritional Sciences, South Dakota State University, Brookings, SD 57007, USA. New and more effective nutritional measures are urgently needed for the prevention of obesity. The role of Ca and vitamin D in obesity has been recently implicated. Low Ca intake and low vitamin D status have been linked with an increased risk of obesity in epidemiological studies; however, clinical intervention trials designed to test this association have produced controversial results. The suggested anti-obesity mechanisms of Ca and vitamin D include the regulation of adipocyte death (apoptosis), adipogenesis and lipid metabolism. Dietary Ca has been also shown to increase faecal fat excretion. The potential role of Ca and vitamin D in shifting energy balance towards a more negative state is an area of considerable interest. Ultimately, a review of recent research findings does not allow the reaching of a definitive conclusion that increasing Ca intake and rising vitamin D status will influence fat mass and body weight or decrease the risk of obesity and overweight. PMID: 22588363 [PubMed - indexed for MEDLINE] 246. Curr Diabetes Rev. 2012 Sep;8(5):362-81. Glucagon and cyclic AMP: time to turn the page? Rodgers RL(1). Author information: (1)Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA. rrodgers@uri.edu It is well established that glucagon can stimulate adipose lipolysis, myocardial contractility, and hepatic glucose output by activating a GPCR and adenylate cyclase (AC) and increasing cAMP production. It is also widely reported that activation of AC in all three tissues requires pharmacological levels of the hormone, exceeding 0.1 nM. Extensive evidence is presented here supporting the view that cAMP does not mediate metabolic actions of glucagon on adipose, heart, or liver in vivo. Only pharmacological levels stimulate AC, adipose lipolysis, or cardiac contractility. Physiological concentrations of glucagon (below 0.1 nM) duplicate metabolic effects of insulin on the heart by activating a PI3K-dependent signal without stimulating AC. In the liver, glucagon can enhance gluconeogenesis and glucose output - by increasing the expression of PEPCK or inhibiting the activity of PK - at pharmacological concentrations by activating AC coupled to a low-affinity GPCR, but also at physiological concentrations by activating a high affinity receptor without generating cAMP. Plausible AC/cAMP-independent signals mediating the increase in gluconeogenesis include p38 MAPK (PEPCK expression) and IP3/DAG/Ca(2+) (PK activity). None of glucagon's physiological effects can be explained by activation of spare receptors or amplification of the AC/cAMP signal. In a new model proposed here, glucagon antagonizes insulin on the liver but mimics insulin on the heart without activating AC. Confirmation of the model would have broad implications, applicable not only to the general field of metabolic endocrinology but also to the specific role of glucagon in the pathogenesis and treatment of diabetes. PMID: 22587514 [PubMed - indexed for MEDLINE] 247. Eur J Nutr. 2012 Aug;51(5):513-28. doi: 10.1007/s00394-012-0370-0. Epub 2012 May 15. The role of adipokines in connective tissue diseases. Krysiak R(1), Handzlik-Orlik G, Okopien B. Author information: (1)Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752, Katowice, Poland. OBJECTIVE: To discuss the relationship between adipokines and connective tissue diseases, by putting special emphasis on the potential role of leptin, adiponectin, resistin, and other adipose tissue products in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus and on possible application of adipokine-targeted therapy in the treatment of these disorders with emphasis on the recent findings. METHODS: PubMed literature search complemented by review of bibliographies listed in identified articles. RESULTS: Most of the data presented by different research groups showed changed levels of leptin, adiponectin, and resistin and occasionally also other adipokines in rheumatoid arthritis and systemic lupus erythematosus. The relationship between the remaining connective tissue diseases and adipokines is less documented. CONCLUSIONS: Plasma levels of adipokines might tell us too little about their role in connective tissue disorders, whereas adipokine effects on synovial tissues might differ from their known metabolic or cardiovascular effects, which implies that some re-appraisal of adipokines role may need to take place. It still remains obscure whether the observed disturbances in various adipokine systems in subjects with connective tissue diseases contribute to their development or only reflect the presence or activity of inflammatory process, which itself is induced by other pro-inflammatory factors. PMCID: PMC3397228 PMID: 22584415 [PubMed - indexed for MEDLINE] 248. J Mol Neurosci. 2012 Nov;48(3):654-9. Epub 2012 May 13. Role of neurotrophins in the development and function of neural circuits that regulate energy homeostasis. Fargali S(1), Sadahiro M, Jiang C, Frick AL, Indall T, Cogliani V, Welagen J, Lin WJ, Salton SR. Author information: (1)Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA. Members of the neurotrophin family, including nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5, and other neurotrophic growth factors such as ciliary neurotrophic factor and artemin, regulate peripheral and central nervous system development and function. A subset of the neurotrophin-dependent pathways in the hypothalamus, brainstem, and spinal cord, and those that project via the sympathetic nervous system to peripheral metabolic tissues including brown and white adipose tissue, muscle and liver, regulate feeding, energy storage, and energy expenditure. We briefly review the role that neurotrophic growth factors play in energy balance, as regulators of neuronal survival and differentiation, neurogenesis, and circuit formation and function, and as inducers of critical gene products that control energy homeostasis. PMCID: PMC3480664 PMID: 22581449 [PubMed - indexed for MEDLINE] 249. Endocrine. 2012 Dec;42(3):514-20. doi: 10.1007/s12020-012-9692-1. Epub 2012 May 12. Androgens for postmenopausal women's health? Montalcini T(1), Migliaccio V, Ferro Y, Gazzaruso C, Pujia A. Author information: (1)Clinical Nutrition Unit, Department of Medical and Surgical Science, University Magna Graecia, Catanzaro, Italy. tmontalcini@unicz.it Obesity, metabolic syndrome, and diabetes are becoming a leading health concern in the developed Countries, due to their link to cardiovascular disease. These conditions are common in women in the post-menopausal period. Unfortunately, actual lifestyle change strategy fail to prevent cardiovascular events for several reasons, thus specific medications are needed. In addition, it was showed an increased cardiovascular diseases and breast cancer risk in postmenopausal women taking estrogens alone or with progestin, thus the optimal therapy for the prevention of chronic disease in women is still lacking. Androgens exert different actions on organs like adipose tissue, brain, bone, and on cardiovascular system. However, a debate still exists on the positive role of androgens on human health, especially in women. Furthermore, the vascular effects of androgens remain poorly understood and have been controversial for a long time. Sex hormones are important determinants of body composition. Aging is, often, accompanied by a decrease in free testosterone levels, a concomitant reduction in muscle mass and an increase in fat mass. Furthermore, numerous studies showed that total serum testosterone levels were inversely related to the atherosclerosis disease incidence in postmenopausal women. New therapeutic targets may, therefore, arise understanding how androgen could influence the fat distribution, the metabolic disease onset, the vascular reactivity and cardiovascular risk, in both sex. PMID: 22581204 [PubMed - indexed for MEDLINE] 250. Exp Diabetes Res. 2012;2012:635472. doi: 10.1155/2012/635472. Epub 2012 Apr 17. Cardiovascular benefits of GLP-1-based herapies in patients with diabetes mellitus type 2: effects on endothelial and vascular dysfunction beyond glycemic control. Forst T(1), Weber MM, Pfützner A. Author information: (1)Institute for Clinical Research and Development, 55116 Mainz, Germany. thomasf@ikfe.de Type 2 diabetes mellitus (T2DM) is a progressive multisystemic disease accompanied by vascular dysfunction and a tremendous increase in cardiovascular mortality. Numerous adipose-tissue-derived factors and beta cell dysfunction contribute to the increased cardiovascular risk in patients with T2DM. Nowadays, numerous pharmacological interventions are available to lower blood glucose levels in patients with type 2 diabetes. Beside more or less comparable glucose lowering efficacy, some of them have shown limited or probably even unfavorable effects on the cardiovascular system and overall mortality. Recently, incretin-based therapies (GLP-1 receptor agonists and DPP-IV inhibitors) have been introduced in the treatment of T2DM. Beside the effects of GLP-1 on insulin secretion, glucagon secretion, and gastrointestinal motility, recent studies suggested a couple of direct cardiovascular effects of GLP-1-based therapies. The goal of this paper is to provide an overview about the current knowledge of direct GLP-1 effects on endothelial and vascular function and potential consequences on the cardiovascular outcome in patients with T2DM treated with GLP-1 receptor agonists or DPP-IV inhibitors. PMCID: PMC3345223 PMID: 22577369 [PubMed - indexed for MEDLINE] 251. Endocr Rev. 2012 Aug;33(4):526-46. doi: 10.1210/er.2011-1042. Epub 2012 May 10. The mammalian tribbles homolog TRIB3, glucose homeostasis, and cardiovascular diseases. Prudente S(1), Sesti G, Pandolfi A, Andreozzi F, Consoli A, Trischitta V. Author information: (1)Instituto di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, Mendel Laboratory, Italy. Insulin signaling plays a physiological role in traditional insulin target tissues controlling glucose homeostasis as well as in pancreatic β-cells and in the endothelium. Insulin signaling abnormalities may, therefore, be pathogenic for insulin resistance, impaired insulin secretion, endothelial dysfunction, and eventually, type 2 diabetes mellitus (T2DM) and cardiovascular disease. Tribbles homolog 3 (TRIB3) is a 45-kDa pseudokinase binding to and inhibiting Akt, a key mediator of insulin signaling. Akt-mediated effects of TRIB3 in the liver, pancreatic β-cells, and skeletal muscle result in impaired glucose homeostasis. TRIB3 effects are also modulated by its direct interaction with other signaling molecules. In humans, TRIB3 overactivity, due to TRIB3 overexpression or to Q84R genetic polymorphism, with R84 being a gain-of-function variant, may be involved in shaping the risk of insulin resistance, T2DM, and cardiovascular disease. TRIB3 overexpression has been observed in the liver, adipose tissue, skeletal muscle, and pancreatic β-cells of individuals with insulin resistance and/or T2DM. The R84 variant has also proved to be associated with insulin resistance, T2DM, and cardiovascular disease. TRIB3 direct effects on the endothelium might also play a role in increasing the risk of atherosclerosis, as indicated by studies on human endothelial cells carrying the R84 variant that are dysfunctional in terms of Akt activation, NO production, and other proatherogenic changes. In conclusion, studies on TRIB3 have unraveled new molecular mechanisms underlying metabolic and cardiovascular abnormalities. Additional investigations are needed to verify whether such acquired knowledge will be relevant for improving care delivery to patients with metabolic and cardiovascular alterations. PMCID: PMC3410226 PMID: 22577090 [PubMed - indexed for MEDLINE] 252. Dig Dis. 2012;30(1):70-4. doi: 10.1159/000335722. Epub 2012 May 3. The role of visceral fat. Batra A(1), Siegmund B. Author information: (1)Charité-Universitätsmedizin Berlin, Medizinische Klinik I, Berlin, Germany. Until a decade ago, fat tissue had been exclusively considered as an endocrine organ. The emerging functional characterization of adipokines as well as adipocytes and preadipocytes suggested for the first time a close link between the endocrine and the immune system. This is emphasized by the changes of the expression pattern of adipokines when the fat tissue is adjacent to inflamed sites. In addition, adipokines are capable of regulating adaptive and acquired immune responses. Remarkably, adipocytes express functional pattern recognition receptors and can consequently respond to bacterial and viral antigens. This seems to be highly relevant for intestinal inflammation and here in particular transmural inflammation where bacteria or bacterial antigens translocalize into the mesenteric fat tissue. Besides phagocytosis of these antigens, adipocytes as well as preadipocytes can be activated resulting in a release of adipokines and chemokines mediating the infiltration of immune cells thus allowing for an immune response. Recent data suggest that the adipokine milieu of the fat tissue closely regulates the polarization of infiltrating immune cells. This is of increasing interest since the pattern of infiltrating cells allows for a characterization of the underlying disease. Thus, in obesity pro-inflammatory M1 macrophages dominate this site. Remarkably, in colorectal carcinoma the presence of M1 and M2 macrophages represents a prognostic marker for the disease course. In conclusion, the visceral fat tissue represents a complex organ with multifaceted function linking the endocrine and the immune system. Copyright © 2012 S. Karger AG, Basel. PMID: 22572689 [PubMed - indexed for MEDLINE] 253. Nutr Hosp. 2012 Jan-Feb;27(1):138-45. doi: 10.1590/S0212-16112012000100016. [Asthma, obesity and diet]. [Article in Spanish] Barranco P(1), Delgado J, Gallego LT, Bobolea I, Pedrosa M, García de Lorenzo A, Quirce S. Author information: (1)Servicio Alergología, Hospital La Paz, IdiPAZ, Madrid, España. pbarranco.hulp@salud.madrid.org Asthma and obesity have a considerable impact on public health and their prevalence has increased in recent years. Numerous studies have linked both disorders. Most prospective studies show that obesity is a risk factor for asthma and have found a positive correlation between baseline body mass index (BMI) and the subsequent development of asthma, although these results are not conclusive when studying the association between airway hyperresponsiveness with BMI. Furthermore, several studies suggest that whereas weight gain increases the risk of asthma, weight loss improves the course of the illness. Different factors could explain this association. Obesity is capable of reducing pulmonary compliance, lung volumes and the diameter of peripheral respiratory airways as well as affecting the volume of blood in the lungs and the ventilation-perfusion relationship. Furthermore, the increase in the normal functioning of adipose tissue in obese subjects leads to a systemic proinflammatory state, which produces a rise in the serum concentrations of several cytokines, the soluble fractions of their receptors and chemokines. Many of these mediators are synthesized and secreted by cells from adipose tissue and receive the generic name of adipokines, including IL-6, IL-10, eotaxin, TNF-α, TGF- 1, PCR, leptin y adiponectin. Finally, specific regions of the human genome which are related to both asthma and obesity have been identified. Most studies point out that obesity is capable of increasing the prevalence and incidence of asthma, although this effect appears to be modest. The treatment of obese asthmatics must include a weight control program. PMID: 22566313 [PubMed - indexed for MEDLINE] 254. Nutr Hosp. 2012 Jan-Feb;27(1):103-8. doi: 10.1590/S0212-16112012000100011. Influence of the dietary intake of medium chain triglycerides on body composition, energy expenditure and satiety: a systematic review. Rego Costa AC(1), Rosado EL, Soares-Mota M. Author information: (1)Instituto de Nutrição Josué de Castro, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil. Increased prevalence of obesity is associated with the growth of chronic degenerative diseases. One of the main factors associated with this increase is the change in nutritional status of individuals. Medium chain triglycerides (MCT) are rapidly metabolized and less stored in the adipose tissue, being a possible tool for weight control. In order to analyze the influence of consumption of this lipid on satiety, body composition and energy expenditure (EE), a literature review was performed of controlled clinical studies reported in PUBMED and ELSEVIER between the years 2000 and 2010. Fourteen articles were selected presenting short and long-term intervention. Among these, six showed a decrease in body mass of individuals, with consequent loss of weight. Only one showed a positive effect on satiation and four showed an increase in EE. Thus the results are inconclusive and there is a need for further controlled studies with standardized amounts of MCT, so that its use can become an alternative for obesity nutritional treatment. PMID: 22566308 [PubMed - indexed for MEDLINE] 255. Drug Discov Today. 2012 Aug;17(15-16):880-9. doi: 10.1016/j.drudis.2012.04.007. Epub 2012 Apr 25. Physiological, pathological and potential therapeutic roles of adipokines. Falcão-Pires I(1), Castro-Chaves P, Miranda-Silva D, Lourenço AP, Leite-Moreira AF. Author information: (1)Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Universidade do Porto, Porto, Portugal. Formerly regarded purely as passive energy storage, adipose tissue is now recognized as a vital endocrine organ. Adipocytes secrete diverse peptide hormones named adipokines, which act in a autocrine, paracrine or endocrine way to influence several biological functions. Adipokines comprise diverse bioactive substances, including cytokines, growth, and complement factors, which perform essential regulatory functions related to energy balance, satiety and immunity. Presently adipokines have been widely implicated in obesity, diabetes, hypertension and cardiovascular diseases. In this article we aim to present a brief description of the roles and potential therapeutic modulation of adipokines, such as leptin, resistin, adiponectin, apelin, visfatin, FABP-4, tumor necrosis factor-α (TNF-α), interleukin-6 and plasminogen activator inhibitor-1 (PAI-1). Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22561894 [PubMed - indexed for MEDLINE] 256. Cell Metab. 2012 May 2;15(5):635-45. doi: 10.1016/j.cmet.2012.04.001. Inflammation and lipid signaling in the etiology of insulin resistance. Glass CK(1), Olefsky JM. Author information: (1)Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0673, USA. ckg@ucsd.edu Inflammation and lipid signaling are intertwined modulators of homeostasis and immunity. In addition to the extensively studied eicosanoids and inositol phospholipids, emerging studies indicate that many other lipid species act to positively and negatively regulate inflammatory responses. Conversely, inflammatory signaling can significantly alter lipid metabolism in the liver, adipose tissue, skeletal muscle, and macrophage in the context of infection, diabetes, and atherosclerosis. Here, we review recent findings related to this interconnected network from the perspective of immunity and metabolic disease. Copyright © 2012 Elsevier Inc. All rights reserved. PMCID: PMC4156155 PMID: 22560216 [PubMed - indexed for MEDLINE] 257. Gynecol Endocrinol. 2012 Dec;28(12):974-8. doi: 10.3109/09513590.2012.683082. Epub 2012 May 4. Mediators of chronic inflammation in polycystic ovarian syndrome. Deligeoroglou E(1), Vrachnis N, Athanasopoulos N, Iliodromiti Z, Sifakis S, Iliodromiti S, Siristatidis C, Creatsas G. Author information: (1)2nd Department of Obstetrics and Gynecology, Aretaieio Hospital, University of Athens Medical School, Athens, Greece. Polycystic ovarian syndrome (PCOS) is an endocrine disorder affecting 5-10% of reproductive-age women. Hyperandrogenemia, which characterizes the syndrome, stimulates the maturation of adipocytes and favors central obesity. The linking hub between obesity and other metabolic manifestations of the syndrome seems to be chronic low-grade inflammation. We discuss the most reliable current data regarding the role of inflammatory mediators in PCOS, with particular focus on the genetic mechanisms implicated. C-reactive protein levels are 96% higher in PCOS patients than in healthy controls. Patients with the -308A polymorphism of the tumor necrosis factor-α gene have elevated androgens in comparison with carriers of the -308G. Interleukin 18 (IL-18) is elevated in lean patients, with a further rise in the presence of obesity and insulin resistance. Polymorphisms of the IL-1a, IL-1b and IL-6 genes have also been associated with PCOS. Plasminogen activator inhibitor-1 levels are positively associated with the syndrome, and carriers of the 4G allele of the 4G/5G polymorphism are at risk of developing PCOS. Other mediators discussed include adhesion molecules, osteoprotegerin, asymmetric dimethylarginine, homocysteine and advanced glycation end-products. The elucidation of the pathogenetic mechanisms implicated in PCOS and their connection with low-grade inflammation may in the future offer the opportunity for the formulation of novel therapeutic strategies and individualized therapy for these patients. PMID: 22553983 [PubMed - indexed for MEDLINE] 258. Ann N Y Acad Sci. 2012 Apr;1254:57-65. doi: 10.1111/j.1749-6632.2012.06519.x. A bird's-eye view of cell therapy and tissue engineering for cardiac regeneration. Soler-Botija C(1), Bagó JR, Bayes-Genis A. Author information: (1)Heart Failure and Cardiac Regeneration (ICREC) Research Program, Health Research Institute Germans Trias i Pujol (IGTP), Cardiology Service, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. Erratum in Ann N Y Acad Sci. 2012 Oct;1270:121. Complete recovery of ischemic cardiac muscle after myocardial infarction is still an unresolved concern. In recent years, intensive research efforts have focused on mimicking the physical and biological properties of myocardium for cardiac repair. Here we show how heart regeneration approaches have evolved from cell therapy to refined tissue engineering. Despite progressive improvements, the best cell type and delivery strategy are not well established. Our group has identified a new population of cardiac adipose tissue-derived progenitor cells with inherent cardiac and angiogenic potential that is a promising candidate for cell therapy to restore ischemic myocardium. We also describe results from three strategies for cell delivery into a murine model of myocardial infarction: intramyocardial injection, implantation of a fibrin patch loaded with cells, and an engineered bioimplant (a combination of chemically designed scaffold, peptide hydrogel, and cells); dual-labeling noninvasive bioluminescence imaging enables in vivo monitoring of cardiac-specific markers and cell survival. © 2012 New York Academy of Sciences. PMID: 22548570 [PubMed - indexed for MEDLINE] 259. Endocr Rev. 2012 Aug;33(4):547-94. doi: 10.1210/er.2011-1015. Epub 2012 Apr 30. The role of adiponectin in cancer: a review of current evidence. Dalamaga M(1), Diakopoulos KN, Mantzoros CS. Author information: (1)Laboratory of Clinical Biochemistry, Attikon General University Hospital, University of Athens, School of Medicine, 12462 Athens, Greece. Excess body weight is associated not only with an increased risk of type 2 diabetes and cardiovascular disease (CVD) but also with various types of malignancies. Adiponectin, the most abundant protein secreted by adipose tissue, exhibits insulin-sensitizing, antiinflammatory, antiatherogenic, proapoptotic, and antiproliferative properties. Circulating adiponectin levels, which are determined predominantly by genetic factors, diet, physical activity, and abdominal adiposity, are decreased in patients with diabetes, CVD, and several obesity-associated cancers. Also, adiponectin levels are inversely associated with the risk of developing diabetes, CVD, and several malignancies later in life. Many cancer cell lines express adiponectin receptors, and adiponectin in vitro limits cell proliferation and induces apoptosis. Recent in vitro studies demonstrate the antiangiogenic and tumor growth-limiting properties of adiponectin. Studies in both animals and humans have investigated adiponectin and adiponectin receptor regulation and expression in several cancers. Current evidence supports a role of adiponectin as a novel risk factor and potential diagnostic and prognostic biomarker in cancer. In addition, either adiponectin per se or medications that increase adiponectin levels or up-regulate signaling pathways downstream of adiponectin may prove to be useful anticancer agents. This review presents the role of adiponectin in carcinogenesis and cancer progression and examines the pathophysiological mechanisms that underlie the association between adiponectin and malignancy in the context of a dysfunctional adipose tissue in obesity. Understanding of these mechanisms may be important for the development of preventive and therapeutic strategies against obesity-associated malignancies. PMCID: PMC3410224 PMID: 22547160 [PubMed - indexed for MEDLINE] 260. Orphanet J Rare Dis. 2012 Apr 30;7:23. doi: 10.1186/1750-1172-7-23. Review of Dercum's disease and proposal of diagnostic criteria, diagnostic methods, classification and management. Hansson E(1), Svensson H, Brorson H. Author information: (1)Department of Clinical Sciences in Malmö, Lund University, Plastic and Reconstructive Surgery, Skåne University Hospital, Malmö, Sweden. emma.hansson@med.lu.se DEFINITION AND CLINICAL PICTURE: We propose the minimal definition of Dercum's disease to be generalised overweight or obesity in combination with painful adipose tissue. The associated symptoms in Dercum's disease include fatty deposits, easy bruisability, sleep disturbances, impaired memory, depression, difficulty concentrating, anxiety, rapid heartbeat, shortness of breath, diabetes, bloating, constipation, fatigue, weakness and joint aches.CLASSIFICATION: We suggest that Dercum's disease is classified into: I. Generalised diffuse form A form with diffusely widespread painful adipose tissue without clear lipomas, II. Generalised nodular form - a form with general pain in adipose tissue and intense pain in and around multiple lipomas, and III. Localised nodular form - a form with pain in and around multiple lipomas IV. Juxtaarticular form - a form with solitary deposits of excess fat for example at the medial aspect of the knee. EPIDEMIOLOGY: Dercum's disease most commonly appears between the ages of 35 and 50 years and is five to thirty times more common in women than in men. The prevalence of Dercum's disease has not yet been exactly established. AETIOLOGY: Proposed, but unconfirmed aetiologies include: nervous system dysfunction, mechanical pressure on nerves, adipose tissue dysfunction and trauma. DIAGNOSIS AND DIAGNOSTIC METHODS: Diagnosis is based on clinical criteria and should be made by systematic physical examination and thorough exclusion of differential diagnoses. Advisably, the diagnosis should be made by a physician with a broad experience of patients with painful conditions and knowledge of family medicine, internal medicine or pain management. The diagnosis should only be made when the differential diagnoses have been excluded. DIFFERENTIAL DIAGNOSIS: Differential diagnoses include: fibromyalgia, lipoedema, panniculitis, endocrine disorders, primary psychiatric disorders, multiple symmetric lipomatosis, familial multiple lipomatosis, and adipose tissue tumours. GENETIC COUNSELLING: The majority of the cases of Dercum's disease occur sporadically. A to G mutation at position A8344 of mitochondrial DNA cannot be detected in patients with Dercum's disease. HLA (human leukocyte antigen) typing has not revealed any correlation between typical antigens and the presence of the condition. MANAGEMENT AND TREATMENT: The following treatments have lead to some pain reduction in patients with Dercum's disease: Liposuction, analgesics, lidocaine, methotrexate and infliximab, interferon α-2b, corticosteroids, calcium-channel modulators and rapid cycling hypobaric pressure. As none of the treatments have led to long lasting complete pain reduction and revolutionary results, we propose that Dercum's disease should be treated in multidisciplinary teams specialised in chronic pain. PROGNOSIS: The pain in Dercum's disease seems to be relatively constant over time. PMCID: PMC3444313 PMID: 22546240 [PubMed - indexed for MEDLINE] 261. Invest Radiol. 2012 Jun;47(6):368-75. doi: 10.1097/RLI.0b013e31824baff3. Hepatic fat quantification: a prospective comparison of magnetic resonance spectroscopy and analysis methods for chemical-shift gradient echo magnetic resonance imaging with histologic assessment as the reference standard. Kang BK(1), Yu ES, Lee SS, Lee Y, Kim N, Sirlin CB, Cho EY, Yeom SK, Byun JH, Park SH, Lee MG. Author information: (1)Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea. OBJECTIVE: The aims of this study were to assess the confounding effects of hepatic iron deposition, inflammation, and fibrosis on hepatic steatosis (HS) evaluation by magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) and to assess the accuracies of MRI and MRS for HS evaluation, using histology as the reference standard. MATERIALS AND METHODS: In this institutional review board-approved prospective study, 56 patients gave informed consents and underwent chemical-shift MRI and MRS of the liver on a 1.5-T magnetic resonance scanner. To estimate MRI fat fraction (FF), 4 analysis methods were used (dual-echo, triple-echo, multiecho, and multi-interference), and MRS FF was calculated with T2 correction. Degrees of HS, iron deposition, inflammation, and fibrosis were analyzed in liver resection (n = 37) and biopsy (n = 19) specimens. The confounding effects of histology on fat quantification were assessed by multiple linear regression analysis. Using the histologic degree of HS as the reference standard, the accuracies of each method in estimating HS and diagnosing an HS of 5% or greater were determined by linear regression and receiver operating characteristic analyses. RESULTS: Iron deposition significantly confounded estimations of FF by the dual-echo (P < 0.001) and triple-echo (P = 0.033) methods, whereas no histologic feature confounded the multiecho and multi-interference methods or MRS. The MRS (r = 0.95) showed the strongest correlation with histologic degree of HS, followed by the multiecho (r = 0.92), multi-interference (r = 0.91), triple-echo (r = 0.90), and dual-echo (r = 0.85) methods. For diagnosing HS, the areas under the curve tended to be higher for MRS (0.96) and the multiecho (0.95), multi-interference (0.95), and triple-echo (0.95) methods than for the dual-echo method (0.88) (P ≥ 0.13). CONCLUSION: The multiecho and multi-interference MRI methods and MRS can accurately quantify hepatic fat, with coexisting histologic abnormalities having no confounding effects. PMID: 22543969 [PubMed - indexed for MEDLINE] 262. J Alzheimers Dis. 2012;30 Suppl 2:S97-112. doi: 10.3233/JAD-2012-120487. Adiposity and cognitive decline: underlying mechanisms. Gustafson DR(1). Author information: (1)Section for Psychiatry and Neurochemistry, Neuropsychiatric Epidemiology Unit at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. deborah.gustafson@neuro.gu.se Level of adiposity is linked to manifest dementia and Alzheimer's disease in epidemiological studies. Overweight and obesity in mid- and late-life may increase risk for dementia, whereas decline in body weight or body mass index and underweight in years preceding and at the time of a dementia diagnosis may also relate to dementia. The role of adiposity during the period of cognitive decline is, as yet, not understood; however, some hypotheses relating adipose tissue to brain can be drawn. This review focuses on potential, varied mechanisms whereby adipose tissue may influence or interact with the brain and/or dementia risk during the dynamic period of life characterized by both body weight and cognitive decline. These mechanisms relate to: a) adipose tissue location and cell types, b) body composition, c) endocrine adipose, and d) the interplay among adipose, brain structure and function, and genes. This review will illustrate that adipose tissue is a quintessential, multifunctional tissue of the human body. PMID: 22543853 [PubMed - indexed for MEDLINE] 263. Meat Sci. 2012 Nov;92(3):297-301. doi: 10.1016/j.meatsci.2012.04.008. Epub 2012 Apr 11. Cultured meat from stem cells: challenges and prospects. Post MJ(1). Author information: (1)Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. m.post@maastrichtuniversity.nl As one of the alternatives for livestock meat production, in vitro culturing of meat is currently studied. The generation of bio-artificial muscles from satellite cells has been ongoing for about 15 years, but has never been used for generation of meat, while it already is a great source of animal protein. In order to serve as a credible alternative to livestock meat, lab or factory grown meat should be efficiently produced and should mimic meat in all of its physical sensations, such as visual appearance, smell, texture and of course, taste. This is a formidable challenge even though all the technologies to create skeletal muscle and fat tissue have been developed and tested. The efficient culture of meat will primarily depend on culture conditions such as the source of medium and its composition. Protein synthesis by cultured skeletal muscle cells should further be maximized by finding the optimal combination of biochemical and physical conditions for the cells. Many of these variables are known, but their interactions are numerous and need to be mapped. This involves a systematic, if not systems, approach. Given the urgency of the problems that the meat industry is facing, this endeavor is worth undertaking. As an additional benefit, culturing meat may provide opportunities for production of novel and healthier products. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22543115 [PubMed - indexed for MEDLINE] 264. Free Radic Biol Med. 2012 May 15;52(10):2108-19. doi: 10.1016/j.freeradbiomed.2012.03.003. Epub 2012 Apr 18. Regulation of adipose tissue energy availability through blood flow control in the metabolic syndrome. Alemany M(1). Author information: (1)Department of Nutrition and Food Science, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain. malemany@ub.edu Maintenance of blood flow rate is a critical factor for tissue oxygen and substrate supply. The potentially large mass of adipose tissue deeply influences the body distribution of blood flow. This is due to increased peripheral resistance in obesity and the role of this tissue as the ultimate destination of unused excess of dietary energy. However, adipose tissue cannot grow indefinitely, and the tissue must defend itself against the avalanche of nutrients provoking inordinate growth and inflammation. In the obese, large adipose tissue masses show lower blood flow, limiting the access of excess circulating substrates. Blood flow restriction is achieved by vasoconstriction, despite increased production of nitric oxide, the vasodilatation effects of which are overridden by catecholamines (and probably also by angiotensin II and endothelin). Decreased blood flow reduces the availability of oxygen, provoking massive glycolysis (hyperglycemic conditions), which results in the production of lactate, exported to the liver for processing. However, this produces local acidosis, which elicits the rapid dissociation of oxyhemoglobin, freeing bursts of oxygen in localized zones of the tissue. The excess of oxygen (and of nitric oxide) induces the production of reactive oxygen species, which deeply affect the endothelial, blood, and adipose cells, inducing oxidative and nitrosative damage and eliciting an increased immune response, which translates into inflammation. The result of the defense mechanism for adipose tissue, localized vasoconstriction, may thus help develop a more generalized pathologic response within the metabolic syndrome parameters, extending its effects to the whole body. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22542444 [PubMed - indexed for MEDLINE] 265. Eur J Immunol. 2012 May;42(5):1073-9. doi: 10.1002/eji.201142305. Molecular control over thymic involution: from cytokines and microRNA to aging and adipose tissue. Dooley J(1), Liston A. Author information: (1)Autoimmune Genetics Laboratory, VIB and University of Leuven, Belgium. james.dooley@vib-kuleuven.be The thymus is the primary organ for T-cell differentiation and maturation. Unlike other major organs, the thymus is highly dynamic, capable of undergoing multiple rounds of almost complete atrophy followed by rapid restoration. The process of thymic atrophy, or involution, results in decreased thymopoiesis and emigration of naïve T cells to the periphery. Multiple processes can trigger transient thymic involution, including bacterial and viral infection(s), aging, pregnancy and stress. Intense investigations into the mechanisms that underlie thymic involution have revealed diverse cellular and molecular mediators, with elaborate control mechanisms. This review outlines the disparate pathways through which involution can be mediated, from the transient infection-mediated pathway, tightly controlled by microRNA, to the chronic changes that occur through aging. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. PMID: 22539280 [PubMed - indexed for MEDLINE] 266. J Physiol Biochem. 2013 Mar;69(1):155-63. doi: 10.1007/s13105-012-0170-2. Epub 2012 Apr 26. Impact of leucine on energy balance. McAllan L(1), Cotter PD, Roche HM, Korpela R, Nilaweera KN. Author information: (1)Teagasc Food Research Centre, Moorepark, Fermoy, Cork, Ireland. Body weight is determined by the balance between energy intake and energy expenditure. When energy intake exceeds energy expenditure, the surplus energy is stored as fat in the adipose tissue, which causes its expansion and may even lead to the development of obesity. Thus, there is a growing interest to develop dietary interventions that could reduce the current obesity epidemic. In this regard, data from a number of in vivo and in vitro studies suggest that the branched-chain amino acid leucine influences energy balance. However, this has not been consistently reported. Here, we review the literature related to the effects of leucine on energy intake, energy expenditure and lipid metabolism as well as its effects on the cellular activity in the brain (hypothalamus) and in peripheral tissues (gastro-intestinal tract, adipose tissue, liver and muscle) regulating the above physiological processes. Moreover, we discuss how obesity may influence the actions of this amino acid. PMID: 22535285 [PubMed - indexed for MEDLINE] 267. Biochimie. 2012 Oct;94(10):2089-96. doi: 10.1016/j.biochi.2012.04.015. Epub 2012 Apr 19. Understanding leptin-dependent regulation of skeletal homeostasis. Motyl KJ(1), Rosen CJ. Author information: (1)Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME, USA. motylk@mmc.org Despite growing evidence for adipose tissue regulation of bone mass, the role of the adipokine leptin in bone remodeling remains controversial. The majority of in vitro studies suggest leptin enhances osteoblastic proliferation and differentiation while inhibiting adipogenic differentiation from marrow stromal cells. Alternatively, some evidence demonstrates either no effect or a pro-apoptotic action of leptin on stromal cells. Similarly, in vivo work has demonstrated both positive and negative effects of leptin on bone mass. Most of the literature supports the idea that leptin suppresses bone mass by acting in the brainstem to reduce serotonin-dependent sympathetic signaling from the ventromedial hypothalamus to bone. However, other studies have found partly or entirely contrasting actions of leptin. Recently one study found a significant effect of surgery alone with intracerebroventricular administration of leptin, a technique crucial for understanding centrally-mediated leptin regulation of bone. Thus, two mainstream hypotheses for the role of leptin on bone emerge: 1) direct regulation through increased osteoblast proliferation and differentiation and 2) indirect suppression of bone formation through a hypothalamic relay. At the present time, it remains unclear whether these effects are relevant in only extreme circumstances (i.e. models with complete deficiency) or play an important homeostatic role in the regulation of peak bone acquisition and skeletal remodeling. Ultimately, determining the actions of leptin on the skeleton will be critical for understanding how the obesity epidemic may be impacting the prevalence of osteoporosis. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMCID: PMC3512082 PMID: 22534195 [PubMed - indexed for MEDLINE] 268. J Pediatr. 2012 Oct;161(4):735-41.e1. doi: 10.1016/j.jpeds.2012.03.023. Epub 2012 Apr 24. Preterm infants of lower gestational age at birth have greater waist circumference-length ratio and ponderal index at term age than preterm infants of higher gestational ages. Stokes TA(1), Holston A, Olsen C, Choi Y, Curtis J, Higginson J, Enright L, Adimora C, Hunt CE. Author information: (1)Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, MD 20814-4799, USA. Theophil.Stokes@usuhs.edu OBJECTIVE: To assess anthropometric changes from birth to hospital discharge in infants born preterm and compare with a reference birth cohort of infants born full-term. STUDY DESIGN: Retrospective chart review was conducted of 501 preterm and 1423 full-term infants. We evaluated birth and hospital discharge weight, length, and waist circumference (WC). WC/length ratio (WLR), ponderal index, and body mass index (BMI) were calculated. Preterm infants were categorized into quartiles (Q1-4) based on birth weight (BW). RESULTS: At birth mean length, WC, WLR, BMI, and ponderal index were all significantly less for preterm infants in the lowest BW quartile (Q1) than preterm infants in higher BW quartiles or full-term infants. Although their weight, length, and BMI remained significantly less at discharge, preterm infants in Q1 had a disproportionate increase in WLR and ponderal index such that at discharge their WLR and ponderal index were greater than infants in Q2-3 and comparable with infants in Q4 and full-term infants. Discharge WLR and ponderal index in Q1 were significantly higher with decreasing postmenstrual age at birth. CONCLUSIONS: Preterm infants of a lower birth postmenstrual age have disproportionate increases in WLR and ponderal index that are suggestive of increased visceral and total adiposity. Published by Mosby, Inc. PMID: 22534153 [PubMed - indexed for MEDLINE] 269. Biochem J. 2012 May 15;444(1):1-10. doi: 10.1042/BJ20120030. SIRT3, a pivotal actor in mitochondrial functions: metabolism, cell death and aging. Giralt A(1), Villarroya F. Author information: (1)Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, University of Barcelona, Spain. SIRT3 is a member of the sirtuin family of protein deacetylases that is preferentially localized to mitochondria. Prominent among the proteins targeted by SIRT3 are enzymes involved in energy metabolism processes, including the respiratory chain, tricarboxylic acid cycle, fatty acid β-oxidation and ketogenesis. Through these actions, SIRT3 controls the flow of mitochondrial oxidative pathways and, consequently, the rate of production of reactive oxygen species. In addition, SIRT3-mediated deacetylation activates enzymes responsible for quenching reactive oxygen species, and thereby exerts a profound protective action against oxidative stress-dependent pathologies, such as cardiac hypertrophy and neural degeneration. SIRT3 also plays a role in multiple additional metabolic processes, from acetate metabolism to brown adipose tissue thermogenesis, often by controlling mitochondrial pathways through the deacetylation of target enzymes. In general, SIRT3 activity and subsequent control of enzymes involved in energy metabolism is consistent with an overall role of protecting against age-related diseases. In fact, experimental and genetic evidence has linked SIRT3 activity with increased lifespan. In the coming years, the identification of drugs and nutrients capable of increasing SIRT3 expression or modulating SIRT3 activity can be expected to provide promising strategies for ameliorating the metabolic syndrome and other oxidative stress-related diseases that appear preferentially with aging, such as cancer, cardiac dysfunction and neural degeneration. PMID: 22533670 [PubMed - indexed for MEDLINE] 270. Int J Obes (Lond). 2013 Mar;37(3):325-32. doi: 10.1038/ijo.2012.59. Epub 2012 Apr 24. MicroRNAs in adipose tissue: their role in adipogenesis and obesity. Hilton C(1), Neville MJ, Karpe F. Author information: (1)OXLIP group, OCDEM, University of Oxford, Churchill Hospital, Oxford, UK. catriona.hilton@ocdem.ox.ac.uk MicroRNAs (miRNAs) are endogenous small RNAs that posttranscriptionally regulate gene expression and that have been shown to have important roles in numerous disease processes. There is growing evidence for an important role of miRNAs in regulating the pathways in adipose tissue that control a range of processes including adipogenesis, insulin resistance and inflammation. Several high-throughput studies have identified differentially expressed miRNAs in adipose tissue pathology and during adipogenesis and a number of these have now been characterised functionally in terms of their actions and targets. This review will summarise the current literature on miRNAs in adipose tissue, as well as discussing the methodologies used in this area of research and the potential application of miRNAs as biomarkers and as therapeutic targets. PMID: 22531086 [PubMed - indexed for MEDLINE] 271. Stem Cells Dev. 2012 Sep 1;21(13):2355-63. doi: 10.1089/scd.2012.0060. Epub 2012 Jun 26. Mesenchymal stem cell-based tumor-targeted gene therapy in gastrointestinal cancer. Bao Q(1), Zhao Y, Niess H, Conrad C, Schwarz B, Jauch KW, Huss R, Nelson PJ, Bruns CJ. Author information: (1)Department of Surgery, University of Munich, Campus Großhadern, Munich, Germany. Mesenchymal stem (or stromal) cells (MSCs) are nonhematopoietic progenitor cells that can be obtained from bone marrow aspirates or adipose tissue, expanded and genetically modified in vitro, and then used for cancer therapeutic strategies in vivo. Here, we review available data regarding the application of MSC-based tumor-targeted therapy in gastrointestinal cancer, provide an overview of the general history of MSC-based gene therapy in cancer research, and discuss potential problems associated with the utility of MSC-based therapy such as biosafety, immunoprivilege, transfection methods, and distribution in the host. PMCID: PMC3424981 PMID: 22530882 [PubMed - indexed for MEDLINE] 272. Molecules. 2012 Apr 23;17(4):4755-69. doi: 10.3390/molecules17044755. Dynamic action of carotenoids in cardioprotection and maintenance of cardiac health. Agarwal M(1), Parameswari RP, Vasanthi HR, Das DK. Author information: (1)Department of Biotechnology, School of Life Sciences, Pondicherry University, Puducherry-605014, India. mhsh.agarwal@gmail.com Retraction in McPhee D. Molecules. 2014;19(3):3850. Oxidative stress has been considered universally and undeniably implicated in the pathogenesis of all major diseases, including those of the cardiovascular system. Oxidative stress activate transcriptional messengers, such as nuclear factor-κB, tangibly contributing to endothelial dysfunction, the initiation and progression of atherosclerosis, irreversible damage after ischemic reperfusion, and even arrhythmia, such as atrial fibrillation. Evidence is rapidly accumulating to support the role of reactive oxygen species (ROS) and reactive nitrogen species (RNS) as intracellular signaling molecules. Despite this connection between oxidative stress and cardiovascular disease (CVD), there are currently no recognized therapeutic interventions to address this important unmet need. Antioxidants that provide a broad, "upstream" approach via ROS/RNS quenching or free radical chain breaking seem an appropriate therapeutic option based on epidemiologic, dietary, and in vivo animal model data. Short-term dietary intervention trials suggest that diets rich in fruit and vegetable intake lead to improvements in coronary risk factors and reduce cardiovascular mortality. Carotenoids are such abundant, plant-derived, fat-soluble pigments that functions as antioxidants. They are stored in the liver or adipose tissue, and are lipid soluble by becoming incorporated into plasma lipoprotein particles during transport. For these reasons, carotenoids may represent one plausible mechanism by which fruits and vegetables reduce the risk of chronic diseases as cardiovascular disease (CVD). This review paper outlines the role of carotenoids in maintaining cardiac health and cardioprotection mediated by several mechanisms including redox signaling. PMID: 22525440 [PubMed - indexed for MEDLINE] 273. Presse Med. 2013 Jan;42(1):13-8. doi: 10.1016/j.lpm.2012.02.041. Epub 2012 Apr 21. [Adipokines: some players of inflammation in inflammatory rheumatic diseases and systemic autoimmune diseases?]. [Article in French] Toussirot E(1). Author information: (1)CHU hôpital Saint-Jacques, pôle recherche, centre investigation clinique - biothérapie 506, 25000 Besançon, France. etoussirot@chu-besancon.fr Adipocytokines or adipokines are a group of molecules (such as leptin, adiponectin, visfatine and resistine) mainly produced by adipose tissue. The adipokines are involved in different physiological processes but their participation to inflammatory and immune responses have been recently described. Their contribution to inflammatory diseases such as chronic inflammatory joint diseases and autoimmune diseases, and osteoarthritis as well, is currently growing, suggesting new pathophysiological schema and treatments. Leptin, visfatin and resistin have pro-inflammatory properties while adiponectin is anti-inflammatory, especially for the vascular wall. Adiponectin is considered to be protective for cardiovascular risk. The influence of the treatments given in inflammatory rheumatic diseases and autoimmune diseases (traditional drugs and biologics) on adipokines requires to be studied. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMID: 22521967 [PubMed - indexed for MEDLINE] 274. Clin Res Hepatol Gastroenterol. 2012 Oct;36(5):412-9. doi: 10.1016/j.clinre.2012.03.008. Epub 2012 Apr 18. Perspective: TGR5 (Gpbar-1) in liver physiology and disease. Keitel V(1), Häussinger D. Author information: (1)Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany. verena.keitel@med.uni-duesseldorf.de Bile acids are signaling molecules with diverse endocrine functions. Bile acid effects are mediated through the nuclear receptor farnesoid X receptor (FXR), the G-protein coupled receptor TGR5 (Gpbar-1) and various other bile acid sensing molecules. TGR5 is almost ubiquitously expressed and has been detected in different non-parenchymal cells of human and rodent liver. Here, TGR5 has anti-inflammatory, anti-apoptotic and choleretic functions. Mice with targeted deletion of TGR5 are protected from the development of cholesterol gallstones. Administration of specific TGR5 agonists lowers serum and liver triglyceride levels thereby reducing liver steatosis. Furthermore, activation of TGR5 promotes intestinal glucagon-like peptide-1 (GLP-1) release, thereby modulating glucose homeostasis and energy expenditure in brown adipose tissue and skeletal muscle. Additionally, TGR5 exerts anti-inflammatory actions resulting in decreased liver injury in animal models of sepsis. These beneficial effects make TGR5 an attractive therapeutic target for metabolic diseases, such as diabetes, obesity, atherosclerosis and steatohepatitis. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMID: 22521118 [PubMed - indexed for MEDLINE] 275. Arterioscler Thromb Vasc Biol. 2012 May;32(5):1094-8. doi: 10.1161/ATVBAHA.111.241489. CIDE proteins and lipid metabolism. Xu L(1), Zhou L, Li P. Author information: (1)Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China. Lipid homeostasis is maintained through the coordination of lipid metabolism in various tissues, including adipose tissue and the liver. The disruption of lipid homeostasis often results in the development of metabolic disorders such as obesity, diabetes mellitus, liver steatosis, and cardiovascular diseases. Cell death-inducing DNA fragmentation factor 45-like effector family proteins, including Cidea, Cideb, and Fsp27 (Cidec), are emerging as important regulators of various lipid metabolic pathways and play pivotal roles in the development of metabolic disorders. This review summarizes the latest cell death-inducing DNA fragmentation factor 45-like effector protein discoveries related to the control of lipid metabolism, with emphasis on the role of these proteins in lipid droplet growth in adipocytes and in the regulation of very low-density lipoprotein lipidation and maturation in hepatocytes. PMID: 22517368 [PubMed - indexed for MEDLINE] 276. Curr Mol Med. 2012 Jun;12(5):574-91. Immunosuppressive properties of mesenchymal stem cells: advances and applications. De Miguel MP(1), Fuentes-Julián S, Blázquez-Martínez A, Pascual CY, Aller MA, Arias J, Arnalich-Montiel F. Author information: (1)Cell Engineering Laboratory, IdiPaz, La Paz Hospital Research Institute, Madrid, Spain. mariapdemiguel@gmail.com Mesenchymal stem cells (MSCs) have been isolated from a variety of tissues, such as bone marrow, skeletal muscle, dental pulp, bone, umbilical cord and adipose tissue. MSCs are used in regenerative medicine mainly based on their capacity to differentiate into specific cell types and also as bioreactors of soluble factors that will promote tissue regeneration from the damaged tissue cellular progenitors. In addition to these regenerative properties, MSCs hold an immunoregulatory capacity, and elicit immunosuppressive effects in a number of situations. Not only are they immunoprivileged cells, due to the low expression of class II Major Histocompatibilty Complex (MHC-II) and costimulatory molecules in their cell surface, but they also interfere with different pathways of the immune response by means of direct cell-to-cell interactions and soluble factor secretion. In vitro, MSCs inhibit cell proliferation of T cells, B-cells, natural killer cells (NK) and dendritic cells (DC), producing what is known as division arrest anergy. Moreover, MSCs can stop a variety of immune cell functions: cytokine secretion and cytotoxicity of T and NK cells; B cell maturation and antibody secretion; DC maturation and activation; as well as antigen presentation. It is thought that MSCs need to be activated to exert their immunomodulation skills. In this scenario, an inflammatory environment seems to be necessary to promote their effect and some inflammation-related molecules such as tumor necrosis factor-α and interferon-γ might be implicated. It has been observed that MSCs recruit T-regulatory lymphocytes (Tregs) to both lymphoid organs and graft. There is great controversy concerning the mechanisms and molecules involved in the immunosuppressive effect of MSCs. Prostaglandin E2, transforming growth factor-β, interleukins- 6 and 10, human leukocyte antigen-G5, matrix metalloproteinases, indoleamine-2,3-dioxygenase and nitric oxide are all candidates under investigation. In vivo studies have shown many discrepancies regarding the immunomodulatory properties of MSCs. These studies have been designed to test the efficacy of MSC therapy in two different immune settings: the prevention or treatment of allograft rejection episodes, and the ability to suppress abnormal immune response in autoimmune and inflammatory diseases. Preclinical studies have been conducted in rodents, rabbits and baboon monkeys among others for bone marrow, skin, heart, and corneal transplantation, graft versus host disease, hepatic and renal failure, lung injury, multiple sclerosis, rheumatoid arthritis, diabetes and lupus diseases. Preliminary results from some of these studies have led to human clinical trials that are currently being carried out. These include treatment of autoimmune diseases such as Crohn's disease, ulcerative colitis, multiple sclerosis and type 1 diabetes mellitus; prevention of allograft rejection and enhancement of the survival of bone marrow and kidney grafts; and treatment of resistant graft versus host disease. We will try to shed light on all these studies, and analyze why the results are so contradictory. PMID: 22515979 [PubMed - indexed for MEDLINE] 277. Nagoya J Med Sci. 2012 Feb;74(1-2):19-30. Adipocytokines and obesity-linked disorders. Ouchi N(1), Ohashi K, Shibata R, Murohara T. Author information: (1)Department of Molecular Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya, 466-8550, Japan. nouchi@med.nagoya-u.ac.jp Obesity is closely associated with an increased risk for metabolic and cardiovascular diseases. Adipose tissue produces a number of secretory bioactive substances, also known as adipocytokines or adipokines, which directly affect adjacent or distant organs. Most adipocytokines are pro-inflammatory, thereby promoting the obesity-linked disorders. In contrast, there are a small number of adipocytokines that exhibit antiinflammatory properties. It is now recognized that dysregulated production or secretion of adipocytokines caused by adipocyte dysfunction leads to the development of obesity-linked complications. In this review, we focus on the functional role of several adipocytokines in metabolic and cardiovascular diseases. PMID: 22515108 [PubMed - indexed for MEDLINE] 278. Biochim Biophys Acta. 2012 Jul;1822(7):1090-5. doi: 10.1016/j.bbadis.2012.03.014. Epub 2012 Apr 4. Controlling a master switch of adipocyte development and insulin sensitivity: covalent modifications of PPARγ. Floyd ZE(1), Stephens JM. Author information: (1)Ubiquitin Biology Laboratory, Pennington Biomedical Research Resaerch Center, Louisiana Sate University Systems, Baton Rouge, LA 70808, USA. Adipocytes are highly specialized cells that play a central role in lipid homeostasis and the maintenance of energy balance. Obesity, an excessive accumulation of adipose tissue, is a major risk factor for the development of Type 2 diabetes mellitus (T2DM), cardiovascular disease, and hypertension. A variety of studies suggest that obesity and T2DM can be linked to a breakdown in the regulatory mechanisms that control the expression and transcriptional activity of PPARγ. PPARγ is a nuclear hormone receptor that functions as a master switch in controlling adipocyte differentiation and development. Also important in controlling glucose homeostasis and insulin sensitivity, PPARγ is a ligand-dependent transcription factor that is the functional receptor for the anti-diabetic thiazolidinediones (TZDs). In the last fifteen years, a variety of covalent modifications of PPARγ activity have been identified and studied. These covalent modifications include phosphorylation, ubiquitylation, O-GlcNAcylation and SUMOylation. Covalent modifications of PPARγ represent key regulatory mechanisms that control both PPARγ protein stability and transcriptional activity. A variety of PPARγ transgenic models, including mice heterozygous for PPARγ, have demonstrated the importance of PPARγ expression in glucose homeostasis and insulin resistance. In the following review, we have highlighted the regulation of PPARγ by covalent modifications, the interplay between these interactions and how these post-translational modifications impact metabolic disease states. © 2012 Elsevier B.V. All rights reserved. PMCID: PMC3355475 PMID: 22504298 [PubMed - indexed for MEDLINE] 279. Expert Opin Biol Ther. 2012 Jun;12(6):713-29. doi: 10.1517/14712598.2012.679652. Epub 2012 Apr 14. Stem cells combined with bone graft substitutes in skeletal tissue engineering. Gamie Z(1), Tran GT, Vyzas G, Korres N, Heliotis M, Mantalaris A, Tsiridis E. Author information: (1)Newcastle University, Institute of Cellular Medicine, Musculoskeletal Research group, Newcastle upon Tyne, Tyne and Wear NE17RU, UK. INTRODUCTION: Bone grafting is used to repair large bone defects and autograft is recognised as producing the best clinical outcome, which is partly due to its cellular component. When autograft is unavailable, allograft and bone graft substitutes can be used; however, they rely on the host bed to provide cellular osteogenic activity. AREAS COVERED: Bone graft substitutes have the potential to benefit from the addition of stem cells aimed at enhancing the rate and quality of defect repair. Mesenchymal stem cells (MSCs) can be isolated from bone marrow or periosteum and culture expanded. Other sources of primary cells include muscle, adipose tissue, human umbilical cord and the pluripotent embryonic stem cells (ESCs). EXPERT OPINION: MSCs isolated from bone marrow have been the best characterised approach for osteogenic differentiation. Their use with synthetic scaffolds such as hydroxyapatite and tricalcium phosphate has produced promising clinical results. MSCs derived from adipose tissue, muscle or human umbilical cord cells combined with various scaffolds are an attractive option. Further in vivo and clinical investigation of their potential is required. Pluripotent ESCs have a theoretical advantage over MSCs; however, purification, cell-specific differentiation, effective delivery vehicles-scaffolds and teratogenesis control are still under in vitro and in vivo evaluation. PMID: 22500826 [PubMed - indexed for MEDLINE] 280. Obes Rev. 2012 Aug;13(8):733-43. doi: 10.1111/j.1467-789X.2012.00997.x. Epub 2012 Apr 12. Leptin as a link between the immune system and kidney-related diseases: leading actor or just a coadjuvant? Moraes-Vieira PM(1), Bassi EJ, Araujo RC, Câmara NO. Author information: (1)Immunology Department, Institute of Biomedical Science, University of São Paulo, SP, Brazil. Food intake and nutritional status modify the physiological responses of the immune system to illness and infection and regulate the development of chronic inflammatory processes, such as kidney disease. Adipose tissue secretes immune-related proteins called adipokines that have pleiotropic effects on both the immune and neuroendocrine systems, linking metabolism and immune physiology. Leptin, an adipose tissue-derived adipokine, displays a variety of immune and physiological functions, and participates in several immune responses. Here, we review the current literature on the role of leptin in kidney diseases, linking adipose tissue and the immune system with kidney-related disorders. The modulation of this adipose hormone may have a major impact on the treatment of several immune- and metabolic-related kidney diseases. © 2012 The Authors. obesity reviews © 2012 International Association for the Study of Obesity. PMID: 22498577 [PubMed - indexed for MEDLINE] 281. Acta Orthop Traumatol Turc. 2012;46(2):139-43. doi: 10.3944/AOTT.2012.2542. Large para-articular osteochondroma of the knee joint: a case report. Singh R(1), Jain M, Siwach R, Rohilla S, Sen R, Kaur K. Author information: (1)Department of Orthopaedic Surgery, Paraplegia & Rehabilitation, Pt. B.D. Sharma University of Health Sciences, Rohtak, India. Comment in Acta Orthop Traumatol Turc. 2012;46(4):320-1; author reply 321-2. A unique case of large intra-articular osteochondroma of the knee of a 15-year duration is presented along with a review of the literature. The tumor may have remained asymptomatic for such a long period because of its slow growth and stretch elongation of the quadriceps mechanism. PMID: 22491430 [PubMed - indexed for MEDLINE] 282. Biol Rev Camb Philos Soc. 2012 Nov;87(4):838-55. doi: 10.1111/j.1469-185X.2012.00227.x. Epub 2012 Apr 5. Genetic explorations of recent human metabolic adaptations: hypotheses and evidence. Brown EA(1). Author information: (1)Harvard University, Department of Human Evolutionary Biology, Peabody Museum, Cambridge, MA 02138-2019, USA. eabrown@fas.harvard.edu Since humans and chimpanzees split from a common ancestor over 6 million years ago, human metabolism has changed dramatically. This change includes adaptations to a high-quality diet, the evolution of an energetically expensive brain, dramatic increases in endurance abilities, and capacity for energy storage in white adipose tissue. Human metabolism continues to evolve in modern human populations in response to local environmental and cultural selective forces. Understanding the nature of these selective forces and the physiological responses during human evolution is a compelling challenge for evolutionary biologists. The complex genetic architecture surrounding metabolic phenotypes indicates that selection probably altered allelic frequencies across many loci in populations experiencing adaptive metabolic change to fit their environment. A recent analysis supports this hypothesis, finding that classic selective sweeps at single loci were rare during the past 250,000 years of human evolution. Detection of selective signatures at multiple loci, as well as exploration of physiological adaptation to environment in humans, will require cross-disciplinary collaboration, including the incorporation of biological pathway analysis. This review explores the Thrifty Genotype Hypothesis, high-altitude adaptation, cold-resistance adaptation, and genetic evidence surrounding these proposed metabolic adaptations in an attempt to clarify current challenges and avenues for future progress. © 2012 The Author. Biological Reviews © 2012 Cambridge Philosophical Society. PMID: 22487590 [PubMed - indexed for MEDLINE] 283. Clin Endocrinol (Oxf). 2012 Aug;77(2):159-68. doi: 10.1111/j.1365-2265.2012.04406.x. Is there sufficient evidence to consider the use of 11β-hydroxysteroid dehydrogenase type 1 inhibition in children? Fürst-Recktenwald S(1), Dörr HG, Quinkler M, Dötsch J, Stewart PM. Author information: (1)F. Hoffmann-La Roche Ltd, Basel, Switzerland. sabine.fuerst-recktenwald@roche.com Manifestations of the metabolic syndrome [obesity, dyslipidaemia, hypertension, blood glucose derangements including prediabetes or type 2 diabetes mellitus (T2DM)] in juvenile populations are becoming increasingly prevalent throughout the world and are at the point of being a global public health concern. Derangements in cortisol regeneration seem to be involved in the pathophysiology. Treatment with selective 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors could be a therapeutic strategy in paediatric patients with manifestations of the metabolic syndrome. Based on preclinical and clinical data regarding development of the 11β-HSD1 enzyme, it appears that maturation occurs within the first year of life. Different changes in biomarkers for assessing the efficacy and safety of 11β-HSD1 inhibitors are to be expected in paediatric patients compared to adults, reflecting differences in metabolism. The effect of 11β-HSD1 treatment in children on bone differentiation and development as well as adrenocorticotropic hormone (ACTH), circulating and local cortisol tissue concentrations, androgens and respective stress response is not yet known. Based on current literature, the concept of inhibition of 11β-HSD1 is considered a potentially effective mean to regulate local cortisol levels in the paediatric population, and 11β-HSD1 inhibitors may provide a valuable target and treatment option for the metabolic syndrome in paediatric patients. However, the uncertainty over effects on the developing skeleton combined with mild increases in adrenal androgen levels raises potential concerns regarding growth as well as onset of puberty as to their future use in children. Future clinical studies are needed to thoroughly assess the risks and benefits of this new class of drugs in the paediatric population. © 2012 Blackwell Publishing Ltd. PMID: 22486586 [PubMed - indexed for MEDLINE] 284. Clin Biochem. 2012 Jun;45(9):610-8. doi: 10.1016/j.clinbiochem.2012.03.024. Epub 2012 Mar 28. Role of mitochondria in nonalcoholic fatty liver disease--from origin to propagation. Grattagliano I(1), de Bari O, Bernardo TC, Oliveira PJ, Wang DQ, Portincasa P. Author information: (1)Department of Interdisciplinary Medicine, Clinica Medica A. Murri, University of Bari Medical School, Bari, Italy. i.grattagliano@semeiotica.uniba.it OBJECTIVES: Mitochondria play a major role in cell energy-generating processes and integrate several signalling pathways to control cellular life and death. DESIGN AND METHODS: Several liver diseases are characterized by mitochondrial alterations which are directly or indirectly dependent on the activation of intracellular stress cascades or receptor-mediated pathways. This article examines the role of mitochondrial dysfunction in critical initiating or propagating events in fatty liver infiltration and nonalcoholic fatty liver disease (NAFLD). Genetic variants and the role of drug-induced toxicity have been considered. RESULTS: Key alterations of mitochondrial physiology associated with hepatocyte fatty changes are described. The value of novel non-invasive diagnostic methods to detect mitochondrial metabolic alterations is also discussed. CONCLUSIONS: Mitochondrial metabolic remodeling is a predominant factor in the appearance and perpetuation of hepatocyte fat accumulation. Non-invasive techniques to identify mitochondrial dysfunction and proper mitochondria protection are two necessary clinical steps for an efficient management of NAFLD. Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. PMID: 22484459 [PubMed - indexed for MEDLINE] 285. Nat Rev Endocrinol. 2012 Apr 3;8(8):457-65. doi: 10.1038/nrendo.2012.49. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Pedersen BK(1), Febbraio MA. Author information: (1)The Centre of Inflammation and Metabolism, Department of Infectious Diseases and CMRC, Rigshospitalet, Section 7641, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. bkp@rh.dk During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain. However, some myokines exert their effects within the muscle itself. Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose tissue and the immune system, and mediates crosstalk between intestinal L cells and pancreatic islets. Other myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the vascular system; and the PGC-1α-dependent myokine irisin, which drives brown-fat-like development. Studies in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could provide a potential mechanism for the association between sedentary behaviour and many chronic diseases. PMID: 22473333 [PubMed - indexed for MEDLINE] 286. Cardiovasc Hematol Agents Med Chem. 2012 Jun;10(2):124-34. PPAR- γ agonist in treatment of diabetes: cardiovascular safety considerations. Abbas A(1), Blandon J, Rude J, Elfar A, Mukherjee D. Author information: (1)Department of Internal Medicine, Texas Tech University, El Paso, Texas 79905, USA. The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors, which contain a type II zinc finger DNA binding motif and a hydrophobic ligand binding pocket. These receptors are thought to play an important role in metabolic diseases such as obesity, insulin resistance, and coronary artery disease. Three subtypes of PPAR receptors have been described: PPARα, PPARδ/β, and PPARγ. PPARα is found in the liver, muscle, kidney, and heart. In the liver, its role is to up-regulate genes involved in fatty acid uptake, binding, β-oxidation and electron transport, and oxidative phosphorylation in subcutaneous fat but not in skeletal muscle. PPARδ/β is expressed in many tissues but markedly in brain, adipose tissue, and skin. PPARγ has high expression in fat, low expression in the liver, and very low expression in the muscle. The thiazolidinediones (TZD) are synthetic ligands of PPARγ. By activating a number of genes in tissues, PPARγ increases glucose and lipid uptake, increases glucose oxidation, decreases free fatty acid concentration, and decreases insulin resistance. Although, there is a rationale for the use of TZDs in patients with type 2 diabetes mellitus, clinical studies have produced conflicting data. While currently used TZDs are clearly associated with heart failure (HF) worsening; with regards to cardiovascular outcomes, pioglitazone seems to be related to a trend toward reduction in cardiovascular morbidity and mortality, whereas rosiglitazone may actually increase risk of cardiovascular events. We review the existing literature on TZDs and discuss role and cardiovascular safety of these agents for the contemporary treatment of diabetes. Other side effects of these agents i.e. increase in osteoporosis and possible risk of bladder cancer is also discussed. PMID: 22471957 [PubMed - indexed for MEDLINE] 287. Indian J Physiol Pharmacol. 2011 Jul-Sep;55(3):197-206. Recent advances in human brown fat physiology. Muralidhara DV(1), Muralidhara KD. Author information: (1)Department of Physiology, Faculty of Medicine and Health Sciences, University Sultan Zainal Abidin, Kuala Terengganu, Malaysia. diviem@yahoo.com Of the two variants of adipose tissue, white fat is traditionally known as a lipid rich tissue which undergoes pathological expansion in obese conditions. To counter the excess accumulation of white fat in states of energy imbalance, the second and unique type of brown fat plays a key role by burning extra energy into heat through a special metabolic pathway. In addition brown fat also plays a vital role in thermoregulation in animals and newborn humans and infants. Recent progress in research areas of these two types of fat tissue has provided compelling evidence to show that they secrete a large number of chemicals that play an important role in body weight control that involves several mechanisms. Brown fat was considered absent in the adult humans until recently. But new techniques have provided ample support for its active existence. Based on the very recent data it has been suggested that brown fat can be a target organ in the treatment of obesity which can lead to exciting and informative outcomes in the future. PMID: 22471225 [PubMed - indexed for MEDLINE] 288. Nutr Hosp. 2011 Jul-Aug;26(4):685-91. doi: 10.1590/S0212-16112011000400004. [Positive effects of physical exercise on reducing the relationship between subcutaneous abdominal fat and morbility risk]. [Article in Spanish] González Calvo G(1), Hernández Sánchez S, Pozo Rosado P, García López D. Author information: (1)Departamento de Didáctica de la Expresión Musical, Plástica y Corporal, Universidad de Valladolid, Valladolid, España. gustavogonzalezcalvo@gmail.com INTRODUCTION: The consequences related to the accumulation of abdominal fat above healthy levels create a considerable organic damage. Among the physiological consequences we can highlight heart diseases, hypertension, type-2 diabetes, obesity and metabolic syndrome, which drastically reduce life expectancy and quality. Evidence shows that health improvement is correlated to greater levels of physical activity. However, physical exercise can create oxidative damage on organs and muscular tissue, more relevant in subjects with a high percentage of abdominal fat. This piece of work determines which are the fundamental variables of the exercise program in order to optimize its advantages while minimizing oxidative stress. MAIN PURPOSE: To know the key variables in the accumulation of abdominal fat above healthy levels, and the role of exercise in prevention and improvement of such issue. SPECIFIC PURPOSES: 1) to identify the key variables in an exercise program aimed at reducing abdominal fat; 2) to understand the relationship between abdominal fat, health and exercise; 3) to review the latest research related to physical exercise and its effect on abdominal adipose tissue. METHODOLOGY: A search and identification of original and reviewed articles will be carried out in indexed impact journals within the main databases. DISCUSSION: Regular physical exercise, most notably aerobic one, reduces body adipose tissue deposits in general, and abdominal ones in particular, both in obese and overweight subjects. PMID: 22470011 [PubMed - indexed for MEDLINE] 289. J Clin Gastroenterol. 2012 Jul;46(6):457-67. doi: 10.1097/MCG.0b013e31824cf51e. The role of nutrients in the development, progression, and treatment of nonalcoholic fatty liver disease. Mouzaki M(1), Allard JP. Author information: (1)Department of Gastroenterology, Hepatology & Nutrition, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada. Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in adults and children and is currently the third most common indication for liver transplantation in North America. Its pathogenesis is thought to be secondary to multiple "hits" derived from the dietary components, adipose tissue, immune system, and intestinal microbiota. Lack of physical activity may contribute as well. Nutrients may exert their effect directly or through alteration of the intestinal microbiota. Research focusing on specific dietary components predisposing to NAFLD has shown conflicting results. Total energy intake, and macronutrients, has been linked to the development of NAFLD. Fructose not only contributes to hepatic steatosis but may trigger inflammatory signals as well. Polyunsaturated fatty acids are thought to exert anti-inflammatory effects. The role of vitamins as well as minerals in this field is actively being investigated. In this review, we discuss the evidence-linking macronutrients (such as carbohydrates and fat in general and fructose, fiber, short chain fatty acids, polyunsaturated fatty, and choline specifically) and micronutrients (such as vitamin E and C and minerals) with the development and treatment of NAFLD. We also discuss the literature on physical activity and NAFLD. PMID: 22469640 [PubMed - indexed for MEDLINE] 290. Stem Cells Dev. 2012 Sep 20;21(14):2724-52. doi: 10.1089/scd.2011.0722. Epub 2012 May 9. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Strioga M(1), Viswanathan S, Darinskas A, Slaby O, Michalek J. Author information: (1)Department of Immunology, Center of Oncosurgery, Institute of Oncology, Vilnius University, Vilnius, Lithuania. marius.strioga@vuoi.lt Mesenchymal stem/stromal cells (MSCs) comprise a heterogeneous population of cells with multilineage differentiation potential, the ability to modulate oxidative stress, and secrete various cytokines and growth factors that can have immunomodulatory, angiogenic, anti-inflammatory and anti-apoptotic effects. Recent data indicate that these paracrine factors may play a key role in MSC-mediated effects in modulating various acute and chronic pathological conditions. MSCs are found in virtually all organs of the body. Bone marrow-derived MSCs (BM-MSCs) were discovered first, and the bone marrow was considered the main source of MSCs for clinical application. Subsequently, MSCs have been isolated from various other sources with the adipose tissue, serving as one of the alternatives to bone marrow. Adipose tissue-derived MSCs (ASCs) can be more easily isolated; this approach is safer, and also, considerably larger amounts of ASCs can be obtained compared with the bone marrow. ASCs and BM-MSCs share many biological characteristics; however, there are some differences in their immunophenotype, differentiation potential, transcriptome, proteome, and immunomodulatory activity. Some of these differences may represent specific features of BM-MSCs and ASCs, while others are suggestive of the inherent heterogeneity of both BM-MSC and ASC populations. Still other differences may simply be related to different isolation and culture protocols. Most importantly, despite the minor differences between these MSC populations, ASCs seem to be as effective as BM-MSCs in clinical application, and, in some cases, may be better suited than BM-MSCs. In this review, we will examine in detail the ontology, biology, preclinical, and clinical application of BM-MSCs versus ASCs. PMID: 22468918 [PubMed - indexed for MEDLINE] 291. Endocrinology. 2012 May;153(5):2070-5. doi: 10.1210/en.2012-1022. Epub 2012 Mar 30. Minireview: The link between fat and bone: does mass beget mass? Zaidi M(1), Buettner C, Sun L, Iqbal J. Author information: (1)Mount Sinai Bone Program and Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA. mone.zaidi@mountsinai.org Osteoporosis is less common in individuals with high fat mass. This putative osteoprotection is likely an adaptive mechanism that allows obese individuals to better carry their increased body mass. Recent studies have focused on hormones that link fat to bone. Adipokines, such as leptin, modulate bone cells through both direct and indirect actions, whereas molecules activating peroxisome proliferator-activated receptor γ drive mesenchymal stem cell differentiation towards adipocytes away from the osteoblastic lineage. There is emerging evidence that bone-derived osteocalcin regulates insulin release and insulin sensitivity and, hence, might indirectly affect fat mass. Despite these molecular connections between fat and bone, animal and human studies call into question a primary role for body fat in determining bone mass. Mice devoid of fat do not have a skeletal phenotype, and in humans, the observed correlations between bone and body mass are not just due to adipose tissue. An improved understanding of the integrative physiology at the fat-bone interface should allow us develop therapies for both osteoporosis and obesity. PMCID: PMC3339646 PMID: 22467495 [PubMed - indexed for MEDLINE] 292. J Gerontol A Biol Sci Med Sci. 2012 Jun;67(6):652-60. doi: 10.1093/gerona/gls086. Epub 2012 Mar 30. GH and IGF1: roles in energy metabolism of long-living GH mutant mice. Brown-Borg HM(1), Bartke A. Author information: (1)Department of Pharmacology, Physiology & Therapeutics, School of Medicine & Health Sciences, University of North Dakota, 501 North Columbia Road, Grand Forks, ND 58202-9037, USA. holly.brown.borg@med.und.edu Of the multiple theories to explain exceptional longevity, the most robust of these has centered on the reduction of three anabolic protein hormones, growth hormone (GH), insulin-like growth factor, and insulin. GH mutant mice live 50% longer and exhibit significant differences in several aspects of energy metabolism as compared with wild-type mice. Mitochondrial metabolism is upregulated in the absence of GH, whereas in GH transgenic mice and dwarf mice treated with GH, multiple aspects of these pathways are suppressed. Core body temperature is markedly lower in dwarf mice, yet whole-body metabolism, as measured by indirect calorimetry, is surprisingly higher in Ames dwarf and Ghr-/- mice compared with normal controls. Elevated adiponectin, a key antiinflammatory cytokine, is also very likely to contribute to longevity in these mice. Thus, several important components related to energy metabolism are altered in GH mutant mice, and these differences are likely critical in aging processes and life-span extension. PMCID: PMC3348496 PMID: 22466316 [PubMed - indexed for MEDLINE] 293. Yakugaku Zasshi. 2012;132(4):425-31. [In vivo imaging reveals adipose tissue inflammation in obesity and multi-cellular processes of developing thrombus]. [Article in Japanese] Nishimura S(1). Author information: (1)Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan. snishi-tky@umin.ac.jp The metabolic syndrome is a major risk factor of cardiovascular events, and obese visceral adipose tissue remodeling based on chronic inflammation plays a central role. To assess dynamic interplay between multiple cell types in obese adipose tissue, a visualization technique in vivo was developed. By this technique we identified inflammatory cell clusters associated with angiogenesis and adipogenesis in obese adipose tissue. We also found increased leukocyte-platelet-endothelial cell interactions in obese adipose tissue microcirculation, which were indicative of local chronic inflammation. Moreover, we found that large numbers of CD8(+) effector T cells infiltrated into obese adipose tissue. Immunological and genetic depletion of CD8(+) T cells reduced inflammatory (M1) macrophage infiltration and adipose tissue inflammation, and ameliorated systemic insulin resistance. Infiltration of CD8(+) T cells is essential for inflammatory macrophage recruitment into obese adipose tissue, and the initiation and development of inflammation therein. Our results clearly demonstrate the power of our imaging technique to analyze complex cellular interplay in vivo, especially parenchymal and stromal cell crosstalk, and to evaluate new therapeutic interventions against conditions arising from these interactions. PMID: 22465917 [PubMed - indexed for MEDLINE] 294. Mol Cell Endocrinol. 2013 Sep 25;378(1-2):23-8. doi: 10.1016/j.mce.2012.03.005. Epub 2012 Mar 23. Role of renin-angiotensin-aldosterone system in adipose tissue dysfunction. Jing F(1), Mogi M, Horiuchi M. Author information: (1)Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan. The renin-angiotensin-aldosterone system (RAAS) is known to be closely linked to the pathogenesis of insulin resistance. The angiotensin (Ang) II type 1 (AT₁) receptor mediates the major effects of Ang II in adipose tissue, and blockade of the AT₁ receptor improves insulin sensitivity, with enhanced adipocyte differentiation. In contrast, the role of angiotensin type 2 (AT₂) receptor activation in insulin sensitivity is still controversial, although AT₂ receptor functions are thought to be mutually antagonistic against those of the AT₁ receptor in the cardiovascular system. Aldosterone exerts its biological roles via the mineralocorticoid receptor (MR), and inhibition of MR signaling in adipose tissue ameliorates inflammation, with upregulation of insulin-mediated glucose transport and adipocyte differentiation. Clinical studies indicate that blockade of RAAS prevents the new onset of type 2 diabetes and improves the metabolic syndrome in diabetic patients. We here review the recent concepts of the roles of RAAS in adipose tissue. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved. PMID: 22465098 [PubMed - indexed for MEDLINE] 295. Public Health Nutr. 2013 Jan;16(1):27-35. doi: 10.1017/S1368980012000894. Epub 2012 Apr 2. Aetiological factors behind adipose tissue inflammation: an unexplored research area. von Scholten BJ(1), Andresen EN, Sørensen TI, Jess T. Author information: (1)Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen, Denmark. OBJECTIVE: Despite extensive research into the biological mechanisms behind obesity-related inflammation, knowledge of environmental and genetic factors triggering such mechanisms is limited. In the present narrative review we present potential determinants of adipose tissue inflammation and suggest ways ahead for future research in the field. DESIGN: We searched the literature for potential determinants of obesity with inflammation through MEDLINE by applying the MeSH headings 'obesity' and 'inflammation' in combination with specific terms for a series of environmental and genetic factors. RESULTS: Numerous articles reported on the association between environmental or genetic factors and respectively obesity and inflammation, whereas only a few studies assessed obesity and inflammation as a combined outcome. Among suggested determinants for obesity with inflammation were Adenovirus-36, the gut microbiota, trans-fatty acids, and the four genes FTO, MC4R, TNF-α and LEPR. CONCLUSIONS: We present a limited number of factors potentially contributing to the development of obesity with inflammation, while concluding that overall the area is indeed sparsely investigated. We present ideas for future studies that can identify relevant aetiological factors. This identification is essential for targeted prevention of obesity with inflammation and the clinical consequences thereof. PMID: 22464010 [PubMed - indexed for MEDLINE] 296. Annu Rev Biochem. 2012;81:715-36. doi: 10.1146/annurev-biochem-052110-115718. Epub 2012 Mar 29. Adipogenesis: from stem cell to adipocyte. Tang QQ(1), Lane MD. Author information: (1)Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. Excessive caloric intake without a rise in energy expenditure promotes adipocyte hyperplasia and adiposity. The rise in adipocyte number is triggered by signaling factors that induce conversion of mesenchymal stem cells (MSCs) to preadipocytes that differentiate into adipocytes. MSCs, which are recruited from the vascular stroma of adipose tissue, provide an unlimited supply of adipocyte precursors. Members of the BMP and Wnt families are key mediators of stem cell commitment to produce preadipocytes. Following commitment, exposure of growth-arrested preadipocytes to differentiation inducers [insulin-like growth factor 1 (IGF1), glucocorticoid, and cyclic AMP (cAMP)] triggers DNA replication and reentry into the cell cycle (mitotic clonal expansion). Mitotic clonal expansion involves a transcription factor cascade, followed by the expression of adipocyte genes. Critical to these events are phosphorylations of the transcription factor CCATT enhancer-binding protein β (C/EBPβ) by MAP kinase and GSK3β to produce a conformational change that gives rise to DNA-binding activity. "Activated" C/EBPβ then triggers transcription of peroxisome proliferator-activated receptor-γ (PPARγ) and C/EBPα, which in turn coordinately activate genes whose expression produces the adipocyte phenotype. PMID: 22463691 [PubMed - indexed for MEDLINE] 297. Vnitr Lek. 2012 Feb;58(2):135-9. [Soft tissues, hormones and the skeleton]. [Article in Czech] Zofková I(1). Author information: (1)Endokrinologický ústav Praha, Reditelka RNDr. Bĕla Bendlová, CSc. izofkova@endo.cz Mechanical load activates bone modeling and increases bone strength. Thus physical activity is extremely important for overall bone health. Muscle volume and muscle contraction are closely related to bone mineral density in men and women, although these relationships are more significat in men. The muscle-bone unit has been defined as a functional system, in which both components are under control of the somatotropin-IGF-I system, androgens and D hormone. These endocrine systems play, via the muscle-bone unit, an important role in development of the skeleton and its stability in adulthood. That is why deficiency of any of these hormonal systems, or reduced physical activity (mainly in childhood) could seriously affect bone density and quality. Bone is also under control of adipose tissue, which modulates its metabolism via mechanical load and more importantly via adipocytokines (leptin, adiponectin and rezistin). Leptin increases bone formation by activation of osteoblasts. This direct effect of leptin is amplified by stimulation of the β-1 adrenergic system, which inhibits the negative osteotropic effects of neuropeptide Y. On the other hand, leptin also activates β-2 adrenergic receptors, which increase bone resorption. In humans, the overall osteo-anabolic effect of leptin tends to be dominant. Furthermore, leptin has a principal role in the start of puberty in girls and maturation, remodeling and development of the female skeleton. Adiponectin (and probably rezistin) has an unambiguous deteriorating effect on the skeleton. Further studies are needed to confirm the clinical importance of soft tissues relative to the integrity of the skeleton. PMID: 22463094 [PubMed - indexed for MEDLINE] 298. Expert Rev Proteomics. 2012 Apr;9(2):181-99. doi: 10.1586/epr.12.12. Angiopoietin-like protein 4: health effects, modulating agents and structure-function relationships. Grootaert C(1), Van de Wiele T, Verstraete W, Bracke M, Vanhoecke B. Author information: (1)Laboratory of Microbial Ecology & Technology (LabMET), Ghent University, Ghent, Belgium. charlotte.grootaert@ugent.be Angiopoietin-like protein 4 (ANGPTL4) has been identified as a multifunctional signal protein. It is produced by a variety of tissues, and is secreted into the bloodstream in glycosylated, oligomerized, native and cleaved isoforms to modulate physiological events such as angiogenesis, cell differentiation and the crosstalk between liver, brain, adipose and muscle tissue in lipid and glucose metabolism. In addition, the expression and isoform appearance of ANGPTL4 are modified by the intestinal microbiota. With an eye on an effective strategy to improve health using ANGPTL4, we will focus on: health issues associated with ANGPTL4 expression, including obesity, Type 2 diabetes, cardiovascular diseases and cancer; several modulators of ANGPTL4 of chemical, microbiological, food and host origin; and the correlation of the specific ANGPTL4 isoforms with these modulators and their health effects. PMID: 22462789 [PubMed - indexed for MEDLINE] 299. J Clin Pharm Ther. 2012 Oct;37(5):525-35. doi: 10.1111/j.1365-2710.2012.01347.x. Epub 2012 Mar 30. Recent advances in the pathophysiology and pharmacological treatment of obesity. Chugh PK(1), Sharma S. Author information: (1)Department of Pharmacology, Maulana Azad Medical College and Associated Hospitals, New Delhi, India. docpreeta@yahoo.com WHAT IS KNOWN AND OBJECTIVE: The increasing prevalence of obesity and associated morbidity present unmet medical needs for safe and effective new drug therapies. Our aim is to review the diverse targets and compounds that are in clinical development. METHODS: Literature searches were conducted using the PUBMED database for studies published in English from January 1985 to December 2011 using combinations of key words, including obesity, overweight, weight loss and treatment in addition to the clinical trials website. Bibliographies of selected references were also evaluated for relevant articles. Press/news releases were also utilized. The collection of information for this review was limited to the most recently available human and animal data. RESULTS AND DISCUSSION: Weight loss drugs in development include compounds that act centrally (neuropeptide Y, AgRP and MCH1 receptors) to limit food intake or reduce the absorption of fat from the gastrointestinal tract (lipase inhibitors) or increase energy expenditure or reduce adipose tissue formation. Among the existing therapy, new combinations (topiramate plus phentermine, bupropion plus naltrexone) offer greater efficacy with reduced adverse effects. WHAT IS NEW AND CONCLUSION: Despite recent setbacks in the pharmacotherapy of obesity (withdrawal of rimonabant and sibutramine), many compounds are in phase II/III trials. The future holds promise for a new drug that alone or in combination with an existing agent could target the initial pathophysiology and morbidities associated with obesity. © 2012 Blackwell Publishing Ltd. PMID: 22462645 [PubMed - indexed for MEDLINE] 300. Annu Rev Nutr. 2012 Aug 21;32:229-43. doi: 10.1146/annurev-nutr-071811-150746. Epub 2012 Mar 29. Visfatin/NAMPT: a multifaceted molecule with diverse roles in physiology and pathophysiology. Dahl TB(1), Holm S, Aukrust P, Halvorsen B. Author information: (1)Research Institute for Internal Medicine, Faculty of Medicine, University of Oslo, Oslo University Hospital Rikshospitalet, Oslo, Norway. tuvad@rr-research.no Visfatin/NAMPT (nicotinamide phosphoribosyltransferase) is a protein with several suggested functions. Although the first discovery of this molecule as a pre-B-cell colony-enhancing factor suggested primarily a cytokine function, its rediscovery as the key enzyme in nicotinamide adenine dinucleotide generation has considerably widened its potential biological activities. Although originally thought to be produced in adipose tissue (i.e., adipocytes and infiltrating macrophages), its production seems to involve other cells and tissues such as skeletal muscle, liver, immune cells, cardiomyocytes, and the brain. Visfatin/NAMPT has both intracellular and extracellular effects influencing several signaling pathways. Its broad spectrum of effects is mirrored by its potential involvement in a wide range of disorders including human immunodeficiency virus infection, septicemia, myocardial failure, atherosclerosis, metabolic disorders, inflammatory diseases, malignancies, and neurodegenerative disorders and aging. Moreover, studies on visfatin/NAMPT in atherosclerotic disorders suggest a rather complex role of this molecule in pathophysiology, potentially mediating both adaptive and maladaptive responses. PMID: 22462624 [PubMed - indexed for MEDLINE] 301. Rev Bras Reumatol. 2012 Mar-Apr;52(2):278-87. Possible role of adipokines in systemic lupus erythematosus and rheumatoid arthritis. [Article in English, Portuguese] Barbosa Vde S(1), Rêgo J, Antônio da Silva N. Author information: (1)Serviço de Reumatologia, Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Goiás. vitalina.barbosa@gmail.com In recent years, mediators synthesized in the adipose tissue, the so-called adipokines, have been described. They have a hormonal action, regulating appetite and glucose metabolism, but also act as cytokines with effects on the immune system, including effects on autoimmunity. The most important adipokines are leptin, adiponectin, resistin and visfatin, and some of them have been assessed in autoimmune rheumatic diseases, especially systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Studies have shown high levels of leptin and adiponectin in SLE, but correlation with disease activity is questionable. In RA, studies have also reported increased levels of leptin and adiponectin, and correlation with disease activity and joint erosion, but the results are conflicting. This review describes the role of leptin and adiponectin on the immune system, as well as on SLE and RA. PMID: 22460416 [PubMed - indexed for MEDLINE] 302. J Mol Endocrinol. 2012 May 29;49(1):R1-7. doi: 10.1530/JME-12-0043. Print 2012 Aug. Role of sex hormones in modulation of brown adipose tissue activity. Quarta C(1), Mazza R, Pasquali R, Pagotto U. Author information: (1)Endocrinology Unit and Centro di Ricerca Biomedica Applicata, Department of Clinical Medicine, University of Bologna, Bologna, Italy. The recent demonstration that metabolically active brown adipose tissue (BAT) is present with a high prevalence in humans undoubtedly represents one of the major advancements in the field of metabolic research in the last few years. The increasing interest in BAT is justified by preclinical observations highlighting an important role of this tissue in energy dissipation and metabolic clearance of substrates from the blood. These findings imply that stimulation of BAT activity may represent a new therapeutic approach for obesity and associated comorbidities. However, before proposing BAT as a target organ for therapeutics in a clinical setting, many further notions about BAT function and modulation need to be explored. Keeping in mind the importance of sex dimorphism in energy metabolism control under physiological and pathological conditions, sex hormones may play a relevant role in the regulation of BAT activity in both males and females. Much of the evidence acquired in the past supports the concept of an important role for different sex hormones in BAT thermogenesis and indicates that this tissue mediates the ability of sex hormones to modulate energy balance. These findings make it plausible that a modified interaction between BAT and sex hormones may contribute to the development and the maintenance of obesity and associated metabolic complications. PMID: 22460126 [PubMed - indexed for MEDLINE] 303. Nutr Rev. 2012 Apr;70(4):218-33. doi: 10.1111/j.1753-4887.2012.00454.x. Relationship between bread consumption, body weight, and abdominal fat distribution: evidence from epidemiological studies. Bautista-Castaño I(1), Serra-Majem L. Author information: (1)Department of Clinical Sciences, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. A long-standing belief held by the general public is that bread fattens. This encourages many people to restrict, or even eliminate, bread from their diet. The present review was conducted to assess whether or not eating patterns that include bread are associated with overall obesity or excess abdominal adiposity, whether in the general population or in subjects undergoing obesity management. The literature search included articles published over the past 30 years that focused on dietary patterns that included bread (refined or whole-grain) and their association with ponderal status and abdominal fat distribution. A total of 38 epidemiological studies fulfilled the inclusion criteria (22 cross-sectional, 11 prospective cohort, and five intervention). The results indicate that dietary patterns that include whole-grain bread do not positively influence weight gain and may be beneficial to ponderal status. With respect to dietary patterns that include refined bread, the majority of cross-sectional studies indicate beneficial effects, while most of the well-designed cohort studies demonstrate a possible relationship with excess abdominal fat. Because differences in the study designs make it difficult to form definitive conclusions, more studies are needed that focus specifically on bread consumption, within different dietary patterns, and its influence on ponderal status. © 2012 International Life Sciences Institute. PMID: 22458695 [PubMed - indexed for MEDLINE] 304. Birth Defects Res C Embryo Today. 2012 Mar;96(1):1-29. doi: 10.1002/bdrc.21006. Organ repair and regeneration: an overview. Baddour JA(1), Sousounis K, Tsonis PA. Author information: (1)Department of Biology and Center for Tissue Regeneration and Engineering, University of Dayton, Dayton, Ohio 45469-2320, USA. A number of organs have the intrinsic ability to regenerate, a distinctive feature that varies among organisms. Organ regeneration is a process not fully yet understood. However, when its underlying mechanisms are unraveled, it holds tremendous therapeutic potential for humans. In this review, we chose to summarize the repair and regenerative potential of the following organs and organ systems: thymus, adrenal gland, thyroid gland, intestine, lungs, heart, liver, blood vessels, germ cells, nervous system, eye tissues, hair cells, kidney and bladder, skin, hair follicles, pancreas, bone, and cartilage. For each organ, a review of the following is presented: (a) factors, pathways, and cells that are involved in the organ's intrinsic regenerative ability, (b) contribution of exogenous cells - such as progenitor cells, embryonic stem cells, induced pluripotent stem cells, and bone marrow-, adipose- and umbilical cord blood-derived stem cells - in repairing and regenerating organs in the absence of an innate intrinsic regenerative capability, (c) and the progress made in engineering bio-artificial scaffolds, tissues, and organs. Organ regeneration is a promising therapy that can alleviate humans from diseases that have not been yet cured. It is also superior to already existing treatments that utilize exogenous sources to substitute for the organ's lost structure and/or function(s). Copyright © 2012 Wiley Periodicals, Inc. PMID: 22457174 [PubMed - indexed for MEDLINE] 305. Sports Med. 2012 May 1;42(5):415-31. doi: 10.2165/11599590-000000000-00000. Effect of acute endurance and resistance exercise on endocrine hormones directly related to lipolysis and skeletal muscle protein synthesis in adult individuals with obesity. Hansen D(1), Meeusen R, Mullens A, Dendale P. Author information: (1)Heart Centre Hasselt, Cardiovascular Medicine and Rehabilitation, Jessa Hospital, Hasselt, Belgium. Hansen_dominique@yahoo.com In subjects with obesity, the implementation of long-term exercise intervention increases lean tissue mass and lowers adipose tissue mass. However, data indicate a blunted lipolytic response, and/or skeletal muscle protein synthesis, when subjects with obesity are exposed to acute endurance or resistance exercise, respectively. Therefore, subjects with obesity seem to display a suboptimal physiological response to acute exercise stimuli. It might be hypothesized that hormonal disturbances contribute, at least in part, to these abnormal physiological reactions in the obese. This review discusses the impact of acute endurance and resistance exercise on endocrine hormones directly related to lipolysis and/or skeletal muscle protein synthesis (insulin, [nor]epinephrine, cortisol, growth hormone, testosterone, triiodothyronine, atrial natriuretic peptide, insulin-like growth factor-1), as well as the impact of long-term endurance and resistance exercise intervention on these hormonal responses to acute endurance and resistance exercise. In the obese, some endocrinological disturbances during acute endurance and resistance exercise have been identified: a blunted blood growth hormone, atrial natriuretic peptide and epinephrine release, and greater cortisol and insulin release. These hormonal disturbances might contribute to a suppressed lipolytic response, and/or suppressed skeletal muscle protein synthesis, as a result of acute endurance or resistance exercise, respectively. In subjects with obesity, the impact of acute endurance and resistance exercise on other endocrine hormones (norepinephrine, testosterone, triiodothyronine, insulin-like growth factor-1) remains elusive. Furthermore, whether long-term endurance and resistance exercise intervention might reverse these hormonal disturbances during acute endurance and resistance exercise in these individuals remains unknown. PMID: 22455310 [PubMed - indexed for MEDLINE] 306. Hormones (Athens). 2012 Jan-Mar;11(1):8-20. Adiponectin: regulation of its production and its role in human diseases. Shehzad A(1), Iqbal W, Shehzad O, Lee YS. Author information: (1)School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu, Korea. Adiponectin is a white and brown adipose tissue hormone, also known as gelatin-binding protein-28 (GBP28), AdipoQ, adipocyte complement-related protein (ACRP30), or apM1. Adiponectin circulates in the bloodstream in trimeric, hexameric, and high-molecular-mass species, while different forms of adiponectin have been found to play distinct roles in the balance of energy homoeostasis. Adiponectin is an insulin sensitizing hormone that exerts its action through its receptors AdipoR1, AdipoR2, and T-cadherin. AdipoR1 is expressed abundantly in muscle, whereas AdipoR2 is predominantly expressed in the liver. Adiponectin is inversely proportional to obesity, diabetes, and other insulin-resistant states. In this review we present the current findings regarding the regulation of its production and several new findings pertaining to its biological effects. Adiponectin enhances AMPK and the PPARα pathway in the liver and skeletal muscle. Adiponectin increases fatty acids oxidation, which lowers circulating free fatty acids and prevents insulin resistance. Adiponectin has been reported to exert an antiatherosclerotic effect. It inhibits macrophage activation and foam cell accumulation, while it also augments endothelial nitrous oxide production and protects the vasculature by reducing platelet aggregation and vasodilation. Apart from causing metabolic dysfunction, adiponectin deficiency may also contribute to coronary heart disease, steatohepatitis, insulin resistance, nonalcoholic fatty liver disease, and a wide array of cancers. In this study, we present ample evidence that adiponectin mediates multiple molecular pathways. We therefore support the concept that it shows distinct potential for being of therapeutic value in the treatment of obesity related diseases, ranging from metabolic syndrome to malignancies. PMID: 22450341 [PubMed - indexed for MEDLINE] 307. Curr Opin Lipidol. 2012 Jun;23(3):190-5. doi: 10.1097/MOL.0b013e328352dcef. The holy grail of metabolic disease: brown adipose tissue. Bartelt A(1), Heeren J. Author information: (1)Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D - 20246 Hamburg, Germany. abartelt@uke.uni-hamburg.de PURPOSE OF REVIEW: The finding that brown adipose tissue (BAT) is present in adults brought BAT physiology into the focus of many researchers interested in energy metabolism. Here, we review recent insight into how BAT develops, functions and might help to treat metabolic disorders in humans. RECENT FINDINGS: BAT is under control of the nervous system, and several pathways have been identified that allow direct manipulation of BAT biology. In addition, some brown adipocytes arise from a distinct subset of white adipocyte precursors and studies were performed that characterize the development of these 'brite' adipocytes. Importantly, progress has been made in understanding how BAT takes up and dissipates nutrients that in metabolic disorders are present in excess. Finally, as it seems that BAT activity declines with age and obesity, we review findings that might shed light on how humans could sustain or increase BAT activity, thus preventing or treating obesity, hyperlipidemia and type 2 diabetes. SUMMARY: BAT is a powerful organ that controls the development of metabolic disease. These powers are boosted by mechanisms that turn white into brown fat and enhance lipid flux into BAT. However, in humans, it remains unclear what was the first: metabolic disease or decreased BAT activity. PMID: 22449813 [PubMed - indexed for MEDLINE] 308. Pulm Pharmacol Ther. 2013 Aug;26(4):427-9. doi: 10.1016/j.pupt.2012.03.003. Epub 2012 Mar 17. Obesity: "priming" the lung for injury. Konter J(1), Baez E, Summer RS. Author information: (1)The Pulmonary Center, Boston University School of Medicine, 80 East Concord St, R-304, Boston, MA 02118, USA. Acute lung injury (ALI) is a severe inflammatory condition that develops in response to local and systemic lung challenges. To date, specific risk factors for development of ALI remain poorly defined. Recent epidemiological studies have reported obesity as an important predisposing factor in the development of this condition. Although the pathogenic mechanisms linking obesity and ALI have not been well-elucidated, emerging scientific evidence has described factors secreted by adipose tissue that have important biological activities in lung and has suggested that altered secretion of these factors during obesity contributes to increased ALI susceptibility. The objective of this manuscript is to highlight recent clinical evidence supporting the association between obesity and ALI and to discuss the posited role for adipose tissue-derived factors in the pathogenesis of this condition. Copyright © 2012 Elsevier Ltd. All rights reserved. PMCID: PMC3387298 PMID: 22449512 [PubMed - indexed for MEDLINE] 309. Am J Physiol Heart Circ Physiol. 2012 Jun 1;302(11):H2148-65. doi: 10.1152/ajpheart.00907.2011. Epub 2012 Mar 23. Inflammation and metabolic dysfunction: links to cardiovascular diseases. Taube A(1), Schlich R, Sell H, Eckardt K, Eckel J. Author information: (1)Paul Langerhans Group, German Diabetes Center, Duesseldorf, Germany. Abdominal obesity is a major risk factor for cardiovascular disease, and recent studies highlight a key role of adipose tissue dysfunction, inflammation, and aberrant adipokine release in this process. An increased demand for lipid storage results in both hyperplasia and hypertrophy, finally leading to chronic inflammation, hypoxia, and a phenotypic change of the cellular components of adipose tissue, collectively leading to a substantially altered secretory output of adipose tissue. In this review we have assessed the adipo-vascular axis, and an overview of adipokines associated with cardiovascular disease is provided. This resulted in a first list of more than 30 adipokines. A deeper analysis only considered adipokines that have been reported to impact on inflammation and NF-κB activation in the vasculature. Out of these, the most prominent link to cardiovascular disease was found for leptin, TNF-α, adipocyte fatty acid-binding protein, interleukins, and several novel adipokines such as lipocalin-2 and pigment epithelium-derived factor. Future work will need to address the potential role of these molecules as biomarkers and/or drug targets. PMID: 22447947 [PubMed - indexed for MEDLINE] 310. Biochimie. 2012 Oct;94(10):2180-9. doi: 10.1016/j.biochi.2012.03.006. Epub 2012 Mar 14. Leptin, adiponectin and pulmonary diseases. Ali Assad N(1), Sood A. Author information: (1)University of New Mexico Health Sciences Center School of Medicine, Department of Medicine, 1 University of New Mexico, MSC 10 5550, Albuquerque, NM 87131, USA. Adipose tissue produces leptin and adiponectin - energy-regulating adipokines that may also play a role in inflammatory pulmonary conditions, as suggested by some murine studies. Leptin and adiponectin and their respective receptors are expressed in the human lung. The association between systemic or airway leptin and asthma in humans is currently controversial, particularly among adults. The majority of the evidence among children however suggests that systemic leptin may be associated with greater asthma prevalence and severity, particularly among prepubertal boys and peripubertal/postpubertal girls. Systemic and airway leptin concentrations may also be disproportionately higher in chronic obstructive pulmonary disease (COPD) patients, particularly among women, and reflect greater airway inflammation and disease severity. Quite like leptin, the association between systemic and airway adiponectin and asthma in humans is also controversial. Some but not all studies, demonstrate that serum adiponectin concentrations are protective against asthma among premenopausal women and peripubertal girls. On the other hand, serum adiponectin concentrations are inversely associated with asthma severity among boys but positively associated among men. Further, systemic and airway adiponectin concentrations are higher in COPD patients than controls, as demonstrated by case-control studies of men. Systemic adiponectin is also positively associated with lung function in healthy adults but inversely associated with lung function in subjects with COPD. It is therefore possible that pro-inflammatory effects of adiponectin dominate under certain physiologic conditions and anti-inflammatory effects under others. The adipokine-lung disease literature has critical gaps that include a lack of adequately powered longitudinal or weight-intervention studies; inadequate adjustment for confounding effect of obesity; and unclear understanding of potential sex interactions. It is also uncertain whether adipokine derangements precede pulmonary disease or are a consequence of it. Future research will determine whether modulation of adipokines, independent of BMI, may allow novel ways to prevent or treat inflammatory pulmonary conditions. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMCID: PMC3399062 PMID: 22445899 [PubMed - indexed for MEDLINE] 311. Trends Endocrinol Metab. 2012 May;23(5):234-41. doi: 10.1016/j.tem.2012.02.005. Epub 2012 Mar 22. Apelin, a promising target for type 2 diabetes treatment? Castan-Laurell I(1), Dray C, Knauf C, Kunduzova O, Valet P. Author information: (1)Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Toulouse, France. Insulin resistance is a main feature of obesity and type 2 diabetes mellitus (T2DM). Several mechanisms linking obesity to insulin resistance have been proposed. Adipose tissue modulates metabolism by secreting a variety of factors, which exhibit altered production during obesity. Apelin, a small peptide present in a number of tissues and also produced and secreted by adipocytes, has emerged as a new player with potent functions in energy metabolism, and in insulin sensitivity improvement. In this review, we describe the various metabolic functions that are affected by apelin and we present an integrated overview of recent findings that collectively propose apelin as a promising target for the treatment of T2DM. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22445464 [PubMed - indexed for MEDLINE] 312. Nucl Recept Signal. 2012;10:e001. doi: 10.1621/nrs.10001. Epub 2012 Feb 27. Post-translational modifications of nuclear receptors and human disease. Anbalagan M(1), Huderson B, Murphy L, Rowan BG. Author information: (1)Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA. Nuclear receptors (NR) impact a myriad of physiological processes including homeostasis, reproduction, development, and metabolism. NRs are regulated by post-translational modifications (PTM) that markedly impact receptor function. Recent studies have identified NR PTMs that are involved in the onset and progression of human diseases, including cancer. The majority of evidence linking NR PTMs with disease has been demonstrated for phosphorylation, acetylation and sumoylation of androgen receptor (AR), estrogen receptor α (ERα), glucocorticoid receptor (GR) and peroxisome proliferator activated receptor γ (PPARγ). Phosphorylation of AR has been associated with hormone refractory prostate cancer and decreased disease-specific survival. AR acetylation and sumoylation increased growth of prostate cancer tumor models. AR phosphorylation reduced the toxicity of the expanded polyglutamine AR in Kennedy's Disease as a consequence of reduced ligand binding. A comprehensive evaluation of ERα phosphorylation in breast cancer revealed several sites associated with better clinical outcome to tamoxifen therapy, whereas other phosphorylation sites were associated with poorer clinical outcome. ERα acetylation and sumoylation may also have predictive value for breast cancer. GR phosphorylation and acetylation impact GR responsiveness to glucocorticoids that are used as anti-inflammatory drugs. PPARγ phosphorylation can regulate the balance between growth and differentiation in adipose tissue that is linked to obesity and insulin resistance. Sumoylation of PPARγ is linked to repression of inflammatory genes important in patients with inflammatory diseases. NR PTMs provide an additional measure of NR function that can be used as both biomarkers of disease progression, and predictive markers for patient response to NR-directed treatments. PMCID: PMC3309075 PMID: 22438791 [PubMed - indexed for MEDLINE] 313. Eur J Endocrinol. 2012 Jun;166(6):959-67. doi: 10.1530/EJE-12-0030. Epub 2012 Mar 21. The endocrine role of the skeleton: background and clinical evidence. Schwetz V(1), Pieber T, Obermayer-Pietsch B. Author information: (1)Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, Graz, Austria. Based on the observation that diabetes, obesity, and hypogonadism influence bone metabolism, the existence of a feedback loop and a common regulation was postulated and an endocrine role ascribed to the skeleton. In the first part of this review, two pathways are described whereby adipose tissue acts on bone mass. In the first, leptin activates the sympathetic nervous system via serotonin and diminishes bone mass accrual. The second pathway functions via the activation of CART (CARTPT) and inhibits bone resorption. The first pathway leads to a decrease in bioactivity of the osteoblast-produced hormone osteocalcin (OC) (part 2). In its undercarboxylated form, OC acts on the three targets pancreas, adipose tissue, and gonads (part 3) and thereby causes an increase in insulin secretion and sensitivity, β-cell proliferation, and male fertility. Insulin (part 4) is part of a recently discovered regulatory feedback loop between pancreas and osteoblasts. It is a strong counterplayer of leptin as it causes a decrease in OPG expression and enhances bone resorption and OC decarboxylation. Numerous clinical studies (part 5) have shown associations of total and undercarboxylated OC and markers of energy metabolism. Interventional studies, to date only performed in murine models, have shown positive effects of OC administration on energy metabolism. Whether bone tissue has an even further-reaching endocrine role remains to be elucidated. PMID: 22436399 [PubMed - indexed for MEDLINE] 314. Animal. 2012 Feb;6(2):327-38. doi: 10.1017/S1751731111001625. Factors in pig production that impact the quality of dry-cured ham: a review. Candek-Potokar M(1), Skrlep M. Author information: (1)Agricultural Institute of Slovenia, Hacquetova ulica 17, 1000 Ljubljana, Slovenia. meta.candek-potokar@kis.si This study reviews the factors of pig production that impact the quality of dry-cured ham. When processing is standardized, the quality of the final dry-cured product is primarily determined by the quality of the meat before curing (green ham). This has been defined as the aptitude for seasoning and is determined by the green ham weight, adipose tissue quantity and quality, meat physico-chemical properties and the absence of visual defects. Various ante-mortem factors including pig age and weight, genetic type, diet, feeding strategy and slaughter conditions determine green ham properties such as the dynamics of water loss, salt intake and, as a consequence, proteolysis and lipolysis. Muscle conditions (pH, salt concentration, water content and availability, temperature) influence enzymatic activity and development of characteristic texture and flavor. Generally, hams of older and heavier pigs present better seasoning aptitude because of higher adiposity. Adiposity is also positively correlated with fat saturation, which is desired to avoid rancidity and oiliness. The fatty acid profile of tissue lipids can be manipulated by diet composition. Feeding strategy affects tissue accretion and protein turnover, thus directly impacting proteolysis. With respect to the impact of pig genotype on dry-cured ham quality, local breeds are generally considered more suitable for producing quality dry hams; however, the majority of dry-cured hams on the market today are from modern pig breeds raised in conventional systems, providing lean hams. The importance of all these factors of pig production is discussed and synthesized, with an emphasis on the main difficulties encountered in dry-cured ham production. PMID: 22436192 [PubMed - indexed for MEDLINE] 315. Endocrine. 2012 Jun;41(3):374-83. doi: 10.1007/s12020-012-9617-z. Epub 2012 Mar 21. Obesidomics: contribution of adipose tissue secretome analysis to obesity research. Pardo M(1), Roca-Rivada A, Seoane LM, Casanueva FF. Author information: (1)Grupo Obesidómica, Laboratorio de Endocrinología Molecular y Celular, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain. maruxapardo@hotmail.com Obesity is presently reaching pandemic proportions and it is becoming a major health concern in developed and developing countries due to its comorbidities like type II diabetes, cardiovascular pathologies, and some cancers. The discovery of the adipose tissue role as an endocrine gland able to secrete adipokines that affects whole-body energy homeostasis has become a key break-through toward a better molecular understanding of obesity. Among the known adipokines involved in the regulation of energy metabolism very few have been clearly seen as central regulators of insulin sensitivity, metabolism, and energy homeostasis. Thus, the discovery and characterization of new adipocyte-derived factors is still in progress. Proteomics technology has emerged as a useful tool to analyze adipose tissue secretion (secretome) dynamics giving a wider picture into the molecular events that control body weight. Besides the identification of new secreted proteins, the advantage of using this approach is the possibility to detect post-translational modifications and protein interactions that generally cannot be predicted by genome studies. In this review, we summarize the recent efforts to identify new bioactive adipokines by proteomics especially in pathological situations such as obesity. PMID: 22434412 [PubMed - indexed for MEDLINE] 316. Proc Nutr Soc. 2012 May;71(2):332-8. doi: 10.1017/S0029665112000092. Epub 2012 Mar 20. Obesity, inflammation and the immune system. de Heredia FP(1), Gómez-Martínez S, Marcos A. Author information: (1)Immunonutrition Research Group, Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition of the Spanish National Research Council (ICTAN-CSIC), Madrid, Spain. fatima.perezdeheredia@ictan.csic.es Obesity shares with most chronic diseases the presence of an inflammatory component, which accounts for the development of metabolic disease and other associated health alterations. This inflammatory state is reflected in increased circulating levels of pro-inflammatory proteins, and it occurs not only in adults but also in adolescents and children. The chronic inflammatory response has its origin in the links existing between the adipose tissue and the immune system. Obesity, like other states of malnutrition, is known to impair the immune function, altering leucocyte counts as well as cell-mediated immune responses. In addition, evidence has arisen that an altered immune function contributes to the pathogenesis of obesity. This review attempts to briefly comment on the various plausible explanations that have been proposed for the phenomenon: (1) the obesity-associated increase in the production of leptin (pro-inflammatory) and the reduction in adiponectin (anti-inflammatory) seem to affect the activation of immune cells; (2) NEFA can induce inflammation through various mechanisms (such as modulation of adipokine production or activation of Toll-like receptors); (3) nutrient excess and adipocyte expansion trigger endoplasmic reticulum stress; and (4) hypoxia occurring in hypertrophied adipose tissue stimulates the expression of inflammatory genes and activates immune cells. Interestingly, data suggest a greater impact of visceral adipose tissue and central obesity, rather than total body fat, on the inflammatory process. In summary, there is a positive feedback loop between local inflammation in adipose tissue and altered immune response in obesity, both contributing to the development of related metabolic complications. PMID: 22429824 [PubMed - indexed for MEDLINE] 317. Clin Biochem. 2012 Aug;45(12):874-9. doi: 10.1016/j.clinbiochem.2012.03.006. Epub 2012 Mar 10. The relationship between adipose tissue and bone metabolism. Gimble JM(1), Nuttall ME. Author information: (1)Stem Cell Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA. gimblejm@pbrc.edu OBJECTIVES: The authors have set out to evaluate the literature relevant to the dynamic regulation of adipogenesis and osteogenesis. DESIGN AND METHODS: A detailed search of the past and recent literature was conducted on Pubmed using a combination of keywords including: adipogenesis, bone marrow, hematopoiesis, mesenchymal stromal/stem cell, and osteogenesis. RESULTS: Throughout one's lifespan, the bone marrow microenvironment provides a unique niche for mesenchymal stromal/stem cells (BMSCs) and hematopoietic stem cells (HSCs). The marrow changes as a function of biological age and pathophysiology. Historically, clinical biochemistry has observed these changes from an HSC and hematological perspective. Nevertheless, these changes also reflect the balance between BMSC adipogenic and osteogenic processes which can display an inverse or reciprocal relationship. Multiple hormonal factors and nuclear hormone receptor ligands and drugs are responsible for BMSC lineage selection. Data from a number of laboratories now implicates endocrine feedback loops between extramedullary adipose depots and the central nervous system. CONCLUSIONS: This concise review provides a perspective on the mechanisms regulating BMSC differentiation in the context of biological aging, obesity, and osteoporosis. Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. PMID: 22429519 [PubMed - indexed for MEDLINE] 318. Circ Res. 2012 Mar 16;110(6):889-900. doi: 10.1161/CIRCRESAHA.111.263186. Lymphocytes and the adventitial immune response in atherosclerosis. Campbell KA(1), Lipinski MJ, Doran AC, Skaflen MD, Fuster V, McNamara CA. Author information: (1)Cardiovascular Research Center, University of Virginia, Charlottesville, USA. Although much of the research on atherosclerosis has focused on the intimal accumulation of lipids and inflammatory cells, there is an increasing amount of interest in the role of the adventitia in coordinating the immune response in atherosclerosis. In this review of the contributions of the adventitia and adventitial lymphocytes to the development of atherosclerosis, we discuss recent research on the formation and structural nature of adventitial immune aggregates, potential mechanisms of crosstalk between the intima, media, and adventitia, specific contributions of B lymphocytes and T lymphocytes, and the role of the vasa vasorum and surrounding perivascular adipose tissue. Furthermore, we highlight techniques for the imaging of lymphocytes in the vasculature. PMCID: PMC3373006 PMID: 22427326 [PubMed - indexed for MEDLINE] 319. Mol Aspects Med. 2012 Oct-Dec;33(5-6):665-75. doi: 10.1016/j.mam.2012.02.004. Epub 2012 Mar 8. Implications of aquaglyceroporins 7 and 9 in glycerol metabolism and metabolic syndrome. Maeda N(1). Author information: (1)Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2-B5 Yamada-oka, Suita, Osaka 565-0871, Japan. norikazu_maeda@endmet.med.osaka-u.ac.jp The discovery of water channel protein (aquaporin [AQP]) has made a great impact on life sciences. So far, 13 AQPs have been identified in human. AQP3, 7, 9, and 10 are subcategorized as aquaglyceroporins which permeabilize glycerol as well as water. Many investigators have demonstrated that AQPs play a crucial role in the maintenance of water homeostasis, but the physiological significance of some AQPs as glycerol channels remains elusive. Adipocyte is a major source of glycerol, which is one of the substrates for hepatic gluconeogenesis. This review focuses on recent studies on glycerol metabolism through AQP7 and AQP9, and briefly discusses the importance of glycerol channel in adipocytes, liver, and heart. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22425521 [PubMed - indexed for MEDLINE] 320. J Craniomaxillofac Surg. 2012 Dec;40(8):750-6. doi: 10.1016/j.jcms.2012.01.025. Epub 2012 Mar 16. Congenital infiltrating lipomatosis of the face with associated involvement of the TMJ structures. Case report and review of the literature. Keramidas T(1), Lagogiannis G, Vlachou V, Katsikeris N. Author information: (1)Department of Oral and Maxillofacial Surgery, "G. Gennimatas" General Hospital of Athens, Athens, Greece. filkeramidas@gmail.com We report a case of congenital infiltrating lipomatosis of the face (CILF) with right TMJ ankylosis causing asymmetry and reduced mouth opening. The management involved soft tissue debulking combined with a right TMJ arthroplasty and is explained in detail. A review of the relevant literature revealed the rarity of this condition. The diagnosis of CILF remains challenging. The currently accepted treatment strategy is less aggressive as facial asymmetry tends to recur. Infiltration of the facial structures from adipose tissue requires several surgical procedures in most cases. Bony hypertrophy on the affected side has been a common finding in reported cases. There have been no previous reports of TMJ ankylosis associated with this condition. CILF is a benign condition with a good long term prognosis. After 2 years of follow up our patient, has maintained full function despite facial asymmetry. Copyright © 2012 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved. PMID: 22425497 [PubMed - indexed for MEDLINE] 321. J Neurol Neurosurg Psychiatry. 2012 May;83(5):488-94. doi: 10.1136/jnnp-2011-302029. Epub 2012 Mar 15. Update on the pathophysiology and management of idiopathic intracranial hypertension. Biousse V(1), Bruce BB, Newman NJ. Author information: (1)Department of Ophthalmology, Emory University, Atlanta, GA, USA. vbiouss@emory.edu Idiopathic intracranial hypertension is a disease of unknown aetiology, typically affecting young obese women, producing a syndrome of increased intracranial pressure without identifiable cause. Despite a large number of hypotheses and publications over the past decade, the aetiology is still unknown. Vitamin A metabolism, adipose tissue as an actively secreting endocrine tissue and cerebral venous abnormalities are areas of active study regarding the pathophysiology of idiopathic intracranial hypertension. There continues to be no evidence based consensus or formal guidelines regarding management and treatment of the disease. Treatment studies show that the diagnostic lumbar puncture is a valuable intervention beyond its diagnostic importance, and that weight management is critical. However, many questions remain regarding the efficacy of acetazolamide, CSF shunting procedures and cerebral transverse venous sinus stenting. PMCID: PMC3544160 PMID: 22423118 [PubMed - indexed for MEDLINE] 322. Semin Liver Dis. 2012 Feb;32(1):49-64. doi: 10.1055/s-0032-1306426. Epub 2012 Mar 13. Obstructive sleep apnea-hypopnea syndrome and nonalcoholic fatty liver disease: emerging evidence and mechanisms. Musso G(1), Olivetti C, Cassader M, Gambino R. Author information: (1)Gradenigo Hospital, Turin, Italy. giovanni_musso@yahoo.it Obstructive sleep apnea syndrome (OSAS) and nonalcoholic fatty liver disease (NAFLD) are common conditions, frequently encountered in patients with metabolic disorders. OSAS has been associated with an increased risk of cardiovascular and metabolic complications. It has been recently suggested that the chronic intermittent hypoxia of OSAS may also affect the presence and severity of NAFLD. We will critically review experimental and human evidence connecting OSAS to NAFLD pathogenesis, trying to dissect the effect of intermittent hypoxia from that of obesity and associated comorbidities, and examine molecular mechanisms connecting OSAS to liver and metabolic disease in NAFLD, including hypoxia inducible factor (HIF), nuclear factor-kappa B, unfolded protein response, hypoxic adipose tissue inflammation, and their therapeutic potential for NAFLD and its complications, including cirrhosis and hepatocellular carcinoma. Finally, we will provide suggestions for the management of NAFLD patients with suspected OSAS and recommendations for future research. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. PMID: 22418888 [PubMed - indexed for MEDLINE] 323. Trends Endocrinol Metab. 2012 Jun;23(6):270-7. doi: 10.1016/j.tem.2012.01.003. Epub 2012 Mar 12. Adipose tissue stem cells: the great WAT hope. Cawthorn WP(1), Scheller EL, MacDougald OA. Author information: (1)Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. The past decade has witnessed an explosion in research into adipose tissue stem cells (ASCs), facilitated by their ease of isolation from white adipose tissue (WAT) and fueled by their therapeutic potential. Recent developments have extended ASC multipotency to include endodermal and ectodermal cell types, as well as the generation of induced pluripotent stem cells. This expanding multipotency has been paralleled by burgeoning translational applications, ranging from tissue engineering to anti-cancer therapy, that are currently subject to clinical trials. However, this promise is tempered by potential pitfalls, such as tumorigenicity, and is further undermined by lingering uncertainties regarding the precise identity of ASCs. Confronting these issues will be essential if we are to bypass the pitfalls and develop the promises of ASCs. Published by Elsevier Ltd. PMCID: PMC3367055 PMID: 22417866 [PubMed - indexed for MEDLINE] 324. Stem Cells. 2012 May;30(5):804-10. doi: 10.1002/stem.1076. Concise review: Adipose-derived stem cells as a novel tool for future regenerative medicine. Mizuno H(1), Tobita M, Uysal AC. Author information: (1)Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo, Japan. hmizuno@juntendo.ac.jp The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs offers a paradigm shift that may provide alternative therapeutic solutions for a number of diseases. The use of either embryonic stem cells (ESCs) or induced pluripotent stem cells in clinical situations is limited due to cell regulations and to technical and ethical considerations involved in the genetic manipulation of human ESCs, even though these cells are, theoretically, highly beneficial. Mesenchymal stem cells seem to be an ideal population of stem cells for practical regenerative medicine, because they are not subjected to the same restrictions. In particular, large number of adipose-derived stem cells (ASCs) can be easily harvested from adipose tissue. Furthermore, recent basic research and preclinical studies have revealed that the use of ASCs in regenerative medicine is not limited to mesodermal tissue but extends to both ectodermal and endodermal tissues and organs, although ASCs originate from mesodermal lineages. Based on this background knowledge, the primary purpose of this concise review is to summarize and describe the underlying biology of ASCs and their proliferation and differentiation capacities, together with current preclinical and clinical data from a variety of medical fields regarding the use of ASCs in regenerative medicine. In addition, future directions for ASCs in terms of cell-based therapies and regenerative medicine are discussed. Copyright © 2012 AlphaMed Press. PMID: 22415904 [PubMed - indexed for MEDLINE] 325. Rev Endocr Metab Disord. 2012 Jun;13(2):129-40. doi: 10.1007/s11154-012-9212-x. Mechanisms affecting neuroendocrine and epigenetic regulation of body weight and onset of puberty: potential implications in the child born small for gestational age (SGA). Roth CL(1), Sathyanarayana S. Author information: (1)Division of Endocrinology, Seattle Children's Hospital Research Institute, 1900 Ninth Avenue, Seattle, WA 98101, USA. christian.roth@seattlechildrens.org Signaling peptides produced in peripheral tissues such as gut, adipose tissue, and pancreas communicate with brain centers, such as hypothalamus and hindbrain to manage energy homeostasis. These regulatory mechanisms of energy intake and storage have evolved during long periods of hunger in the evolution of man to protect the species from extinction. It is now clear that these circuitries are influenced by prenatal and postnatal environmental factors including endocrine disruptive chemicals. Hypothalamic appetite regulatory systems develop and mature in utero and early infancy, and involve signaling pathways that are important also for the regulation of puberty onset. Recent studies in humans and animals have shown that metabolic pathways involved in regulation of growth, body weight gain and sexual maturation are largely affected by epigenetic programming that can impact both current and future generations. In particular, intrauterine and early infantile developmental phases of high plasticity are susceptible to factors that affect metabolic programming that therefore, affect metabolic function throughout life. In children born small for gestational age, poor nutritional conditions during gestation can modify metabolic systems to adapt to expectations of chronic undernutrition. These children are potentially poorly equipped to cope with energy-dense diets and are possibly programmed to store as much energy as possible, leading to later obesity, metabolic syndrome, disturbed regulation of normal puberty and early onset of cardiovascular disease. Most cases of disturbed energy balance are likely a result of a combination of genetics, epigenetics and environment. This review will discuss potential mechanisms linking intrauterine growth retardation with changes in growth, energy homeostasis and sexual maturation. PMID: 22415297 [PubMed - indexed for MEDLINE] 326. Proc Nutr Soc. 2012 May;71(2):263-75. doi: 10.1017/S0029665112000195. Epub 2012 Mar 14. Energy restriction and the prevention of breast cancer. Harvie M(1), Howell A. Author information: (1)Nightingale Centre, University Hospital of South Manchester, Manchester M23 9LT, UK. michelle.harvie@manchester.ac.uk Erratum in Proc Nutr Soc. 2012 Aug;71(3):433. Energy restriction (ER) to control weight is a potential strategy for breast cancer prevention. The protective effects of habitual continuous energy restriction (CER) and weight loss on breast tumour formation have been conclusively demonstrated in animal studies over the past 100 years, and more recently in women using data from observational studies and bariatric surgery. Intermittent energy restriction (IER) and intermittent fasting (IF) are possible alternative preventative approaches which may be easier for individuals to undertake and possibly more effective than standard CER. Here, we summarise the available data on CER, IER and IF with special emphasis on their potential for breast cancer prevention. In animals, IER is superior or equivalent to CER with the exception of carcinogen-induced tumour models when initiated soon after carcinogen exposure. There are no human data on IER and breast cancer risk, but three studies demonstrated IER and CER to be equivalent for weight loss. IF regimens also reduce mammary tumour formation in animal models and also led to weight loss in human subjects, but have not been directly compared with CER. Animal and some human data suggest that both IER and IF may differ mechanistically compared with CER and may bring about greater reduction in hepatic and visceral fat stores, insulin-like growth factor 1 (IGF-1) levels and cell proliferation, and increased insulin sensitivity and adiponectin levels. Although IER and IF were first studied 65 years ago, we conclude that further studies are required to assess their values compared with CER. PMID: 22414375 [PubMed - indexed for MEDLINE] 327. Eur Heart J. 2012 May;33(10):1190-200. doi: 10.1093/eurheartj/ehr453. Epub 2012 Mar 8. Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor? Bhatia LS(1), Curzen NP, Calder PC, Byrne CD. Author information: (1)National Institute of Health Research Biomedical Research Unit, Southampton University Hospitals NHS Trust, Southampton General Hospital, Tremona Road, Southampton, UK. loke.bhatia@soton.ac.uk Non-alcoholic fatty liver disease (NAFLD) affects up to a third of the population worldwide and may confer increased cardiometabolic risk with consequent adverse cardiovascular outcomes independent of traditional cardiovascular risk factors and the metabolic syndrome. It is characterized almost universally by insulin resistance and is strongly associated with type 2 diabetes and obesity. Non-alcoholic fatty liver disease is a marker of pathological ectopic fat accumulation combined with a low-grade chronic inflammatory state. This results in several deleterious pathophysiological processes including abnormal glucose, fatty acid and lipoprotein metabolism, increased oxidative stress, deranged adipokine profile, hypercoaguability, endothelial dysfunction, and accelerated progression of atherosclerosis. This ultimately leads to a dysfunctional cardiometabolic phenotype with cardiovascular mortality representing the main mode of premature death in NAFLD. This review is aimed at introducing NAFLD to the clinical cardiologist by discussing in-depth the evidence to date linking NAFLD with cardiovascular disease, reviewing the likely mechanisms underlying this association, as well as summarizing from a cardiologist's perspective, current and potential future treatment options for this increasingly prevalent disease. PMID: 22408036 [PubMed - indexed for MEDLINE] 328. Inflamm Bowel Dis. 2012 Aug;18(8):1550-7. doi: 10.1002/ibd.22893. Epub 2012 Mar 8. Adipose tissue and inflammatory bowel disease pathogenesis. Fink C(1), Karagiannides I, Bakirtzi K, Pothoulakis C. Author information: (1)Inflammatory Bowel Disease Center, Division of Digestive Diseases, University of California at Los Angeles, Los Angeles, California 90095, USA. Creeping fat has long been recognized as an indicator of Crohn's disease (CD) activity. Although most patients with CD have normal or low body mass index (BMI), the ratio of intraabdominal fat to total abdominal fat is far greater than that of controls. The obesity epidemic has instructed us on the inflammatory nature of hypertrophic adipose tissue and similarities between mesenteric depots in obese and CD patients can be drawn. However, several important physiological differences exist between these two depots as well. While the molecular basis of the crosstalk between mesenteric adipose and the inflamed intestine in CD is largely unknown, novel evidence implicates neuropeptides along with adipocyte-derived paracrine mediators (adipokines) as potential targets for future investigations and highlight adipose tissue physiology as a potential important determinant in the course of IBD. Copyright © 2012 Crohn's & Colitis Foundation of America, Inc. PMCID: PMC3374883 PMID: 22407798 [PubMed - indexed for MEDLINE] 329. Annu Rev Nutr. 2012 Aug 21;32:261-86. doi: 10.1146/annurev-nutr-071811-150623. Epub 2012 Mar 9. Mechanisms of inflammatory responses in obese adipose tissue. Sun S(1), Ji Y, Kersten S, Qi L. Author information: (1)Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York 14853, USA. The fields of immunology and metabolism are rapidly converging on adipose tissue. During obesity, many immune cells infiltrate or populate in adipose tissue and promote a low-grade chronic inflammation. Studies to date have suggested that perturbation of inflammation is critically linked to nutrient metabolic pathways and to obesity-associated complications such as insulin resistance and type 2 diabetes. Despite these advances, however, many open questions remain including how inflammatory responses are initiated and maintained, how nutrients impact the function of various immune populations, and how inflammatory responses affect systemic insulin sensitivity. Here we review recent studies on the roles of various immune cells at different phases of obesity and discuss molecular mechanisms underlying obesity-associated inflammation. Better understanding of the events occurring in adipose tissue will provide insights into the pathophysiological role of inflammation in obesity and shed light on the pathogenesis of obesity-associated metabolic syndrome. PMCID: PMC4041712 PMID: 22404118 [PubMed - indexed for MEDLINE] 330. Diabetologia. 2012 Jun;55(6):1597-606. doi: 10.1007/s00125-012-2505-5. Epub 2012 Mar 9. Adipose tissue and fetal programming. Symonds ME(1), Pope M, Sharkey D, Budge H. Author information: (1)The Early Life Nutrition Research Unit, Academic Division of Child Health, School of Clinical Sciences, University Hospital, Nottingham, NG7 2UH, UK. michael.symonds@nottingham.ac.uk Adipose tissue function changes with development. In the newborn, brown adipose tissue (BAT) is essential for ensuring effective adaptation to the extrauterine environment, and its growth during gestation is largely dependent on glucose supply from the mother to the fetus. The amount, location and type of adipose tissue deposited can also determine fetal glucose homeostasis. Adipose tissue first appears at around mid-gestation. Total adipose mass then increases through late gestation, when it comprises a mixture of white and brown adipocytes. BAT possesses a unique uncoupling protein, UCP1, which is responsible for the rapid generation of large amounts of heat at birth. Then, during postnatal life some, but not all, depots are replaced by white fat. This process can be utilised to investigate the physiological conversion of brown to white fat, and how it is re-programmed by nutritional changes in pre- and postnatal environments. A reduction in early BAT deposition may perpetuate through the life cycle, thereby suppressing energy expenditure and ultimately promoting obesity. Normal fat development profiles in the offspring are modified by changes in maternal diet at defined stages of pregnancy, ultimately leading to adverse long-term outcomes. For example, excess macrophage accumulation and the onset of insulin resistance occur in an adipose tissue depot-specific manner in offspring born to mothers fed a suboptimal diet from early to mid-gestation. In conclusion, the growth of the different fetal adipose tissue depots varies according to maternal diet and, if challenged in later life, this can contribute to insulin resistance and impaired glucose homeostasis. PMID: 22402988 [PubMed - indexed for MEDLINE] 331. Radiat Res. 2012 Apr;177(4):398-435. Epub 2012 Mar 8. Magnetic resonance spectroscopy of cancer metabolism and response to therapy. McIntyre DJ(1), Madhu B, Lee SH, Griffiths JR. Author information: (1)Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK. Dominick.McIntyre@cancer.org.uk Magnetic resonance spectroscopy allows noninvasive in vivo measurements of biochemical information from living systems, ranging from cultured cells through experimental animals to humans. Studies of biopsies or extracts offer deeper insights by detecting more metabolites and resolving metabolites that cannot be distinguished in vivo. The pharmacokinetics of certain drugs, especially fluorinated drugs, can be directly measured in vivo. This review briefly describes these methods and their applications to cancer metabolism, including glycolysis, hypoxia, bioenergetics, tumor pH, and tumor responses to radiotherapy and chemotherapy. PMID: 22401303 [PubMed - indexed for MEDLINE] 332. Adv Exp Med Biol. 2012;728:25-40. doi: 10.1007/978-1-4614-0887-1_2. Klotho and βKlotho. Kuro-o M(1). Author information: (1)Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. makoto.kuro-o@utsouthwestern.edu Endocrine fibroblast growth factors (FGFs) have been recognized as hormones that regulate a variety of metabolic processes. FGF19 is secreted from intestine upon feeding and acts on liver to suppress bile acid synthesis. FGF21 is secreted from liver upon fasting and acts on adipose tissue to promote lipolysis and responses to fasting. FGF23 is secreted from bone and acts on kidney to inhibit phosphate reabsorption and vitamin D synthesis. One critical feature of endocrine FGFs is that they require the Klotho gene family of transmembrane proteins as coreceptors to bind their cognate FGF receptors and exert their biological activities. This chapter overviews function of Klotho family proteins as obligate coreceptors for endocrine FGFs and discusses potential link between Klothos and age-related diseases. PMID: 22396160 [PubMed - indexed for MEDLINE] 333. Nat Med. 2012 Mar 6;18(3):363-74. doi: 10.1038/nm.2627. The cellular and signaling networks linking the immune system and metabolism in disease. Osborn O(1), Olefsky JM. Author information: (1)Department of Medicine, Division of Endocrinology and Metabolism, University of California-San Diego, La Jolla, California, USA. It is now recognized that obesity is driving the type 2 diabetes epidemic in Western countries. Obesity-associated chronic tissue inflammation is a key contributing factor to type 2 diabetes and cardiovascular disease, and a number of studies have clearly demonstrated that the immune system and metabolism are highly integrated. Recent advances in deciphering the various cellular and signaling networks that participate in linking the immune and metabolic systems together have contributed to understanding of the pathogenesis of metabolic diseases and may also inform new therapeutic strategies based on immunomodulation. Here we discuss how these various networks underlie the etiology of the inflammatory component of insulin resistance, with a particular focus on the central roles of macrophages in adipose tissue and liver. PMID: 22395709 [PubMed - indexed for MEDLINE] 334. Gynecol Endocrinol. 2012 Mar;28 Suppl 1:27-32. doi: 10.3109/09513590.2012.651930. Neuroendocrine control of metabolism. Kuliczkowska-Plaksej J(1), Milewicz A, Jakubowska J. Author information: (1)Department of Endocrinology, Diabetology and Isotope Therapy, Wroclaw Medical University, Wroclaw, Poland. kuliczk@interia.pl Metabolism is controlled through homeostatic system consisting of central centers, gut hormones, hormones from adipose tissue and the other hormonal axes. This cooperation is based on cross-talk between central and peripheral signals. Among them the hypothalamus plays a crucial role, with interconnected nuclei forming neuronal circuits. Other regions in the brain, such as the brain stem, the endocannabinoid system, the vagal afferents, are also involved in energy balance. The second component is peripheral source of signals--the gastrointestinal tract hormones. Additionally, adipokines from adipose tissue, thyrotropic, gonadotropic and somatotropic axes play a role in energy homeostasis. Knowledge about all components of this neuroendocrine circuit will be helpful in developing novel therapeutic approaches against the metabolic syndrome and its components. PMID: 22394301 [PubMed - indexed for MEDLINE] 335. Cold Spring Harb Perspect Med. 2012 Mar;2(3):a007724. doi: 10.1101/cshperspect.a007724. Connecting type 1 and type 2 diabetes through innate immunity. Odegaard JI(1), Chawla A. Author information: (1)Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA. The escalating epidemic of obesity has driven the prevalence of both type 1 and 2 diabetes mellitus to historically high levels. Chronic low-grade inflammation, which is present in both type 1 and type 2 diabetics, contributes to the pathogenesis of insulin resistance. The accumulation of activated innate immune cells in metabolic tissues results in release of inflammatory mediators, in particular, IL-1β and TNFα, which promote systemic insulin resistance and β-cell damage. In this article, we discuss the central role of innate immunity and, in particular, the macrophage in insulin sensitivity and resistance, β-cell damage, and autoimmune insulitis. We conclude with a discussion of the therapeutic implications of this integrated understanding of diabetic pathology. PMCID: PMC3282495 PMID: 22393536 [PubMed - indexed for MEDLINE] 336. J Dermatol Sci. 2012 Apr;66(1):3-11. doi: 10.1016/j.jdermsci.2012.02.007. Epub 2012 Feb 24. Multi-layered environmental regulation on the homeostasis of stem cells: the saga of hair growth and alopecia. Chen CC(1), Chuong CM. Author information: (1)Institute of Clinical Medicine and Department of Dermatology, National Yang-Ming University and Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan. docs1.tw@yahoo.com.tw Stem cells are fascinating because of their potential in regenerative medicine. Stem cell homeostasis has been thought to be mainly regulated by signals from their adjacent micro-environment named the "stem cell niche". However, recent studies reveal that there can be multiple layers of environmental controls. Here we review these environmental controls using the paradigm of hair stem cells, because to observe and analyze the growth of hair is easier due to their characteristic cyclic regeneration pattern. The length of hair fibers is regulated by the duration of the growth period. In the hair follicles, hair stem cells located in the follicle bulge interact with signals from the dermal papilla. Outside of the follicle, activation of hair stem cells has been shown to be modulated by molecules released from the intra-dermal adipose tissue as well as body hormone status, immune function, neural activities, and aging. The general physiological status of an individual is further influenced by circadian rhythms and changing seasons. The interactive networks of these environmental factors provide new understanding on how stem cell homeostasis is regulated, inspiring new insights for regenerative medicine. Therapies do not necessarily have to be achieved by using stem cells themselves which may constitute a higher risk but by modulating stem cell activity through targeting one or multiple layers of their micro- and macro-environments. Copyright © 2012. Published by Elsevier Ireland Ltd. PMCID: PMC3684257 PMID: 22391240 [PubMed - indexed for MEDLINE] 337. Chronobiol Int. 2012 Apr;29(3):227-51. doi: 10.3109/07420528.2012.658127. Clock genes and clock-controlled genes in the regulation of metabolic rhythms. Mazzoccoli G(1), Pazienza V, Vinciguerra M. Author information: (1)Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza, Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo (FG), Italy. g.mazzoccoli@operapadrepio.it Daily rotation of the Earth on its axis and yearly revolution around the Sun impose to living organisms adaptation to nyctohemeral and seasonal periodicity. Terrestrial life forms have developed endogenous molecular circadian clocks to synchronize their behavioral, biological, and metabolic rhythms to environmental cues, with the aim to perform at their best over a 24-h span. The coordinated circadian regulation of sleep/wake, rest/activity, fasting/feeding, and catabolic/anabolic cycles is crucial for optimal health. Circadian rhythms in gene expression synchronize biochemical processes and metabolic fluxes with the external environment, allowing the organism to function effectively in response to predictable physiological challenges. In mammals, this daily timekeeping is driven by the biological clocks of the circadian timing system, composed of master molecular oscillators within the suprachiasmatic nuclei of the hypothalamus, pacing self-sustained and cell-autonomous molecular oscillators in peripheral tissues through neural and humoral signals. Nutritional status is sensed by nuclear receptors and coreceptors, transcriptional regulatory proteins, and protein kinases, which synchronize metabolic gene expression and epigenetic modification, as well as energy production and expenditure, with behavioral and light-dark alternance. Physiological rhythmicity characterizes these biological processes and body functions, and multiple rhythms coexist presenting different phases, which may determine different ways of coordination among the circadian patterns, at both the cellular and whole-body levels. A complete loss of rhythmicity or a change of phase may alter the physiological array of rhythms, with the onset of chronodisruption or internal desynchronization, leading to metabolic derangement and disease, i.e., chronopathology. PMID: 22390237 [PubMed - indexed for MEDLINE] 338. Obes Rev. 2012 Jul;13(7):578-91. doi: 10.1111/j.1467-789X.2012.00988.x. Epub 2012 Mar 2. Resistance training, visceral obesity and inflammatory response: a review of the evidence. Strasser B(1), Arvandi M, Siebert U. Author information: (1)Institute for Nutritional Sciences and Physiology, University for Health Sciences, Medical Informatics and Technology, Hall in Tirol, Austria. barbara.strasser@umit.at Intra-abdominal obesity is an important risk factor for low-grade inflammation, which is associated with increased risk for diabetes mellitus and cardiovascular disease. For the most part, recommendations to treat or prevent overweight and obesity via physical activity have focused on aerobic endurance training as it is clear that aerobic training is associated with much greater energy expenditure during the exercise session than resistance training. However, due to the metabolic consequences of reduced muscle mass, it is understood that normal ageing and/or decreased physical activity may lead to a higher prevalence of metabolic disorders. Whether resistance training alters visceral fat and the levels of several pro-inflammatory cytokines produced in adipose tissue has not been addressed in earlier reviews. Because evidence suggests that resistance training may promote a negative energy balance and may change body fat distribution, it is possible that an increase in muscle mass after resistance training may be a key mediator leading to a better metabolic control. Considering the benefits of resistance training on visceral fat and inflammatory response, an important question is: how much resistance training is needed to confer such benefits? Therefore, the purpose of this review was to address the importance of resistance training on abdominal obesity, visceral fat and inflammatory response. © 2012 The Authors. obesity reviews © 2012 International Association for the Study of Obesity. PMID: 22385646 [PubMed - indexed for MEDLINE] 339. Adv Ther. 2012 Mar;29(3):249-66. doi: 10.1007/s12325-012-0004-1. Epub 2012 Feb 29. Exploring channeling optimized radiofrequency energy: a review of radiofrequency history and applications in esthetic fields. Belenky I(1), Margulis A, Elman M, Bar-Yosef U, Paun SD. Author information: (1)Clinical Department, Viora, Inc., Jersey City, NJ 07306, USA. inna@vioramed.com INTRODUCTION: Because of its high efficiency and safety, radiofrequency (RF) energy is widely used in the dermatological field for heating biological tissue in various esthetic applications, including skin tightening, skin lifting, body contouring, and cellulite reduction. This paper reviews the literature on the use of nonablative RF energy in the esthetic field and its scientific background. The purpose of this article is to describe in detail the extensive use of medical devices based on RF technology, the development of these medical devices over the years, and recent developments and trends in RF technology. METHODS: The authors conducted a systematic search of publications that address safety and efficacy issues, technical system specifications, and clinical techniques. Finally, the authors focused on their own clinical experiences with the use of patented Channeling Optimized RF Energy technique and mechanical massage. An in-vivo study was conducted in domestic pigs, with a thermal video camera. Twenty-seven female patients participated in a cellulite and body shaping study. The treatments were conducted according to a three-phase protocol. An additional 16 females participated in a skin tightening case study. All of the patients underwent three treatment sessions at 3-week intervals, each according to a protocol specific to the area being treated. RESULTS: The review of the literature on RF-based systems revealed that these systems are safe, with low risks for potential side effects, and effective for cellulite, body contouring, and skin tightening procedures. The in-vivo measurements confirmed the theory that the penetration depth of RF is an inverse function of its frequency, and using a vacuum mechanism makes an additional contribution to the RF energy penetration. The heating effect of RF was also found to increase blood circulation and to induce collagen remodeling. The results from the cellulite and body shaping treatments showed an overall average improvement of 55% in the appearance of cellulite, with an average circumferential reduction of 3.31 cm in the buttocks, 2.94 cm in the thighs, and 2.14 cm in the abdomen. The results from the skin tightening procedure showed moderate improvement of skin appearance in 50% and significant improvement in 31%. At the follow-up visits the results were found to be sustained without any significant side effects. CONCLUSION: Of all tissue heating techniques, RF-based technologies appear to be the most established and clinically proven. The design and specifications of the described vacuumassisted bipolar RF device fall within the range of the specifications currently prescribed for esthetic, nonablative RF systems. PMID: 22382873 [PubMed - indexed for MEDLINE] 340. Minerva Endocrinol. 2012 Mar;37(1):25-40. Neuroendocrine and endocrine dysfunction in the hyperinsulinemic PCOS patient: the role of metformin. Weickert MO(1), Hodges P, Tan BK, Randeva HS. Author information: (1)Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK. m.weickert@warwick.ac.uk Metformin is a widely used and extensively studied insulin sensitising drug for the treatment of women with polycystic ovary syndrome (PCOS), with various actions in tissues responding to insulin that include the liver, skeletal muscle, adipose tissue, the endothelium of blood vessels, and the ovaries. Treatment of PCOS women with metformin has been shown to reduce fasting glucose levels, blood pressure, and serum androgens; further effects of metformin in women with PCOS may include direct effects on the central nervous system; and indirect effects via the modification of gut hormone and adipokine synthesis and/or secretion. A number of "novel" adipokines and metabolic factors have been recently identified which may play a role both in the pathogenesis and the treatment of women with PCOS. We here discuss recent advances in the area, with a focus on neuroendocrine and endocrine dysfunctions in women with PCOS and the potential role of metformin in this context. PMID: 22382613 [PubMed - indexed for MEDLINE] 341. J Antimicrob Chemother. 2012 Jun;67(6):1305-10. doi: 10.1093/jac/dks066. Epub 2012 Mar 1. Altered vancomycin pharmacokinetics in obese and morbidly obese patients: what we have learned over the past 30 years. Grace E(1). Author information: (1)Presbyterian College School of Pharmacy, 307 North Broad Street, Clinton, SC 29325, USA. eegrace@presby.edu Vancomycin was the first glycopeptide antibiotic introduced into clinical practice. Despite the numerous benefits of vancomycin, clinicians have struggled to dose vancomycin successfully in obese patients to achieve a therapeutic concentration for optimal bacterial killing. Owing to the hydrophilicity of vancomycin and the increase in both adipose tissue and muscle mass associated with obesity, the volume of distribution of vancomycin in obese patients is likely to be altered compared with non-obese patients. In addition to an increase in body mass, obesity is associated with an increase in certain circulating proteins, which results in altered free serum vancomycin concentration. Another alteration that occurs in obesity is increased blood flow secondary to increased cardiac output and blood volume, resulting in increased vancomycin clearance in obese patients. Vancomycin pharmacokinetics in the obese population remain an area of much debate, one that requires continued research given the rising number of obese patients in both the USA and worldwide. PMID: 22382471 [PubMed - indexed for MEDLINE] 342. Bratisl Lek Listy. 2012;113(1):52-6. Brown fat tissue - a potential target to combat obesity. Ginter E(1), Simko V. Author information: (1)Institute of Preventive and Clinical Medicine, Brtislava, Slovakia. ginter.emil@mail.t-com.sk From the global population perspective, the epidemic of "globesity" (more than one billion adults being overweight) represents one of the largest public health problems (1). Traditional reasoning related to the dysbalance between caloric intake and energy expenditure does not provide a satisfying explanation for a complexfailure to combat obesity. The brown adipose tisue (BAT) has a unique chemical structure and a specific metabolic role. A potential preventive co-factor is thermogenesis. BAT has the ability to dissipate energy byproducing heat, rather than storing energy as triglycerides. The cells of the white adipose tissue (WAT) contain one large globule of triglycerides which displaces the cell nucleus and other cell organelles excentrically, to the cell periphery. BAT contains numerous smaller droplets of triglycerides, much higher number of mitochondria and a specific uncoupling protein 1 or thermogenin. This specialized protein uncouples ATP production from mitochondrial respiration and converts energy into heat. Using sophisticated diagnostic techniques (e.g. imaging combination of positron-emisson tomography and computed tomography), scientists confirmed the importance of BAT not only in the newborn but also in adults who were found to possess considerable body stores of BAT.The highest proportion of BAT has been detected in lean individuals. As the body mass increases, BAT proportionately drops. Data both from animal and human studies suggest that BAT and mitochondrial uncoupling can be targeted for interventions to prevent and treat obesity. Melatonin and arginine have been proposed as possible interventional tools. The scientific world eagerly awaits further advanced studies to document possible metabolic and pharmacologic interventions, using BAT as a primary target to prevent and manage obesity (Fig. 5, Ref. 41). PMID: 22380505 [PubMed - indexed for MEDLINE] 343. Int J Obes (Lond). 2013 Feb;37(2):163-6. doi: 10.1038/ijo.2012.28. Epub 2012 Feb 28. Activins in adipogenesis and obesity. Dani C(1). Author information: (1)Institute Biology of Valrose (iBV), CNRS/Inserm, Faculty of Medicine, University of Nice Sophia-Antipolis, Nice, Cedex, France. dani@unice.fr Activins are secreted proteins members of the transforming growth factor-β family. They are involved in many biological responses including regulation of apoptosis, proliferation and differentiation of different cell types. Activins A, B and AB are highly expressed in adipose tissue, and in this review we will illustrate that activins have a role in several steps of physiological and pathological development of adipose tissue. Activin A has been shown to be a critical regulator of human adipocyte progenitor proliferation and a potent inhibitor of their differentiation. Activin A could also be a mediator of fibrosis observed in obese adipose tissue. Activin B/AB is proposed as a new adipokine having a role in energy balance and insulin insensitivity associated with obesity. Therefore, activin pathway could represent a potential therapeutic target both for controlling the size and the phenotype of the adipose precursor pool and for obesity-associated metabolic complications. PMID: 22370854 [PubMed - indexed for MEDLINE] 344. Int J Obes (Lond). 2012 Dec;36(12):1494-502. doi: 10.1038/ijo.2012.21. Epub 2012 Feb 28. Liver X receptors and fat cell metabolism. Laurencikiene J(1), Rydén M. Author information: (1)Karolinska Institutet, Department of Medicine (H7), Karolinska University Hospital, Huddinge, Sweden. Jurga.Laurencikiene@ki.se Liver X receptors (LXRs) are members of the nuclear receptor family and are present in two isoforms, α and β, encoded by two separate genes. Originally described in the liver, LXRs have in the last 15 years been implicated in central metabolic pathways, including bile acid synthesis, lipid and glucose homeostasis. Although the vast majority of studies have been performed in non-adipose cells/tissues, results in recent years suggest that LXRs may have important modulatory roles in adipose tissue and adipocytes. Although several authors have published reviews on LXR, there have been no attempts to summarize the effects reported specifically in adipose systems. This overview gives a brief introduction to LXR and describes the sometimes-contradictory results obtained in murine cell systems and in rodent adipose tissue. The so far very limited number of studies performed in human adipocytes and adipose tissue are also presented. It should be apparent that although LXR may impact on several different pathways in metabolism, the clinical role of LXR modulation in adipose tissue is still not clear. PMCID: PMC3520012 PMID: 22370853 [PubMed - indexed for MEDLINE] 345. Arch Pharm Res. 2012 Feb;35(2):213-21. doi: 10.1007/s12272-012-0202-z. Epub 2012 Feb 28. Immunomodulatory properties of mesenchymal stem cells and their therapeutic applications. Yi T(1), Song SU. Author information: (1)Clinical Research Center, Inha Research Institute, Inha University School of Medicine, Incheon 400-712, Korea. Mesenchymal stem cells (MSCs) are adult stem cells that can be isolated from most adult tissues, including bone marrow, adipose, liver, amniotic fluid, lung, skeletal muscle and kidney. The term MSC is currently being used to represent both mesenchymal stem cells and multipotent mesenchymal stromal cells. Numerous reports on systemic administration of MSCs leading to functional improvements based on the paradigm of engraftment and differentiation have been published. However, it is not only difficult to demonstrate extensive engraftment of cells, but also no convincing clinical results have been generated from phase 3 trials as of yet and prolonged responses to therapy have been noted after identification of MSCs had discontinued. It is now clear that there is another mechanism by which MSCs exert their reparative benefits. Recently, MSCs have been shown to possess immunomodulatory properties. These include suppression of T cell proliferation, influencing dendritic cell maturation and function, suppression of B cell proliferation and terminal differentiation, and immune modulation of other immune cells such as NK cells and macrophages. In terms of the clinical applications of MSCs, they are being tested in four main areas: tissue regeneration for cartilage, bone, muscle, tendon and neuronal cells; as cell vehicles for gene therapy; enhancement of hematopoietic stem cell engraftment; and treatment of immune diseases such as graft-versus-host disease, rheumatoid arthritis, experimental autoimmune encephalomyelitis, sepsis, acute pancreatitis and multiple sclerosis. In this review, the mechanisms of immunomodulatory effects of MSCs and examples of animal and clinical uses of their immunomodulatory effects are described. PMID: 22370776 [PubMed - indexed for MEDLINE] 346. Proc Nutr Soc. 2012 May;71(2):290-7. doi: 10.1017/S0029665112000079. Epub 2012 Feb 28. Effect of vitamin A deficiency on the immune response in obesity. García OP(1). Author information: (1)School of Natural Sciences, Universidad Autónoma de Querétaro, Av de la Ciencia S/N, Juriquilla, Querétaro 76230, Mexico. olga.garcia@uaq.mx Obesity has been associated with low-grade systemic inflammation and with micronutrient deficiencies. Obese individuals have been found to have lower vitamin A levels and lower vitamin A intake compared with normal-weight individuals. Vitamin A plays a major role in the immune function, including innate immunity, cell-mediated immunity and humoral antibody immunity. It has also been recognised recently that vitamin A has important regulatory functions. Vitamin A status has an important effect on the chronic inflammatory response. Vitamin A deficiency increases a T-helper type 1 (Th1) response, elevates levels of pro-inflammatory cytokines, increases the expression of leptin, resistin and uncoupling proteins (UCP) and promotes adipogenesis. The effect of vitamin A deficiency on obesity might be increasing the risk of fat deposition and also the risk of chronic inflammation associated with obesity. Supplementation with vitamin A in vitro and in animal models has been found to reduce concentrations of adipocytokines, such as leptin and resistin. In conclusion, vitamin A deficiency increases a Th1 response in the presence of obesity and thus, increases the inflammatory process involved in chronic inflammation and fat deposition. The metabolism of leptin and other adipocytokines may play a critical role in the effect of vitamin A deficiency in the inflammatory response observed in obesity. PMID: 22369848 [PubMed - indexed for MEDLINE] 347. Arch Toxicol. 2012 Sep;86(9):1337-48. doi: 10.1007/s00204-012-0814-6. Epub 2012 Feb 25. Cytokines in alcoholic liver disease. An L(1), Wang X, Cederbaum AI. Author information: (1)Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA. Comment in Arch Toxicol. 2012 Sep;86(9):1331-2. Alcoholic liver disease (ALD) is associated with a spectrum of liver injury ranging from steatosis and steatohepatitis to fibrosis and cirrhosis. While multifactorial pathogenesis plays a role in the disease progression, enhanced inflammation in the liver during ethanol exposure is a major feature of ALD. Dysregulated cytokine metabolism and activity are crucial to the initiation of alcohol-induced liver injury. The pro-inflammatory cytokine tumor necrosis factor (TNF-α) has been demonstrated to be one of the key factors in the various aspects of pathophysiology of ALD. The immunomodulatory cytokines such as interleukin 10 and interleukin 6 play roles in exerting hepatic protective effects. Adiponectin is an adipose tissue-derived hormone, which displays protective actions on ethanol-induced liver injury. Treatment for mice with adiponectin decreases TNF-α expression, steatosis and prevents alcohol-induced liver injury. Adiponectin exerts its anti-inflammatory effects via suppression of TNF-α expression and induction of anti-inflammatory cytokines such as IL-10. Adiponectin attenuates alcoholic liver injury by the complex network of multiple signaling pathways in the liver, leading to enhanced fatty acid oxidation and reduced steatosis. Interactions between pro- and anti-inflammatory cytokines such as TNFα and adiponectin and other cytokines are likely to play important roles in the development and progression of alcoholic liver disease. PMID: 22367091 [PubMed - indexed for MEDLINE] 348. Vascul Pharmacol. 2012 May-Jun;56(5-6):204-9. doi: 10.1016/j.vph.2012.02.003. Epub 2012 Feb 15. Paracrine regulation of vascular tone, inflammation and insulin sensitivity by perivascular adipose tissue. Eringa EC(1), Bakker W, van Hinsbergh VW. Author information: (1)Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands. A small amount of adipose tissue associated with small arteries and arterioles is encountered both in mice and man. This perivascular adipose tissue (PVAT) has a paracrine effect on the vascular tone regulation. PVAT is expanded in obesity and in diabetes. This expansion not only involves enlargement of fat cells, but also the accumulation of inflammatory cells and a shift in the production of adipokines and cytokines. This effect is illustrated in this review by the effect of PVAT-derived factors of insulin-mediated vasoregulation in mouse resistance arteries. Insulin sensitivity of endothelial cells is also involved in the insulin-mediated regulation of muscle glucose uptake. Insulin affects vasoregulation by acting on different signaling pathways regulating NO and endothelin-1 release. This process is influenced by various adipokines and inflammatory mediators released from PVAT, and is affected by the degree of expansion and content of inflammatory cells. It is modulated by adiponectin (via 5' adenosine monophosphate-activated protein kinase, AMPK), TNFα (via c-jun N-terminal kinase) and free fatty acids (via protein kinase C-θ). PVAT thus provides an important site of control of vascular (dys)function in obesity and type 2 diabetes. An altered profile of adipokine and cytokine production by PVAT of resistance arteries may also contribute to or modulate hypertension, but a causal role in hypertension has still to be established. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22366250 [PubMed - indexed for MEDLINE] 349. Sheng Li Ke Xue Jin Zhan. 2011 Dec;42(6):467-71. [Research on MSTN coordination body fat and skeletal muscle cell proliferation and differentiation and energy metabolization balance]. [Article in Chinese] Ji YT, Qu CQ. PMID: 22363990 [PubMed - indexed for MEDLINE] 350. Environ Health Prev Med. 2012 Sep;17(5):348-56. doi: 10.1007/s12199-012-0271-0. Epub 2012 Feb 24. Preventive and improvement effects of exercise training and supplement intake in white adipose tissues on obesity and lifestyle-related diseases. Sakurai T(1), Ogasawara J, Kizaki T, Ishibashi Y, Sumitani Y, Takahashi K, Ishida H, Miyazaki H, Saitoh D, Haga S, Izawa T, Ohno H. Author information: (1)Department of Molecular Predictive Medicine and Sport Science, School of Medicine, Kyorin University, Shinkawa, Mitaka, Tokyo, Japan. sakutaku@ks.kyorin-u.ac.jp Recent increases in the number of obese individuals and individuals suffering from lifestyle-related diseases, such as type 2 diabetes, that accompany obesity have become a serious social problem. White adipose tissue (WAT) is more than a mere organ for storage of energy; it is also a highly active metabolic and endocrine organ that secretes physiologically active substances collectively known as adipokines, including tumor necrosis factor-α and adiponectin. Dysregulated expression of adipokines in WAT that is hypertrophied by obesity has been closely associated with the phenomenon of insulin resistance. Therefore, WAT is currently considered to be one of the tissues that promote lifestyle-related diseases. Reduction of excess WAT that results from obesity is seen as an important strategy in preventing and improving lifestyle-related diseases. This review shows that exercise training as well as intake of supplements, such as polyphenols, is one strategy for this, because this regimen can result in reduction of WAT mass, which affects the expression and secretory response of adipokines. PMCID: PMC3437364 PMID: 22362099 [PubMed - indexed for MEDLINE] 351. Curr Pharm Des. 2012;18(13):1821-45. Clinical applications and biosafety of human adult mesenchymal stem cells. Mariani E(1), Facchini A. Author information: (1)Laboratorio di Immunoreumatologia e Rigenerazione Tissutale and Laboratorio RAMSES, Rizzoli Orthopedic Institute, Bologna, Dipartimento di Medicina Clinica, University of Bologna, Italy. erminia.mariani@unibo.it Mesenchymal Stem Cells (MSCs) are a population of adherent cells that can differentiate into mesenchymal lineage populations (cartilage, bone and fat tissue). In addition, they seem to be able to differentiate also into a broader type of lineages other than the original mesodermal germ layer. Bone marrow MSCs are a standard in the field of adult stem cell biology and clinical applications; however adipose-derived MSCs are becoming an attractive alternative due to their minimally invasive accessibility and availability in the body. MSCs modulate several effector immune functions by interacting both with innate and adoptive immune responses. Several local signals from the tissue microenvironment, together with cytokine and soluble factors released by MSCs influence anti-inflammatory and tissue repair properties of infused MSCs. Therefore, cellular therapies utilizing ex vivo expanded MSCs may be an interesting approach for inflammatory and autoimmune diseases. Biosafety is still one of the most important aspects; therefore the production of clinical-grade MSCs requires the careful identification and control of all the phases of cell manipulation and release. Many clinical applications of adult MSCs are in progress and are using bone marrow or adipose tissue-derived MSCs for the treatment of Graft Versus Host Disease (GVHD), inflammatory joint diseases and osteocartilagineous defects, digestive tract, cardiovascular and neurological diseases. PMID: 22352750 [PubMed - indexed for MEDLINE] 352. J Physiol. 2012 Apr 15;590(Pt 8):1787-801. doi: 10.1113/jphysiol.2011.221036. Epub 2012 Feb 20. Obesity and adipokines: effects on sympathetic overactivity. Smith MM(1), Minson CT. Author information: (1)Department of Human Physiology, University of Oregon, Eugene, OR 97403-1240, USA. Excess body weight is a major risk factor for cardiovascular disease, increasing the risk of hypertension, hyperglycaemia and dyslipidaemia, recognized as the metabolic syndrome. Adipose tissue acts as an endocrine organ by producing various signalling cytokines called adipokines (including leptin, free fatty acids, tumour necrosis factor-α, interleukin-6, C-reactive protein, angiotensinogen and adiponectin). A chronic dysregulation of certain adipokines can have deleterious effects on insulin signalling. Chronic sympathetic overactivity is also known to be present in central obesity, and recent findings demonstrate the consequence of an elevated sympathetic outflow to organs such as the heart, kidneys and blood vessels. Chronic sympathetic nervous system overactivity can also contribute to a further decline of insulin sensitivity, creating a vicious cycle that may contribute to the development of the metabolic syndrome and hypertension. The cause of this overactivity is not clear, but may be driven by certain adipokines. The purpose of this review is to summarize how obesity, notably central or visceral as observed in the metabolic syndrome, leads to adipokine expression contributing to changes in insulin sensitivity and overactivity of the sympathetic nervous system. PMCID: PMC3573303 PMID: 22351630 [PubMed - indexed for MEDLINE] 353. J Physiol Biochem. 2012 Dec;68(4):701-11. doi: 10.1007/s13105-012-0154-2. Epub 2012 Feb 17. Oxidative stress and inflammation interactions in human obesity. Bondia-Pons I(1), Ryan L, Martinez JA. Author information: (1)Department of Nutrition, Food Science, Physiology and Toxicology Research Building, University of Navarra, C/ Irunlarrea 1, 31008 Pamplona, Spain. Obesity is often characterized by increased oxidative stress and exacerbated inflammatory outcomes accompanying infiltration of immune cells in adipocytes. The oxidative stress machinery and inflammatory signaling are not only interrelated, but their impairment can lead to an inhibition of insulin responses as well as a higher risk of cardiovascular diseases and associated features. Mitochondria, in addition to energy transformation, play a role in apoptosis, cellular proliferation, as well as in the cellular redox state control. Under certain circumstances, protons are able to re-enter the mitochondrial matrix via different uncoupling proteins, disturbing free radical production by mitochondria. Disorders of the mitochondrial electron transport chain, over-generation of reactive oxygen species, and lipoperoxides or alterations in antioxidant defenses have been reported in situations of obesity and type-2 diabetes. On the other hand, obesity has been linked to a low grade pro-inflammatory state, in which impairments in the oxidative stress and antioxidant mechanism could be involved. The current scientific evidence highlights the need of investigating the interplay between oxidative stress and inflammation with obesity/diabetes onset as well as the interactions of such factors either as a cause or consequence of obesity. The signaling mediated by the activation of inflammatory markers or nuclear factor kappa β and other transcription factors as central regulators of inflammation are key issues to understanding oxidative stress responses in obesity. This review aims at summarizing the main mechanisms and interplay factors between oxidative stress and inflammation in human obesity according to the last 10 years of research in the field. PMID: 22351038 [PubMed - indexed for MEDLINE] 354. Sheng Li Xue Bao. 2012 Feb 25;64(1):96-100. [Effects of visfatin gene polymorphisms on glycolipid metabolism and exercise-induced weight reduction in obesity]. [Article in Chinese] Lai AP(1), Chen WH. Author information: (1)Physical Education Department of Zhejiang College of Sports, Hangzhou 311231, China. lap810@163.com Visfatin, also named nicotinamide phosphoribosyl transferase (NAMPT), is a cytokine secreted from adipose tissue. Visfatin can regulate immune action and is involved in the NAD+ salvage pathway. In addition, recent researches have shown that visfatin helps the regulation of glucose and lipid metabolism, especially in exercise-induced weight reduction for obesity. The aim of this review is to provide an overview of the contribution of visfatin gene polymorphisms to glucose and lipid metabolism and exercise-induced weight reduction in obesity. PMID: 22348967 [PubMed - indexed for MEDLINE] 355. World J Gastroenterol. 2012 Feb 7;18(5):393-400. doi: 10.3748/wjg.v18.i5.393. Estrogen, male dominance and esophageal adenocarcinoma: is there a link? Yang H, Sukocheva OA, Hussey DJ, Watson DI. Esophageal adenocarcinoma is a cancer with poor prognosis, and its incidence has risen sharply over recent decades. Obesity is a major risk factor for developing this cancer and there is a clear male gender bias in the incidence that cannot be fully explained by known risk factors. It is possible that a difference in the expression of estrogen, or its signaling axes, may contribute to this gender bias. We undertook a comprehensive literature search and analyzed the available data regarding estrogen and estrogen receptor expression, and the possible sex-specific links with esophageal adenocarcinoma development. Potentially relevant associations between visceral vs subcutaneous fat deposition and estrogen expression, and the effect of crosstalk between estrogen and leptin signaling were identified. We also found limited studies suggesting a role for estrogen receptor β expression in esophageal adenocarcinoma development. The current literature supports speculation on an etiological role for estrogen in the male gender bias in esophageal adenocarcinoma, but further studies are required. PMCID: PMC3270506 PMID: 22346245 [PubMed - indexed for MEDLINE] 356. Drug Discov Today. 2012 Jul;17(13-14):702-9. doi: 10.1016/j.drudis.2012.02.001. Epub 2012 Feb 10. Myostatin: more than just a regulator of muscle mass. Argilés JM(1), Orpí M, Busquets S, López-Soriano FJ. Author information: (1)Cancer Research Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Spain. The presence of sufficient skeletal muscle mass is of paramount importance for body function and the myostatin cascade is known to inhibit muscle growth in mammals. In addition, myostatin seems to have an important role in the cross-talk between skeletal muscle and adipose tissue and is involved in insulin sensitivity. In this article we highlight the latest developments related to the myostatin system, emphasizing therapeutic implications for wasting diseases and also the involvement of the system in other organs, in addition to skeletal muscle, such as heart or adipose tissue. Moreover, we highlight the possible role of the myostatin system in the cross-talk between skeletal muscle and adipose tissue, an important aspect that deserves consideration in wasting diseases. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22342983 [PubMed - indexed for MEDLINE] 357. Biochimie. 2012 Oct;94(10):2172-9. doi: 10.1016/j.biochi.2012.01.021. Epub 2012 Feb 4. Adiponectin and leptin in human severe insulin resistance - diagnostic utility and biological insights. Groeneveld MP(1), Huang-Doran I, Semple RK. Author information: (1)University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. There is an intimate interplay between systemic insulin action and the actions of the adipocyte-derived proteins leptin and adiponectin. Concordant findings in humans and rodents demonstrate that leptin gates critical physiological functions to the prevailing nutritional state, however the physiological functions of adiponectin are less convincingly established. Murine evidence suggests that adiponectin can exert insulin-sensitising effects, plasma concentrations of adiponectin in humans correlate in most populations with insulin sensitivity, and increasingly strong evidence suggests an association between common genetic variation around the adiponectin gene and diabetes. However rare and severe genetic variants lowering adiponectin levels have not been convincingly associated with insulin resistance, and the discordant and sometimes extreme hyperadiponectinaemia seen in patients with severe insulin resistance due to loss of insulin receptor function poses a challenge to the widely held view that low adiponectin in humans plays a role in causing prevalent insulin resistance. The mechanism underlying this phenomenon remains to be elucidated, but the best available evidence implicates increased production of adiponectin in states of insulin receptor dysfunction, attributable at least in part to increased transcription of the ADIPOQ gene. Further investigation of the cellular basis of insulin receptoropathy-related hyperadiponectinaemia may shine further light on the human pathobiology of this most abundant and enigmatic product of adipose tissue. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMID: 22342226 [PubMed - indexed for MEDLINE] 358. Rev Med Suisse. 2012 Jan 25;8(325):220-1. [The optimum weight...and how can it be reached and sustained ]. [Article in German] Imoberdorf R(1). Author information: (1)CA Klinik für Innere Medizin, Winterthur Kantonsspital, 8400 Winterthur. reinhard.imoberdorf@ksw.ch PMID: 22338524 [PubMed - indexed for MEDLINE] 359. Adv Nutr. 2011 Jul;2(4):304-16. doi: 10.3945/​an.111.000505. Epub 2011 Jun 28. (n-3) Fatty acids alleviate adipose tissue inflammation and insulin resistance: mechanistic insights. Kalupahana NS(1), Claycombe KJ, Moustaid-Moussa N. Author information: (1)The University of Tennessee (UT) Obesity Research Center, Knoxville, TN 37996, USA. Obesity is associated with the metabolic syndrome, a significant risk factor for developing type 2 diabetes and cardiovascular diseases. Chronic low-grade inflammation occurring in the adipose tissue of obese individuals is causally linked to the pathogenesis of insulin resistance and the metabolic syndrome. Although the exact trigger of this inflammatory process is unknown, adipose tissue hypoxia, endoplasmic reticular stress, and saturated fatty acid-mediated activation of innate immune processes have been identified as important processes in these disorders. Furthermore, macrophages and T lymphocytes have important roles in orchestrating this immune process. Although energy restriction leading to weight loss is the primary dietary intervention to reverse these obesity-associated metabolic disorders, other interventions targeted at alleviating adipose tissue inflammation have not been explored in detail. In this regard, (n-3) PUFA of marine origin both prevent and reverse high-fat-diet-induced adipose tissue inflammation and insulin resistance in rodents. We provide an update on the pathogenesis of adipose tissue inflammation and insulin resistance in obesity and discuss potential mechanisms by which (n-3) PUFA prevent and reverse these changes and the implications in human health. PMCID: PMC3125680 PMID: 22332072 [PubMed - indexed for MEDLINE] 360. Adv Nutr. 2011 May;2(3):261-74. doi: 10.3945/an.111.000422. Epub 2011 Apr 30. Effects of adiposity on plasma lipid response to reductions in dietary saturated fatty acids and cholesterol. Flock MR(1), Green MH, Kris-Etherton PM. Author information: (1)Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802, USA. Dietary SFA and cholesterol are major targets for reducing plasma total and LDL cholesterol as a strategy to decrease cardiovascular disease risk. However, many studies show that excess adiposity attenuates the expected lipid and lipoprotein response to a plasma cholesterol-lowering diet. Diets low in SFA and cholesterol are less effective in improving the lipid profile in obese individuals and in patients with metabolic syndrome. In contrast, lean persons are more responsive to reductions in dietary SFA and cholesterol. Multiple mechanisms likely contribute to the altered plasma lipid responses to dietary changes in individuals with excess adiposity. The greater rate of hepatic cholesterol synthesis in obese individuals suppresses the expression of hepatic LDL receptors (LDLR), thereby reducing hepatic LDL uptake. Insulin resistance develops as a result of adipose-tissue induced inflammation, causing significant changes in enzymes necessary for normal lipid metabolism. In addition, the LDLR-mediated uptake in obesity is attenuated by alterations in neuroendocrine regulation of hormonal secretions (e.g. growth hormone, thyroid hormone, and cortisol) as well as the unique gut microbiota, the latter of which appears to affect lipid absorption. Reducing adipose tissue mass, especially from the abdominal region, is an effective strategy to improve the lipid response to dietary interventions by reducing inflammation, enhancing insulin sensitivity, and improving LDLR binding. Thus, normalizing adipose tissue mass is an important goal for maximizing the diet response to a plasma cholesterol-lowering diet. PMCID: PMC3090171 PMID: 22332058 [PubMed - indexed for MEDLINE] 361. Nat Rev Endocrinol. 2012 Feb 14;8(6):352-62. doi: 10.1038/nrendo.2012.15. The genetics of familial combined hyperlipidaemia. Brouwers MC(1), van Greevenbroek MM, Stehouwer CD, de Graaf J, Stalenhoef AF. Author information: (1)Department of Internal Medicine and Endocrinology, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX, Maastricht, The Netherlands. Almost 40 years after the first description of familial combined hyperlipidaemia (FCHL) as a discrete entity, the genetic and metabolic basis of this prevalent disease has yet to be fully unveiled. In general, two strategies have been applied to elucidate its complex genetic background, the candidate-gene and the linkage approach, which have yielded an extensive list of genes associated with FCHL or its related traits, with a variable degree of scientific evidence. Some genes influence the FCHL phenotype in many pedigrees, whereas others are responsible for the affected state in only one kindred, thereby adding to the genetic and phenotypic heterogeneity of FCHL. This Review outlines the individual genes that have been described in FCHL and how these genes can be incorporated into the current concept of metabolic pathways resulting in FCHL: adipose tissue dysfunction, hepatic fat accumulation and overproduction, disturbed metabolism and delayed clearance of apolipoprotein-B-containing particles. Genes that affect metabolism and clearance of plasma lipoprotein particles have been most thoroughly studied. The adoption of new traits, in addition to the classic plasma lipid traits, could aid in the identification of new genes implicated in other pathways in FCHL. Moreover, systems genetic analysis, which integrates genetic polymorphisms with data on gene expression levels, lipidomics or metabolomics, will attribute functions to genetic variants in addition to revealing new genes. PMID: 22330738 [PubMed - indexed for MEDLINE] 362. Curr Opin Endocrinol Diabetes Obes. 2012 Apr;19(2):81-7. doi: 10.1097/MED.0b013e3283514e13. What causes the insulin resistance underlying obesity? Hardy OT(1), Czech MP, Corvera S. Author information: (1)Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. PURPOSE OF REVIEW: The association between obesity and insulin resistance is an area of much interest and enormous public health impact, with hundreds of articles being published in the last year focused on the possible mechanisms that underlie this association. The purpose to this review is to highlight some of the key recent literature with emphasis on emerging concepts. RECENT FINDINGS: The specific link between visceral adipose tissue accumulation and insulin resistance continues to be discerned. Visceral adiposity is correlated with accumulation of excess lipid in liver, and results in cell autonomous impairment in insulin signaling. Visceral adipose tissue is also prone to inflammation and inflammatory cytokine production, which also contribute to impairment in insulin signaling. The expansion of visceral adipose tissue and excess lipid accumulation in liver and muscle may result from limited expandability of subcutaneous adipose tissue, due to the properties of its extracellular matrix and capacity for capillary growth. SUMMARY: Recent studies underscore the need to better understand the mechanisms linking visceral adiposity with liver fat accumulation, the mechanisms by which ectopic fat accumulation cause insulin resistance, and the mechanisms by which the size of adipose tissue depots is determined. PMCID: PMC4038351 PMID: 22327367 [PubMed - indexed for MEDLINE] 363. Mol Med Rep. 2012 May;5(5):1135-40. doi: 10.3892/mmr.2012.785. Epub 2012 Feb 10. Gene expression of adipose tissue, endothelial cells and platelets in subjects with metabolic syndrome (Review). Pérez PM(1), Moore-Carrasco R, González DR, Fuentes EQ, Palomo IG. Author information: (1)Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile. Metabolic syndrome is a combination of medical disorders including hypertension, dyslipidemia, hyperglycemia, insulin resistance and increased waist circumference, and is associated with a higher risk of cardiovascular disease. An increase in adipose tissue mass is associated with the augmented secretion of certain adipokines, such as interleukin-6, tumor necrosis factor-α and resistin, which cause endothelial dysfunction (an increase in vasoconstrictor molecules and in the expression of adhesion molecules as well as a decrease of vasodilator molecules, amongst other features) and hemostasis alterations that also favor a prothrombotic state (increased fibrinogen and plasminogen activator inhibitor-1 concentrations and platelet activation/aggregation). This interaction between adipose tissue, endothelial cells and platelets is associated with an increase or decrease in the expression of several transcription factors (peroxisome proliferator-activated receptors, CCAAT-enhancer-binding proteins, carbohydrate responsive element-binding proteins and sterol regulatory element-binding proteins) that play a crucial role in the regulation of distinct metabolic pathways related to the metabolic syndrome. In the present review, we present the primary changes in adipose tissue, endothelial cells and platelets in subjects with metabolic syndrome and their possible target sites at the gene expression level. PMID: 22327350 [PubMed - indexed for MEDLINE] 364. Gastroenterology. 2012 Apr;142(4):711-725.e6. doi: 10.1053/j.gastro.2012.02.003. Epub 2012 Feb 8. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Cusi K(1). Author information: (1)Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida 32610-0226, USA. kenneth.cusi@medicine.ufl.edu As obesity reaches epidemic proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a frequent cause of patient referral to gastroenterologists. There is a close link between dysfunctional adipose tissue in NAFLD and common conditions such as metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. This review focuses on the pathophysiology of interactions between adipose tissue and target organs in obesity and the resulting clinical implications for the management of nonalcoholic steatohepatitis. The release of fatty acids from dysfunctional and insulin-resistant adipocytes results in lipotoxicity, caused by the accumulation of triglyceride-derived toxic metabolites in ectopic tissues (liver, muscle, pancreatic beta cells) and subsequent activation of inflammatory pathways, cellular dysfunction, and lipoapoptosis. The cross talk between dysfunctional adipocytes and the liver involves multiple cell populations, including macrophages and other immune cells, that in concert promote the development of lipotoxic liver disease, a term that more accurately describes the pathophysiology of nonalcoholic steatohepatitis. At the clinical level, adipose tissue insulin resistance contributes to type 2 diabetes mellitus and cardiovascular disease. Treatments that rescue the liver from lipotoxicity by restoring adipose tissue insulin sensitivity (eg, significant weight loss, exercise, thiazolidinediones) or preventing activation of inflammatory pathways and oxidative stress (ie, vitamin E, thiazolidinediones) hold promise in the treatment of NAFLD, although their long-term safety and efficacy remain to be established. Better understanding of pathways that link dysregulated adipose tissue, metabolic dysfunction, and liver lipotoxicity will result in improvements in the clinical management of these challenging patients. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved. PMID: 22326434 [PubMed - indexed for MEDLINE] 365. J Androl. 2012 Sep-Oct;33(5):763-76. Epub 2012 Feb 9. Diet, obesity, and prostate health: are we missing the link? Tewari R(1), Rajender S, Natu SM, Dalela D, Goel A, Goel MM, Tandon P. Author information: (1)Department of Pathology, Chatrapati Shahuji Maharaj Medical University, Lucknow, Uttar Pradesh, India. Prostate problems, such as benign prostatic hyperplasia, prostatic intra-epithelial neoplasia, prostatitis, and prostate cancer have been recognized as problems largely related to androgens and genetic factors. They affect a large fraction of the elderly population, contributing significantly to morbidity and mortality. Estrogen has also now been recognized as one of the important regulators of prostate growth. Diet, general health, and obesity were disregarded as the causative or complicating factors until very recently. Increasing episodes of prostate problems, complications in overweight/obese individuals, or both have attracted attention toward these contemporary risk factors. Prostate problems are reportedly less frequent or less severe in areas in which a plant-based diet is predominant. Consumption of certain fatty acids, particularly of animal origin, has been correlated with increased prostate problems. As adipose tissue is increasingly being regarded as hormonally active tissue, high body fat and obesity need in-depth exploration to understand the associated risk of prostate problems. Adipose tissue is now known to affect circulating levels of several bioactive messengers and therefore could affect the risk of developing prostate problems in addition to several other well-recognized health problems. Nevertheless, increased plasma volume, excess tissue growth, and fat deposition could affect resection and number of biopsies required, thus adding further complications because of a delayed diagnosis. In short, evidence is gathering to support the influence of diet and obesity on prostate health. In this review article, we have tried to make this connection more apparent using supporting published data. PMID: 22323623 [PubMed - indexed for MEDLINE] 366. Diabetes Obes Metab. 2012 Oct;14(10):869-81. doi: 10.1111/j.1463-1326.2012.01582.x. Epub 2012 Mar 8. 11β-Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus. Pereira CD(1), Azevedo I, Monteiro R, Martins MJ. Author information: (1)Department of Biochemistry (U38/FCT), Faculty of Medicine, University of Porto, Portugal. Recent evidence strongly argues for a pathogenic role of glucocorticoids and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in obesity and the metabolic syndrome, a cluster of risk factors for atherosclerotic cardiovascular disease and type 2 diabetes mellitus (T2DM) that includes insulin resistance (IR), dyslipidaemia, hypertension and visceral obesity. This has been partially prompted not only by the striking clinical resemblances between the metabolic syndrome and Cushing's syndrome (a state characterized by hypercortisolism that associates with metabolic syndrome components) but also from monogenic rodent models for the metabolic syndrome (e.g. the leptin-deficient ob/ob mouse or the leptin-resistant Zucker rat) that display overall increased secretion of glucocorticoids. However, systemic circulating glucocorticoids are not elevated in obese patients and/or patients with metabolic syndrome. The study of the role of 11β-HSD system shed light on this conundrum, showing that local glucocorticoids are finely regulated in a tissue-specific manner at the pre-receptor level. The system comprises two microsomal enzymes that either activate cortisone to cortisol (11β-HSD1) or inactivate cortisol to cortisone (11β-HSD2). Transgenic rodent models, knockout (KO) for HSD11B1 or with HSD11B1 or HSD11B2 overexpression, specifically targeted to the liver or adipose tissue, have been developed and helped unravel the currently undisputable role of the enzymes in metabolic syndrome pathophysiology, in each of its isolated components and in their prevention. In the transgenic HSD11B1 overexpressing models, different features of the metabolic syndrome and obesity are replicated. HSD11B1 gene deficiency or HSD11B2 gene overexpression associates with improvements in the metabolic profile. In face of these demonstrations, research efforts are now being turned both into the inhibition of 11β-HSD1 as a possible pharmacological target and into the role of dietary habits on the establishment or the prevention of the metabolic syndrome, obesity and T2DM through 11β-HSD1 modulation. We intend to review and discuss 11β-HSD1 and obesity, the metabolic syndrome and T2DM and to highlight the potential of its inhibition for therapeutic or prophylactic approaches in those metabolic diseases. © 2012 Blackwell Publishing Ltd. PMID: 22321826 [PubMed - indexed for MEDLINE] 367. Clin Liver Dis. 2012 Feb;16(1):95-131. doi: 10.1016/j.cld.2011.12.009. Epub 2012 Jan 23. Malnutrition in cirrhosis: contribution and consequences of sarcopenia on metabolic and clinical responses. Periyalwar P(1), Dasarathy S. Author information: (1)Department of Gastroenterology, Metrohealth Medical Center, 2500 Metrohealth Drive, Cleveland, OH 44109, USA. Malnutrition is the most common, reversible complication of cirrhosis that adversely affects survival, response to other complications, and quality of life. Sarcopenia, or loss of skeletal muscle mass, and loss of adipose tissue and altered substrate use as a source of energy are the 2 major components of malnutrition in cirrhosis. Current therapies include high protein supplementation especially as a late evening snack. Exercise protocols have the potential of aggravating hyperammonemia and portal hypertension. Recent advances in understanding the molecular regulation of muscle mass has helped identify potential novel therapeutic targets including myostatin antagonists, and mTOR resistance. Copyright © 2012 Elsevier Inc. All rights reserved. PMCID: PMC4383161 PMID: 22321468 [PubMed - indexed for MEDLINE] 368. Am J Physiol Endocrinol Metab. 2012 May 1;302(10):E1157-70. doi: 10.1152/ajpendo.00351.2011. Epub 2012 Feb 7. Update on adipose tissue blood flow regulation. Sotornik R(1), Brassard P, Martin E, Yale P, Carpentier AC, Ardilouze JL. Author information: (1)Diabetes and Metabolism Research Group, Division of Endocrinology, Department of Medicine, Centre Hospitalier, Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Quebec, Canada. According to Fick's principle, any metabolic or hormonal exchange through a given tissue depends on the product of the blood flow to that tissue and the arteriovenous difference. The proper function of adipose tissue relies on adequate adipose tissue blood flow (ATBF), which determines the influx and efflux of metabolites as well as regulatory endocrine signals. Adequate functioning of adipose tissue in intermediary metabolism requires finely tuned perfusion. Because metabolic and vascular processes are so tightly interconnected, any disruption in one will necessarily impact the other. Although altered ATBF is one consequence of expanding fat tissue, it may also aggravate the negative impacts of obesity on the body's metabolic milieu. This review attempts to summarize the current state of knowledge on adipose tissue vascular bed behavior under physiological conditions and the various factors that contribute to its regulation as well as the possible participation of altered ATBF in the pathophysiology of metabolic syndrome. PMID: 22318953 [PubMed - indexed for MEDLINE] 369. J Gastroenterol. 2012 Mar;47(3):215-25. doi: 10.1007/s00535-012-0527-x. Epub 2012 Feb 7. Inflammation and fibrogenesis in steatohepatitis. Fujii H(1), Kawada N. Author information: (1)Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahimachi, Abeno-ku, Osaka 545-8585, Japan. Nonalcoholic fatty liver disease consists of a range of disorders characterized by excess accumulation of triglyceride within the liver. Whereas simple steatosis is clinically benign, nonalcoholic steatohepatitis (NASH) often progresses to cirrhosis. Inflammation and fibrogenesis are closely inter-related and are major targets of NASH research. Experimental data have shown that inflammation in NASH is caused by insulin resistance, systemic lipotoxicity due to overnutrition, lipid metabolites, the production of proinflammatory cytokines and adipokines by visceral adipose tissue, gut-derived bacteria, and oxidative stress. In NASH-associated fibrosis, the principal cell type responsible for extracellular matrix production is recognized as the hepatic stellate cell. Although the fibrotic mechanisms underlying NASH are largely similar to those observed in other chronic liver diseases, the altered patterns of circulating adipokines, the generation of oxidative stress, and the hormonal profile associated with the metabolic syndrome might play unique roles in the fibrogenesis associated with the disease. Information on the basic pathogenesis of NASH with a focus on the generation of inflammation and fibrosis will be discussed. PMID: 22310735 [PubMed - indexed for MEDLINE] 370. Lipids Health Dis. 2012 Feb 6;11:20. doi: 10.1186/1476-511X-11-20. Effects of sterol regulatory element-binding protein (SREBP) in chickens. Khesht FA(1), Hassanabadi A. Author information: (1)Department of Animal Science, Faculty of Agriculture, Ferdowsi University of Mashhad, Mashhad, Iran. Alipour_387@yahoo.com Sterol regulatory element binding protein- 1 and -2 (SREBP-1 and -2) are key transcription factors involved in the biosynthesis of cholesterol and fatty acids. The SREBP have mostly been studied in rodents in which lipogenesis is regulated in both liver and adipose tissue. There is, though, a paucity of information on birds, in which lipogenesis occurs essentially in the liver as in humans. Since a prelude to the investigation of the role of SREBP in lipid metabolism regulation in chicken, we review Size and Tissue expression Pattern of SREBP and role of this protein in chickens. PMCID: PMC3305589 PMID: 22309629 [PubMed - indexed for MEDLINE] 371. Cell Microbiol. 2012 May;14(5):634-43. doi: 10.1111/j.1462-5822.2012.01764.x. Epub 2012 Feb 24. Mechanisms of Trypanosoma cruzi persistence in Chagas disease. Nagajyothi F(1), Machado FS, Burleigh BA, Jelicks LA, Scherer PE, Mukherjee S, Lisanti MP, Weiss LM, Garg NJ, Tanowitz HB. Author information: (1)Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA. Trypanosoma cruzi infection leads to development of chronic Chagas disease. In this article, we provide an update on the current knowledge of the mechanisms employed by the parasite to gain entry into the host cells and establish persistent infection despite activation of a potent immune response by the host. Recent studies point to a number of T. cruzi molecules that interact with host cell receptors to promote parasite invasion of the diverse host cells. T. cruzi expresses an antioxidant system and thromboxane A(2) to evade phagosomal oxidative assault and suppress the host's ability to clear parasites. Additional studies suggest that besides cardiac and smooth muscle cells that are the major target of T. cruzi infection, adipocytes and adipose tissue serve as reservoirs from where T. cruzi can recrudesce and cause disease decades later. Further, T. cruzi employs at least four strategies to maintain a symbiotic-like relationship with the host, and ensure consistent supply of nutrients for its own survival and long-term persistence. Ongoing and future research will continue to help refining the models of T. cruzi invasion and persistence in diverse tissues and organs in the host. © 2012 Blackwell Publishing Ltd. PMCID: PMC3556388 PMID: 22309180 [PubMed - indexed for MEDLINE] 372. Am J Physiol Heart Circ Physiol. 2012 Apr 15;302(8):H1539-45. doi: 10.1152/ajpheart.00626.2011. Epub 2012 Feb 3. Bariatric surgery to unload the stressed heart: a metabolic hypothesis. Algahim MF(1), Sen S, Taegtmeyer H. Author information: (1)Division of Cardiology, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, Texas 77030, USA. Obesity is an independent risk factor for cardiovascular disease. Data from the Framingham Study have reported a higher incidence of heart failure in obese individuals compared with a normal cohort. The body initially copes with the abundance of fuel present in an obese milieu by storing it in adipose tissue. However, when the storage capacity is exceeded, the excess energy is taken up and stored ectopically as fat in vital organs such as the heart. Indeed, intramyocardial lipid overload is present in hearts of obese patients, as well as in hearts of animal models of obesity, and is associated with a distinct gene expression profile and cardiac dysfunction. By imposing a metabolic stress on the heart, obesity causes it to hypertrophy and ultimately to fail. Conventional measures to treat obesity include diet, exercise, and drugs. More recently, weight loss surgery (WLS) has achieved increasing prominence because of its ability to reduce the neurohumoral load, normalize metabolic dysregulation, and improve overall survival. The effects of WLS on systemic metabolic, neurohumoral, and hemodynamic parameters are well described and include an early normalization of serum glucose and insulin levels as well as reduction in blood pressure. WLS is also associated with reverse cardiac remodeling, regression of left ventricular hypertrophy, and improved left ventricular and right ventricular function. By targeting the source of the excess energy, we hypothesize that WLS improves contractile function by limiting exogenous substrate availability to the metabolically overloaded heart. These changes have also been found to be associated with increased levels of adiponectin and improved insulin sensitivity. Taken together, the sustained beneficial effects of WLS on left ventricular mass and function highlight the need to better understand the mechanism by which obesity regulates cardiovascular physiology. PMCID: PMC3330804 PMID: 22307676 [PubMed - indexed for MEDLINE] 373. Physiol Rev. 2012 Jan;92(1):157-91. doi: 10.1152/physrev.00012.2011. Physical activity and exercise in the regulation of human adipose tissue physiology. Thompson D(1), Karpe F, Lafontan M, Frayn K. Author information: (1)Department for Health, University of Bath, Bath, UK. d.thompson@bath.ac.uk Physical activity and exercise are key components of energy expenditure and therefore of energy balance. Changes in energy balance alter fat mass. It is therefore reasonable to ask: What are the links between physical activity and adipose tissue function? There are many complexities. Physical activity is a multifaceted behavior of which exercise is just one component. Physical activity influences adipose tissue both acutely and in the longer term. A single bout of exercise stimulates adipose tissue blood flow and fat mobilization, resulting in delivery of fatty acids to skeletal muscles at a rate well-matched to metabolic requirements, except perhaps in vigorous intensity exercise. The stimuli include adrenergic and other circulating factors. There is a period following an exercise bout when fatty acids are directed away from adipose tissue to other tissues such as skeletal muscle, reducing dietary fat storage in adipose. With chronic exercise (training), there are changes in adipose tissue physiology, particularly an enhanced fat mobilization during acute exercise. It is difficult, however, to distinguish chronic "structural" changes from those associated with the last exercise bout. In addition, it is difficult to distinguish between the effects of training per se and negative energy balance. Epidemiological observations support the idea that physically active people have relatively low fat mass, and intervention studies tend to show that exercise training reduces fat mass. A much-discussed effect of exercise versus calorie restriction in preferentially reducing visceral fat is not borne out by meta-analyses. We conclude that, in addition to the regulation of fat mass, physical activity may contribute to metabolic health through beneficial dynamic changes within adipose tissue in response to each activity bout. PMID: 22298655 [PubMed - indexed for MEDLINE] 374. Ann Pharmacother. 2012 Feb;46(2):240-7. doi: 10.1345/aph.1Q629. Epub 2012 Jan 31. Tesamorelin: a growth hormone-releasing factor analogue for HIV-associated lipodystrophy. Spooner LM(1), Olin JL. Author information: (1)School of Pharmacy-Worcester/Manchester, Massachusetts College of Pharmacy and Health Sciences, USA. linda.spooner@mcphs.edu OBJECTIVE: To evaluate the efficacy and safety of tesamorelin, a growth hormone releasing factor analogue approved by the Food and Drug Administration in November 2010 for the treatment of lipodystrophy associated with HIV infection. DATA SOURCES: Literature was obtained through MEDLINE (1948-November 2011) and International Pharmaceutical Abstracts (1970-October 2011) using the search terms tesamorelin, TH9507, growth hormone releasing factor, and HIV-associated lipodystrophy syndrome. Additional publications were obtained through review of references within primary literature publications as well as pertinent Web sites. STUDY SELECTION AND DATA EXTRACTION: All articles published in English identified from the data sources were evaluated and all pertinent information was included. All studies relevant to the evaluation of efficacy and safety of tesamorelin in the management of HIV-associated lipodystrophy were included, with a focus on trials completed in humans. DATA SYNTHESIS: In 2 Phase 3 clinical trials and their pooled analyses, tesamorelin was proven to significantly decrease waist circumference and visceral adipose tissue (VAT) following 26 weeks of treatment. Both trials also demonstrated significant improvements in some subjective body image parameters. Both studies had 26-week extension phases that confirmed maintenance of VAT improvements on treatment without adverse impact on blood glucose and lipid parameters. Limited data support off-label uses of tesamorelin at this time. CONCLUSIONS: Tesamorelin is effective in improving visceral adiposity and body image in patients with HIV-associated lipodystrophy over 26-52 weeks of treatment. Potential limitations for its use include high cost and lack of long-term safety and adherence data. Tesamorelin provides a useful treatment option for management of patients with significant lipodystrophy related to HIV infection. PMID: 22298602 [PubMed - indexed for MEDLINE] 375. Nutr Res Rev. 2011 Dec;24(2):206-27. doi: 10.1017/S0954422411000114. Human health effects of conjugated linoleic acid from milk and supplements. McCrorie TA(1), Keaveney EM, Wallace JM, Binns N, Livingstone MB. Author information: (1)Northern Ireland Centre for Food and Health (NICHE), University of Ulster, Cromore Road, Coleraine, County Londonderry BT52 1SA, UK. t.mccrorie@ulster.ac.uk The primary purpose of the present review was to determine if the scientific evidence available for potential human health benefits of conjugated linoleic acid (CLA) is sufficient to support health claims on foods based on milk naturally enriched with cis-9, trans-11-CLA (c9, t11-CLA). A search of the scientific literature was conducted and showed that almost all the promising research results that have emerged in relation to cancer, heart health, obesity, diabetes and bone health have been in animal models or in vitro. Most human intervention studies have utilised synthetic CLA supplements, usually a 50:50 blend of c9, t11-CLA and trans-10, cis-12-CLA (t10, c12-CLA). Of these studies, the only evidence that is broadly consistent is an effect on body fat and weight reduction. A previous review of the relevant studies found that 3.2 g CLA/d resulted in a modest body fat loss in human subjects of about 0.09 kg/week, but this effect was attributed to the t10, c12-CLA isomer. There is no evidence of a consistent benefit of c9, t11-CLA on any health conditions; and in fact both synthetic isomers, particularly t10, c12-CLA, have been suspected of having pro-diabetic effects in individuals who are already at risk of developing diabetes. Four published intervention studies using naturally enriched CLA products were identified; however, the results were inconclusive. This may be partly due to the differences in the concentration of CLA administered in animal and human studies. In conclusion, further substantiation of the scientific evidence relating to CLA and human health benefits are required before health claims can be confirmed. PMID: 22296934 [PubMed - indexed for MEDLINE] 376. World J Gastroenterol. 2012 Jan 21;18(3):212-24. doi: 10.3748/wjg.v18.i3.212. Hepatitis C virus induced insulin resistance impairs response to anti viral therapy. El-Zayadi AR(1), Anis M. Author information: (1)Tropical Medicine Department, Faculty of Medicine, Ain-Shams University and Cairo liver center, Dokki, Giza 12311, Egypt. clcz@tedata.net.eg Hepatitis C virus (HCV) infection is an important risk factor for insulin resistance (IR). The latter is the pathogenic foundation underlying metabolic syndrome, steatosis and cirrhosis, and possibly hepatocellular carcinoma (HCC). The interplay between genetic and environmental risk factors ultimately leads to the development of IR. Obesity is considered a major risk factor, with dysregulation of levels of secreted adipokines from distended adipose tissue playing a major role in IR. HCV-induced IR may be due to the HCV core protein inducing proteasomal degradation of insulin receptor substrates 1 and 2, blocking intracellular insulin signaling. The latter is mediated by increased levels of both tumour necrosis factor-α (TNF-α) and suppressor of cytokine signaling 3 (SOC-3). IR, through different mechanisms, plays a role in the development of steatosis and its progression to steatohepatitis, cirrhosis and even HCC. In addition, IR has a role in impairing TNF signaling cascade, which in turn blocks STAT-1 translocation and interferon stimulated genes production avoiding the antiviral effect of interferon. PMCID: PMC3261538 PMID: 22294824 [PubMed - indexed for MEDLINE] 377. Cell Mol Life Sci. 2012 Jul;69(13):2135-46. doi: 10.1007/s00018-012-0917-5. A role for sphingolipids in the pathophysiology of obesity-induced inflammation. Bikman BT(1). Author information: (1)Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA. benjamin_bikman@byu.edu Following the initial discovery that adipose tissue actively synthesizes and secretes cytokines, obesity-induced inflammation has been implicated in the etiology of a host of disease states related to obesity, including cardiovascular disease and type II diabetes. Interestingly, a growing body of evidence similarly implicates sphingolipids as prime instigators in these same diseases. From the recent discovery that obesity-related inflammatory pathways modulate sphingolipid metabolism comes a novel perspective—sphingolipids may act as the dominant mediators of deleterious events stemming from obesity-induced inflammation. This paradigm may identify sphingolipids as an effective target for future therapeutics aimed at ameliorating diseases associated with chronic inflammation. PMID: 22294100 [PubMed - indexed for MEDLINE] 378. Pathologe. 2012 Feb;33(1):61-4. doi: 10.1007/s00292-011-1547-7. [Granular cell tumor of the stomach]. [Article in German] Gilg MM(1), Mrak K, Vieth M, Langner C. Author information: (1)Institut für Pathologie, Medizinische Universität Graz, Auenbruggerplatz 25, 8036, Graz, Österreich. Granular cell tumors are peripheral neuroectodermal tumors. Within the gastrointestinal tract, they have to be differentiated from gastrointestinal stromal tumors (GIST). We present the case of a 61-year-old patient who was diagnosed with a granular cell tumor of the stomach. The tumor cells showed transmural infiltration form the mucosa into the adipose tissue of the lesser curvature. The tumor cells were diffusely positive for S100-protein and negative for KIT, CD34 und SMA. The MIB1-proliferation index was below 2%. Granular cell tumors rarely occur within the gastrointestinal tract. Oesophagus and colon are most commonly affected. Diagnostic criteria and differential diagnosis of this peculiar lesion are thoroughly discussed. PMID: 22293791 [PubMed - indexed for MEDLINE] 379. Gen Comp Endocrinol. 2012 May 15;177(1):28-36. doi: 10.1016/j.ygcen.2012.01.009. Epub 2012 Jan 28. Leptin and the hypothalamo-pituitary-adrenal stress axis. Roubos EW(1), Dahmen M, Kozicz T, Xu L. Author information: (1)Department of Cellular Animal Physiology, Faculty of Science, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, PO Box 9010, 6500 GL Nijmegen, The Netherlands. roubos@science.ru.nl Leptin is a 16-kDa protein mainly produced and secreted by white adipose tissue and informing various brain centers via leptin receptor long and short forms about the amount of fat stored in the body. In this way leptin exerts a plethora of regulatory functions especially related to energy intake and metabolism, one of which is controlling the activity of the hypothalamo-pituitary-adrenal (HPA) stress axis. First, this review deals with the basic properties of leptin's structure and signaling at the organ, cell and molecule level, from lower vertebrates to humans but with emphasis on rodents because these have been investigated in most detail. Then, attention is given to the various interactions of adipose leptin with the HPA-axis, at the levels of the hypothalamus (especially the paraventricular nucleus), the anterior lobe of the pituitary gland (action on corticotropes) and the adrenal gland, where it releases corticosteroids needed for adequate stress adaptation. Also, possible local production and autocrine and paracrine actions of leptin at the hypothalamic and pituitary levels of the HPA-axis are being considered. Finally, a schematic model is presented showing the ways peripherally and centrally produced leptin may modulate, via the HPA-axis, stress adaptation in conjunction with the control of energy homeostasis. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22293575 [PubMed - indexed for MEDLINE] 380. Biochem Cell Biol. 2012 Apr;90(2):142-52. doi: 10.1139/o11-079. Epub 2012 Jan 31. Roles of vitamin A status and retinoids in glucose and fatty acid metabolism. Zhao S(1), Li R, Li Y, Chen W, Zhang Y, Chen G. Author information: (1)The Diabetes Center, Wuhan Central Hospital, Wuhan, Hubei 430014, China. The rising prevalence of metabolic diseases, such as obesity and diabetes, has become a public health concern. Vitamin A (VA, retinol) is an essential micronutrient for a variety of physiological processes, such as tissue differentiation, immunity, and vision. However, its role in glucose and lipid metabolism has not been clearly defined. VA activities are mediated by the metabolite of retinol catabolism, retinoic acid, which activates the retinoic acid receptor and retinoid X receptor (RXR). Since RXR is an obligate heterodimeric partner for many nuclear receptors involved in metabolism, it is reasonable to assume that VA status and retinoids contribute to glucose and lipid homeostasis. To date, the impacts of VA and retinoids on energy metabolism in animals and humans have been demonstrated in some basic and clinical investigations. This review summarizes the effects of VA status and retinoid treatments on metabolism of the liver, adipocytes, pancreatic β-cells, and skeletal muscle. It proposes a mechanism by which the dietary and hormonal signals converge on the promoter of sterol regulatory element-binding protein 1c gene to induce its expression, and in turn, the expression of lipogenic genes in hepatocytes. Future research projects relevant to the VA's roles in metabolic diseases are also discussed. PMID: 22292422 [PubMed - indexed for MEDLINE] 381. Korean J Gastroenterol. 2012 Jan;59(1):16-26. [Obesity and colorectal cancer]. [Article in Korean] Na SY(1), Myung SJ. Author information: (1)Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. Obesity worldwide is constantly increasing. Obesity acts as an independent significant risk factor for malignant tumors of various organs including colorectal cancer. Visceral adipose tissue is physiologically more important than subcutaneous adipose tissue. The relative risk of colorectal cancer of obese patients is about 1.5 times higher than the normal-weight individuals, and obesity is also associated with premalignant colorectal adenoma. The colorectal cancer incidence of obese patients has gender-specific and site-specific characteristics that it is higher in men than women and in the colon than rectum. Obesity acts as a risk factor of colorectal carcinogenesis by several mechanisms. Isulin, insulin-like growth factor, leptin, adiponectin, microbiome, and cytokines of chronic inflammation etc. have been understood as its potential mechanisms. In addition, obesity in patients with colorectal cancer negatively affects the disease progression and response of chemotherapy. Although the evidence is not clear yet, there are some reports that weight loss as well as life-modification such as dietary change and physical activity can reduce the risk of colorectal cancer. It is very important knowledge in the point that obesity is a potentially modifiable risk factor that can alter the incidence and outcome of the colorectal cancer. PMID: 22289950 [PubMed - indexed for MEDLINE] 382. Korean J Gastroenterol. 2012 Jan;59(1):8-15. [Obesity and gastrointestinal cancer-related factor]. [Article in Korean] Kim DJ(1). Author information: (1)Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Seoul, Korea. djkim@paik.ac.kr Despite a higher incidence and less favorable outcome of malignant tumors in obese patients, much less recognized is the link between obesity and cancer. The mechanism of the association of obesity with carcinogenesis remains incompletely understood. Postulated mechanisms include insulin resistance, insulin-like growth factor signaling, chronic inflammation, immunomodulation, hyperglycemia-induced oxidative stress, and changes of intestinal microbiome. Insulin resistance leads to direct mitogenic and antiapoptotic signaling by insulin and the insulin-like growth factor axis. Obesity can be considered to be a state of chronic low-grade inflammation. In obesity, numerous proinflammatory cytokines are released from adipose tissue which may involve in carcinogenesis. Hyperglycemia in susceptible cells results in the overproduction of superoxide and this process is the key to initiating all damaging pathways related to diabetes. This hyperglycemia-induced oxidative stress could be one possible link among obesity, diabetes, and cancer development. The role of obesity-related changes in the intestinal microbiome in gastrointestinal carcinogenesis deserves further attention. PMID: 22289949 [PubMed - indexed for MEDLINE] 383. Biochim Biophys Acta. 2012 Apr;1825(2):207-22. doi: 10.1016/j.bbcan.2012.01.002. Epub 2012 Jan 24. Oncogenic role and therapeutic target of leptin signaling in breast cancer and cancer stem cells. Guo S(1), Liu M, Wang G, Torroella-Kouri M, Gonzalez-Perez RR. Author information: (1)Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA. Significant correlations between obesity and incidence of various cancers have been reported. Obesity, considered a mild inflammatory process, is characterized by a high level of secretion of several cytokines from adipose tissue. These molecules have disparate effects, which could be relevant to cancer development. Among the inflammatory molecules, leptin, mainly produced by adipose tissue and overexpressed with its receptor (Ob-R) in cancer cells is the most studied adipokine. Mutations of leptin or Ob-R genes associated with obesity or cancer are rarely found. However, leptin is an anti-apoptotic molecule in many cell types, and its central roles in obesity-related cancers are based on its pro-angiogenic, pro-inflammatory and mitogenic actions. Notably, these leptin actions are commonly reinforced through entangled crosstalk with multiple oncogenes, cytokines and growth factors. Leptin-induced signals comprise several pathways commonly triggered by many cytokines (i.e., canonical: JAK2/STAT; MAPK/ERK1/2 and PI-3K/AKT1 and, non-canonical signaling pathways: PKC, JNK and p38 MAP kinase). Each of these leptin-induced signals is essential to its biological effects on food intake, energy balance, adiposity, immune and endocrine systems, as well as oncogenesis. This review is mainly focused on the current knowledge of the oncogenic role of leptin in breast cancer. Additionally, leptin pro-angiogenic molecular mechanisms and its potential role in breast cancer stem cells will be reviewed. Strict biunivocal binding-affinity and activation of leptin/Ob-R complex makes it a unique molecular target for prevention and treatment of breast cancer, particularly in obesity contexts. Copyright © 2012 Elsevier B.V. All rights reserved. PMCID: PMC3307887 PMID: 22289780 [PubMed - indexed for MEDLINE] 384. Biofactors. 2012 Jan-Feb;38(1):14-23. doi: 10.1002/biof.201. Epub 2012 Jan 30. Adipokines, an adipose tissue and placental product with biological functions during pregnancy. D'Ippolito S(1), Tersigni C, Scambia G, Di Simone N. Author information: (1)Department of Obstetrics and Gynecology, Policlinico A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy. Latter half of pregnancy is characterized by a "physiological diabetogenic state" since changes in insulin-sensitivity have been well documented. These changes ensure continuous supply of nutrients to the growing fetus. In the last years the role of adipocyte-derived signaling molecules, collectively known as adipokines has been object of different in vitro and in vivo studies. Of interest, adipokines and/or their receptors are expressed in the placental tissue which, therefore, can contribute to development of maternal insulin-resistance and, as a consequence, fetal growth. Leptin, adiponectin, and resistin represent the most well studied adipokines and, with the exception of adiponectin, their serum and placental levels increase as pregnancy progresses. High levels of adipokines have also been detected in umbilical plasma hence suggesting a possible role on fetal development and metabolism; however, it remains still unclear if such adipokines can directly stimulate fetal tissues development acting as growth factors. In addition to their well known metabolic effects, we also reported studies describing the role of adipokines in promoting proliferation and invasiveness of trophoblast cells and affecting local angiogenic processes. These observations strongly suggest that adipokines, by alternatively interfering with placental development, may affect pregnancy outcome and fetal growth. However, further studies are needed to better understand the local regulation of their expression. © 2012 International Union of Biochemistry and Molecular Biology, Inc. Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc. PMID: 22287297 [PubMed - indexed for MEDLINE] 385. Obesity (Silver Spring). 2012 May;20(5):923-31. doi: 10.1038/oby.2011.398. Epub 2012 Jan 26. Adipose tissue as a potential source of hematopoietic stem/progenitor cells. Błogowski W(1), Ratajczak MZ, Zyżniewska-Banaszak E, Dołęgowska B, Starzyńska T. Author information: (1)Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland. drannab@wp.pl It has been more than 30 years since adipose tissue (AT) has been recognized as a central modulator orchestrating sophisticated process termed "immunometabolism". Nonetheless, despite its unique involvement in the regulation of immune and endocrine homeostasis, recent studies demonstrated that AT also contains significant number of hematopoietic stem/progenitor cells (HSPCs) that may be there "settling down" throughout life. In this article we will focus on presenting the current concepts regarding endocrine, immunological, and molecular mechanisms that may contribute to and regulate bone marrow (BM)-derived HSPCs homing into AT environment, as well as, highlight various structural and morphological similarities between BM and AT that might be involved in creating appropriate tissue niches for BM-derived HSPCs in AT. Finally, we will discuss how development of obesity or type 2 diabetes may influence balance of homing signals for HSPCs in AT environment. PMID: 22282043 [PubMed - indexed for MEDLINE] 386. Curr Opin Lipidol. 2012 Apr;23(2):111-21. doi: 10.1097/MOL.0b013e3283508c4f. Bone marrow transplantation as an established approach for understanding the role of macrophages in atherosclerosis and the metabolic syndrome. Aparicio-Vergara M(1), Shiri-Sverdlov R, Koonen DP, Hofker MH. Author information: (1)Molecular Genetics, Medical Biology Section, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. PURPOSE OF REVIEW: Bone marrow transplantation (BMT) technology is a firmly established tool for studying atherosclerosis. Only recently it is helping us to understand the inflammatory mechanisms leading to the development of obesity, insulin resistance and type 2 diabetes. Here we review the use of BMT as a tool for studying the metabolic syndrome. RECENT FINDINGS: Bone marrow-derived cells, and particularly monocytes and macrophages, have been a major subject in the study of atherogenesis, and they are highly amenable for research purposes because of their application in bone marrow transplantations. For example, the many pathways studied using BMT have helped unmask ABC transporters as the genes controlling reverse cholesterol transport and foam cell formation, as well as other genes like CCR2 and IκBα controlling leukocyte development, migration and activation. The invasion of leukocytes, not only in the vessel wall, but also in adipose tissue and liver, shares many common mechanisms relevant to atherosclerosis and metabolic diseases. SUMMARY: BMT is an efficient and versatile tool for assessing the roles of specific genes that are restricted to hematopoietic cells, and especially the monocytes and macrophages in metabolic syndrome and its related pathologies. PMID: 22274753 [PubMed - indexed for MEDLINE] 387. J Burn Care Res. 2012 Jul-Aug;33(4):471-82. doi: 10.1097/BCR.0b013e318247959b. Obesity and burns. Goutos I(1), Sadideen H, Pandya AA, Ghosh SJ. Author information: (1)Department of Plastic and Reconstructive Surgery, John Radcliffe Hospital, Headley Way, Headington, Oxford, United Kingdom. The population of overweight patients presenting to burn facilities is expected to increase significantly over the next decades due to the global epidemic of obesity. Excess adiposity mediates alterations to key physiological responses and poses challenges to the optimal management of burns. The purpose of this study is to document the general epidemiological aspects of thermal injuries in the obese population, outline relevant physiological aspects associated with obesity, and draw attention to topics relating to the management, rehabilitation, and prognosis of burns in this emerging subpopulation of patients. PMID: 22274633 [PubMed - indexed for MEDLINE] 388. J Physiol. 2012 Mar 1;590(Pt 5):1059-68. doi: 10.1113/jphysiol.2011.225011. Epub 2012 Jan 23. Regulation and limitations to fatty acid oxidation during exercise. Jeppesen J(1), Kiens B. Author information: (1)Molecular Physiology Group, Department of Exercise and Sport Sciences, University of Copenhagen, Denmark. Fatty acids (FAs) as fuel for energy utilization during exercise originate from different sources: FAs transported in the circulation either bound to albumin or as triacylglycerol (TG) carried by very low density lipoproteins and FAs from lipolysis of muscle TG stores. Despite a high rate of energy expenditure during high intensity exercise the total FA oxidation is suppressed to below that observed during moderate intensity exercise. Although this has been known for many years, the mechanisms behind this phenomenon are still not fully elucidated. A failure of adipose tissue to deliver sufficient FAs to exercising muscle has been proposed, but evidence is emerging that factors within the muscle might be of more importance. The high rate of glycolysis during high intensity exercise might be the 'driving force' via the increased production of acetyl-CoA, which in turn is trapped by carnitine. This will lead to decreased availability of free carnitine for long chain FA transport into mitochondria. This review summarizes our present view on how FA metabolism is regulated during exercise with a special focus on the limitations in FA oxidation in the transition from moderate to high intensity exercise in humans. PMCID: PMC3381814 PMID: 22271865 [PubMed - indexed for MEDLINE] 389. Semin Reprod Med. 2012 Jan;30(1):14-22. doi: 10.1055/s-0031-1299593. Epub 2012 Jan 23. Tissue-specific regulation of genes by estrogen receptors. Leitman DC(1), Paruthiyil S, Yuan C, Herber CB, Olshansky M, Tagliaferri M, Cohen I, Speed TP. Author information: (1)Department of Nutritional Science and Toxicology, University of California, Berkeley, California 94720, USA. dale@leitmanlab.com Estrogens are frequently used in reproductive medicine. The Women's Health Initiative trial found that the risks of menopausal hormone therapy (MHT) exceed the benefits. The estrogens in MHT, however, were introduced prior to our understanding of the mechanism of action of estrogens. Estrogen signaling is highly complex, involving various DNA regulatory elements to which estrogen receptors bind. Numerous transcription factors and co-regulatory proteins modify chromatin structure to further regulate gene transcription. With a greater understanding of estrogen action, the major problem with the current estrogens in MHT appears to be that they are nonselective. This produces beneficial effects in bone, brain, and adipose tissue but increases the risk of breast and endometrial cancer and thromboembolism. Resurrecting MHT for long-term therapy will require the development of more selective estrogens, such as estrogen receptor (ER)β-selective estrogens and tissue-selective ERα agonists. These compounds will offer the best prospects to expand the indications of MHT and thus prevent the chronic conditions associated with menopause. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. PMID: 22271290 [PubMed - indexed for MEDLINE] 390. Cell Mol Neurobiol. 2012 Jul;32(5):645-59. doi: 10.1007/s10571-011-9793-z. Epub 2012 Jan 24. NPY and stress 30 years later: the peripheral view. Hirsch D(1), Zukowska Z. Author information: (1)Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA. dalay.hirsch@gmail.com Almost 30 years ago, neuropeptide Y (NPY) was discovered as a sympathetic co-transmitter and one of the most evolutionarily conserved peptides abundantly present all over the body. Soon afterward, NPY's multiple receptors were characterized and cloned, and the peptide's role in stress was first documented. NPY has proven to be pivotal for maintaining many stress responses. Most notably, NPY is known for activating long-lasting vasoconstriction in many vascular beds, including coronary arteries. More recently, NPY was found to play a role in stress-induced accretion of adipose tissue which many times can lead to detrimental metabolic changes. It is however due to its prominent actions in the brain, one of which is its powerful ability to stimulate appetite as well as its anxiolytic activities that NPY became a peptide of importance in neuroscience. In contrast, its actions in the rest of the body, including its role as a stress mediator, remained, surprisingly underappreciated and not well understood. Our research has focused on that other, "peripheral" side of NPY. In this review, we will discuss those actions of NPY on the cardiovascular system and metabolism, as they relate to adaptation to stress, and attempt to both distinguish NPY's effects from and integrate them with the effects of the classical stress mediators, glucocorticoids, and catecholamines. To limit the bias of someone (ZZ) who has viewed the world of stress through the eyes of NPY for over 20 years, fresh insight (DH) has been solicited to more objectively assess NPY's contributions to stress-related diseases and the body's ability to adapt to stress. PMCID: PMC3492947 PMID: 22271177 [PubMed - indexed for MEDLINE] 391. J Mol Med (Berl). 2012 May;90(5):523-34. doi: 10.1007/s00109-012-0861-8. Epub 2012 Jan 22. Evolutionary medicine and chronic inflammatory state--known and new concepts in pathophysiology. Straub RH(1). Author information: (1)Laboratory of Experimental Rheumatology and Neuroendocrino-Immunology, Division of Rheumatology, Department of Internal Medicine I, University Hospital Regensburg, 93042 Regensburg, Germany. rainer.straub@klinik.uni-regensburg.de During the last 10 years, a series of exciting observations has led to a new theory of pathophysiology using insights from evolutionary biology and neuroendocrine immunology to understand the sequelae of chronic inflammatory disease. According to this theory, disease sequelae can be explained based on redirection of energy-rich fuels from storage organs to the activated immune system. These disease sequelae are highly diverse and include the following: sickness behavior, anorexia, malnutrition, muscle wasting-cachexia, cachectic obesity, insulin resistance with hyperinsulinemia, dyslipidemia, increase of adipose tissue near inflamed tissue, alterations of steroid hormone axes, elevated sympathetic tone and local sympathetic nerve fiber loss, decreased parasympathetic tone, hypertension, inflammation-related anemia, and osteopenia. Since these disease sequelae can be found in many animal models of chronic inflammatory diseases with mammals (e.g., monkeys, mice, rats, rabbits, etc.), the evolutionary time line goes back at least 70 million years. While the initial version of this theory could explain prominent sequelae of chronic inflammatory disease, it did not however address two features important in the pathogenesis of immune-mediated diseases: the time point when an acute inflammatory disease becomes chronic, and the appearance of hypertension in chronic inflammation. To address these aspects more specifically, a new version of the theory has been developed. This version defines more precisely the moment of transition from acute inflammatory disease to chronic inflammatory disease as a time in which energy stores become empty (complete energy consumption). Depending on the amount of stored energy, this time point can be calculated to be 19-43 days. Second, the revised theory addresses the mechanisms of essential hypertension since, on the basis of water loss, acute inflammatory diseases can stimulate water retention using a positively selected water retention system (identical to the energy provision system). In chronic smoldering inflammation, however, there is no increased water loss. In contrast, there is increased water generation in inflamed tissue and inflammatory cells, and the activation of the water retention system persists. This combination leads to a net increase of the systemic fluid volume, which is hypothesized to be the basis of essential hypertension (prevalence in adults 22-32%). PMCID: PMC3354326 PMID: 22271169 [PubMed - indexed for MEDLINE] 392. J Burn Care Res. 2012 May-Jun;33(3):e101-7. doi: 10.1097/BCR.0b013e318239c5d7. Spontaneous human combustion in the light of the 21st century. Koljonen V(1), Kluger N. Author information: (1)Department of Plastic Surgery, Töölö Hospital, University of Helsinki, Helsinki, Finland. The term "spontaneous human combustion" refers to a situation when a human body is found with significant portions of the middle parts of the body reduced to ashes, much less damage to the head and extremities, and minimal damage to the direct surroundings of the body. Typically, no observable source of ignition is found in the vicinity of the victim and a bad smelling oily substance is noted. In the past, such a situation was erroneously attributed to supernatural powers, as such phenomenon occurs in the absence of any witness. The purpose of this review article was to analyze articles published from January 1, 2000, on this unique type of burn injury. Further aims were to gather and present data on the causes and events leading to this situation. The literature was reviewed with PubMed interface using the key words spontaneous human combustion and preternatural combustion. Specific inclusion criteria resulted in 12 patients. A unique sequence of events takes place for the human body to incinerate to ashes. The flame burn victim has to die for the body fat to start melting. A tear in the skin has to occur for the melted fat to impregnate the charred clothes, igniting a wick effect that produces localized heat for extended period. A phenomenon called spontaneous human combustion is reality. The term "spontaneous human combustion" has nuances which are not applicable to this situation or to these modern times, therefore we suggest a new term "fat wick burns." PMID: 22269823 [PubMed - indexed for MEDLINE] 393. Brain Behav Immun. 2012 Jul;26(5):691-8. doi: 10.1016/j.bbi.2012.01.004. Epub 2012 Jan 17. Cannabinoid signalling regulates inflammation and energy balance: the importance of the brain-gut axis. Cluny NL(1), Reimer RA, Sharkey KA. Author information: (1)Hotchkiss Brain Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada. Energy balance is controlled by centres of the brain which receive important inputs from the gastrointestinal tract, liver, pancreas, adipose tissue and skeletal muscle, mediated by many different signalling molecules. Obesity occurs when control of energy intake is not matched by the degree of energy expenditure. Obesity is not only a state of disordered energy balance it is also characterized by systemic inflammation. Systemic inflammation is triggered by the leakage of bacterial lipopolysaccharide through changes in intestinal permeability. The endocannabinoid system, consisting of the cannabinoid receptors, endogenous cannabinoid ligands and their biosynthetic and degradative enzymes, plays vital roles in the control of energy balance, the control of intestinal permeability and immunity. In this review we will discuss how the endocannabinoid system, intestinal microbiota and the brain-gut axis are involved in the regulation of energy balance and the development of obesity-associated systemic inflammation. Through direct and indirect actions throughout the body, the endocannabinoid system controls the development of obesity and its inflammatory complications. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22269477 [PubMed - indexed for MEDLINE] 394. Dermatol Surg. 2012 Jul;38(7 Pt 2):1112-27. doi: 10.1111/j.1524-4725.2011.02291.x. Epub 2012 Jan 23. Hand rejuvenation: a review and our experience. Fabi SG(1), Goldman MP. Author information: (1)Goldman, Butterwick, Fitzpatrick, and Groff Cosmetic Laser Dermatology, San Diego, CA 92121, USA. sgfabi@gmail.com BACKGROUND: The aged hand is characterized by cutaneous and dermal atrophy, with deep intermetacarpal spaces, prominent bones and tendons, and bulging reticular veins. Epidermal changes include solar lentigines, seborrheic keratoses, actinic keratoses, skin laxity, rhytides, tactile roughness, and telangiectasia. STUDY DESIGN: A Medline search was performed on hand rejuvenation from 1989 to 2011, and results are summarized. Practical applications of these procedures are also discussed. RESULTS: Reports of injectable hyaluronic acid, calcium hydroxylapatite, poly-L-lactic acid, autologous fat transfer, vein treatment, and chemical peels, along with lasers and light sources such as Q-switched laser, intense pulsed light, photodynamic therapy, nonablative resurfacing lasers, and ablative resurfacing lasers, in the rejuvenation of hands were found. CONCLUSION: Review of the literature revealed options for minimally invasive treatment for rejuvenation of the skin and volume restoration of the dorsal hand. These treatments include injectables and fat transfer for volume restoration; sclerotherapy or vein ablation for dorsal hand vein treatment; and chemical peels, lasers, light, and energies for the treatment of epidermal and dermal changes. © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. PMID: 22268976 [PubMed - indexed for MEDLINE] 395. Curr Diabetes Rev. 2012 Mar;8(2):131-43. Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Saad F(1), Aversa A, Isidori AM, Gooren LJ. Author information: (1)Bayer Pharma, Scientific Affairs Men’s Healthcare, Berlin, Germany. Farid.Saad@bayer.com OBJECTIVE: Obesity negatively affects human health. Limiting food intake, while producing some weight loss, results in reduction of lean body mass. Combined with moderate exercise it produces significant weight loss, maintains lean body mass and improves insulin sensitivity, but appears difficult to adhere to. Bariatric surgery is clinically effective for severely obese individuals compared with non-surgical interventions, but has limitations. Clinical and pre-clinical studies have implicated a role for testosterone (T) in the patho-physiology of obesity. METHODS: EVIDENCE ACQUISITION AND SYNTHESIS: A literature search in PubMed on the role of T in counteracting obesity and its complications. RESULTS: Obesity per se impairs testicular T biosynthesis. Furthermore, lower-than-normal T levels increase accumulation of fat depots, particularly abdominal (visceral) fat. This fat distribution is associated with development of metabolic syndrome (MetS) and its sequels, namely type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). T treatment reverses fat accumulation with significant improvement in lean body mass, insulin sensitivity and biochemical profiles of cardiovascular risk. The contribution of T to combating obesity in hypogonadal men remains largely unknown to medical professionals managing patients with obesity and metabolic syndrome. Many physicians associate T treatment in men with risks for prostate malignancy and CVD. These beliefs are not supported by recent insights. CONCLUSION: While overall treatment of obesity is unsuccessful, T treatment of hypogonadal men may be effective, also because it improves mood, energy, reduces fatigue and may motivate men to adhere to diet and exercise regimens designed to combat obesity. © 2012 Bentham Science Publishers PMCID: PMC3296126 PMID: 22268394 [PubMed - indexed for MEDLINE] 396. Prog Lipid Res. 2012 Jul;51(3):267-71. doi: 10.1016/j.plipres.2011.12.004. Epub 2012 Jan 13. Novel qualitative aspects of tissue fatty acids related to metabolic regulation: lessons from Elovl6 knockout. Shimano H(1). Author information: (1)Department of Internal Medicine-Endocrinology and Metabolism, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. hshimano@md.tsukuba.ac.jp Insulin resistance, often associated with obesity, precipitates metabolic syndrome, type 2 diabetes, and finally, atherosclerosis. Sources of excess energy cause abnormal accumulation of tissue lipids leading to cellular dysfunction through cellular stress and inflammation. This process is often referred to as lipotoxicity. Until date, effective approaches that aim to overcome insulin resistance involve amelioration of obesity by caloric restriction and/or exercise. Quantitative control of lipids, especially triglycerides and fatty acids in adipose and other tissues, and plasma can be addressed using these measures. However, altering tissue lipid composition may provide another strategy to prevent or control lipotoxicity. Endogenous fatty acid synthesis plays a crucial role in determining tissue energy states. As a target gene of SREBP-1 that controls lipogenesis we identified a unique enzyme, Elovl6, which is responsible for the final step in endogenous saturated fatty acid synthesis, thereby controlling tissue fatty acid composition. Elovl6-deficient mice become obese and develop hepatosteatosis when fed a high-fat diet or when mated to leptin-deficient ob/ob mice. However, the mice exhibited marked protection from hyperinsulinemia, hyperglycemia, and hyperleptinemia. Hepatic fatty acid composition is a novel determinant of insulin sensitivity independent of cellular energy balance. Inhibiting Elovl6 activity may provide a novel therapeutic approach for treating insulin resistance, diabetes, metabolic syndrome, and cardiovascular risks by circumventing obesity problems. In this review, we consider fatty acid metabolism and lipotoxicity, and discuss the role of Elovl6 in newly recognized aspects of metabolic regulation. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22266797 [PubMed - indexed for MEDLINE] 397. Nutr Metab Cardiovasc Dis. 2012 Feb;22(2):81-7. doi: 10.1016/j.numecd.2011.11.001. Epub 2012 Jan 21. Can vitamin D deficiency cause diabetes and cardiovascular diseases? Present evidence and future perspectives. Muscogiuri G(1), Sorice GP, Ajjan R, Mezza T, Pilz S, Prioletta A, Scragg R, Volpe SL, Witham MD, Giaccari A. Author information: (1)Endocrinologia e Malattie del Metabolismo, Università Cattolica, Rome, Italy. giovanna.muscogiuri@edu.rm.unicatt.it Several studies have shown that vitamin D may play a role in many biochemical mechanisms in addition to bone and calcium metabolism. Recently, vitamin D has sparked widespread interest because of its involvement in the homeostasis of the cardiovascular system. Hypovitaminosis D has been associated with obesity, related to trapping in adipose tissue due to its lipophilic structure. In addition, vitamin D deficiency is associated with increased risk of cardiovascular disease (CVD) and this may be due to the relationship between low vitamin D levels and obesity, diabetes mellitus, dyslipidaemia, endothelial dysfunction and hypertension. However, although vitamin D has been identified as a potentially important marker of CVD, the mechanisms through which it might modulate cardiovascular risk are not fully understood. Given this background, in this work we summarise clinical retrospective and prospective observational studies linking vitamin D levels with cardio-metabolic risk factors and vascular outcome. Moreover, we review various randomised controlled trials (RCTs) investigating the effects of vitamin D supplementation on surrogate markers of cardiovascular risk. Considering the high prevalence of hypovitaminosis D among patients with high cardiovascular risk, vitamin D replacement therapy in this population may be warranted; however, further RCTs are urgently needed to establish when to begin vitamin D therapy, as well as to determine the dose and route and duration of administration. Copyright © 2011 Elsevier B.V. All rights reserved. PMID: 22265795 [PubMed - indexed for MEDLINE] 398. Best Pract Res Clin Rheumatol. 2011 Dec;25(6):779-84. doi: 10.1016/j.berh.2011.11.009. Joint appendages: the structures which have historically been overlooked in arthritis research and therapy development. Ash Z(1), McGonagle D. Author information: (1)Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, UK. Z.Ash@leeds.ac.uk Rheumatologists have largely conceptualised joint disease in inflammatory and degenerative arthritis in terms of bone, cartilage and the synovial lining, but have tended to overlook other integral components of the joints which are attached close to joint margins. We discuss these structures under the umbrella term of 'appendages'. These structures include ligaments, tendons, entheses or joint insertions, regional fibrocartilages, bursae and other peri-articular joint structures including fat pads and nails. In this review, we highlight how these structures play key pathophysiological roles in inflammatory arthritis and we emphasise how an understanding of these structures is collectively important for both clinical practice and future rheumatological research. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 22265260 [PubMed - indexed for MEDLINE] 399. Semin Immunol. 2012 Feb;24(1):67-74. doi: 10.1016/j.smim.2011.11.011. Epub 2012 Jan 20. Immuno-microbiota cross and talk: the new paradigm of metabolic diseases. Burcelin R(1), Garidou L, Pomié C. Author information: (1)Institut National de la Santé et de la Recherche Médicale, U1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), BP 84225, 31432 Toulouse, France. remy.burcelin@inserm.fr Over the last decades the rising occurrence of metabolic diseases throughout the world points to the failure of preventive and therapeutic strategies and of the corresponding molecular and physiological concepts. Therefore, a new paradigm needs to be elucidated. Very recently the intimate cross talk of the intestinal microbiota with the host immune system has opened new avenues. The large diversity of the intestinal microbes' genome, i.e. the metagenome, and the extreme plasticity of the immune system provide a unique balance which, when finely tuned, maintains a steady homeostasis. The discovery that a new microbiota repertoire is one of the causes responsible for the onset of metabolic disease suggests that the relationship with the immune system is impaired. Therefore, we here review the recent arguments that support the view that an alteration in the microbiota to host immune system balance leads to an increased translocation of bacterial antigens towards metabolically active tissues, and could result in a chronic inflammatory state and consequently impaired metabolic functions such as insulin resistance, hepatic fat deposition, insulin unresponsiveness, and excessive adipose tissue development. This imbalance could be at the onset of metabolic disease, and therefore the early treatment of the microbiota dysbiosis or immunomodulatory strategies should prevent and slow down the epidemic of metabolic diseases and hence the corresponding lethal cardiovascular consequences. Copyright © 2011. Published by Elsevier Ltd. PMID: 22265028 [PubMed - indexed for MEDLINE] 400. Cesk Fysiol. 2011;60(2):40-7. [Insulin resistance and nitric oxide: molecular mechanisms and pathophysiological associations]. [Article in Czech] Tousková V(1), Haluzík M. Author information: (1)Univerzita Karlova, 1. lékarská fakulta a VFN v Praze, III. interní klinika, Praha. Vera.Touskova@vfn.cz Subclinical inflammation that primarily arises in adipose tissue as a result of its excessive infiltration by immunocompetent cells represents one of the typical etiopathogenetic mechanisms underlying the development of insulin resistance and type 2 diabetes. Immunocompetent cells together with adipocytes are a major source of proinflammatory cytokines triggering proinflammatory cascades that in turn interfere with postreceptor insulin signalling cascade. Recent studies have suggested that inducible nitric oxide synthase plays a key role in this process. Obesity is associated with increased inducible nitric oxide synthase mRNA expression, with subsequent overproduction of nitric oxide and reactive nitrogen species leading to S-nitrosylation of proteins involved in insulin signalling cascade. These post-translational modifications decrease their activity and eventually lead to insulin resistance. Number of experimental studies demonstrated that inhibition of inducible nitric oxide synthase attenuates insulin resistance. The aim of this review is to summarize the current knowledge about the physiology and patophysiology of nitric oxide and inducible nitric oxide synthase with respect to its relationship to insulin resistance and to discuss the possibility of improvement of insulin resistance and type 2 diabetes mellitus by modulating inducible nitric oxide synthase activity. PMID: 22263324 [PubMed - indexed for MEDLINE] 401. Gerontology. 2012;58(4):337-43. doi: 10.1159/000335166. Epub 2012 Jan 18. Healthy aging: is smaller better? - a mini-review. Bartke A(1). Author information: (1)Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, 62794-9628, USA. abartke@siumed.edu A recent report of virtually complete protection from diabetes and cancer in a population of people with hereditary dwarfism revived interest in elucidating the relationships between growth, adult body size, age-related disease and longevity. In many species, smaller individuals outlive those that are larger and a similar relationship was shown in studies of various human populations. Adult body size is strongly dependent on the actions of growth hormone (GH) and the absence of GH or GH receptor in mice leads to a remarkable extension of longevity. Many mechanisms that may account for, or contribute to, this association have been identified. It is suggested that modest modifications of the diet at different ages may extend human healthspan and lifespan by reducing levels of hormones that stimulate growth. Copyright © 2012 S. Karger AG, Basel. PMCID: PMC3893695 PMID: 22261798 [PubMed - indexed for MEDLINE] 402. Orv Hetil. 2012 Jan 29;153(4):125-36. doi: 10.1556/OH.2012.29287. [Interactions of insulin and estrogen in the regulation of cell proliferation and carcinogenesis]. [Article in Hungarian] Suba Z(1), Kásler M. Author information: (1)Országos Onkológiai Intézet Sebészeti és Molekuláris Tumorpatológiai Osztály Budapest Ráth György u. subazdr@gmail.com Equilibrium of sexual steroids and metabolic processes has close correlations. Insulin is a potent regulator of human sexual steroid hormone production and modulates their signals at receptor level. Insulin resistance and excessive insulin production provoke hyperandrogenism and estrogen deficiency in women resulting not only in anovulatory dysfunction but also a high risk for cardiovascular diseases and cancer. Physiologic functions of all female organs have higher estrogen demand as compared with men. In healthy women estrogen predominance against androgens is a favor in their reproductive period, which means a strong defense against insulin resistance and its complications. However, in postmenopausal cases the increasing prevalence of insulin resistance and type-2 diabetes associated with estrogen deficiency and androgen excess, result in a gender specific higher risk for precancerous lesions and cancer as compared with men. Estrogen has beneficial effect on the energy metabolism, glucose homeostasis and on the lipid metabolism of liver and of peripheral tissues as well. A moderate or severe decrease in serum estrogen level enhances the prevalence of insulin resistant states. In premenopausal women long or irregular menstrual cycles are predictors for the risk of insulin resistance and type-2 diabetes. Moreover, in postmenopausal estrogen deficient cases elevated fasting glucose, increased body weight and abdominal fat deposition are often observed progressively with age in correlation with an impaired glucose tolerance. In the rare cases of estrogen deficient men severe type-2 diabetes seems to be a characteristic complication. Upon becoming familiar with the cancer risk of insulin resistance and estrogen deficiency, there would be plenty of possibilities for primary cancer prevention. In patients with cancer the treatment of hormonal and metabolic disturbances may become effective adjuvant therapy. PMID: 22257509 [PubMed - indexed for MEDLINE] 403. Nutrients. 2011 Jan;3(1):27-39. doi: 10.3390/nu3010027. Epub 2011 Jan 6. Vitamin A metabolism and adipose tissue biology. Frey SK(1), Vogel S. Author information: (1)Department of Medicine and the Institute of Human Nutrition, Columbia University, New York, NY 10032, USA. mail@simonefrey.de In recent years, the importance of vitamin A in adipose tissue biology, obesity and type II diabetes has become apparent. This review focuses on recent developments within the area of vitamin A and adipose tissue biology. Adipose tissue has an active vitamin A metabolism as it not only stores vitamin A but retinol is also converted to its active metabolite retinoic acid. Several mouse models point to a relationship between vitamin A metabolism and the development of adiposity. Similarly, in vitro studies provide new molecular mechanisms for the function of different forms of vitamin A and retinol- or retinoic acid-binding proteins in adipose tissue. PMCID: PMC3257733 PMID: 22254074 [PubMed - indexed for MEDLINE] 404. Nutrients. 2010 Dec;2(12):1212-30. doi: 10.3390/nu2121212. Epub 2010 Dec 9. Long-chain omega-3 polyunsaturated fatty acids may be beneficial for reducing obesity-a review. Buckley JD(1), Howe PR. Author information: (1)Nutritional Physiology Research Centre, University of South Australia Adelaide, South Australia, 5000, Australia. jon.buckley@unisa.edu.au Current recommendations for counteracting obesity advocate the consumption of a healthy diet and participation in regular physical activity, but many individuals have difficulty complying with these recommendations. Studies in rodents and humans have indicated that long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) potentially elicit a number of effects which might be useful for reducing obesity, including suppression of appetite, improvements in circulation which might facilitate nutrient delivery to skeletal muscle and changes in gene expression which shift metabolism toward increased accretion of lean tissue, enhanced fat oxidation and energy expenditure and reduced fat deposition. While LC n-3 PUFA supplementation has been shown to reduce obesity in rodents, evidence in humans is limited. Epidemiological associations between LC n-3 PUFA intakes and obesity are inconclusive but small cross-sectional studies have demonstrated inverse relationships between markers of LC n-3 PUFA status and markers of obesity. Human intervention trials indicate potential benefits of LC n-3 PUFA supplementation, especially when combined with energy-restricted diets or exercise, but more well-controlled and long-term trials are needed to confirm these effects and identify mechanisms of action. PMCID: PMC3257626 PMID: 22254005 [PubMed - indexed for MEDLINE] 405. Diabetes Metab. 2012 Jun;38(3):183-91. doi: 10.1016/j.diabet.2011.11.006. Epub 2012 Jan 16. Inflammation and type 2 diabetes. Calle MC(1), Fernandez ML. Author information: (1)Department of Nutritional Sciences, University of Connecticut, 3624 Horsebarn Road, ext. U-4017, Storrs, CR 06269, USA. Low-grade inflammation is a common feature in subjects with type 2 diabetes (T2D). Heart disease, the metabolic syndrome and T2D all have in common the increased concentration of circulatory cytokines as a result of inflammation. Inflammatory cytokines are produced by different cell types and secreted into the circulation, where they regulate different tissues through their local, central and peripheral actions. This review focuses on C-reactive protein (CRP), a well-established marker of the development of inflammation, on tumour necrosis factor (TNF)-α, an inflammatory marker strongly associated with diabetes, and on adiponectin, a cytokine produced by adipose tissue and associated with insulin sensitivity. While it is clear from the literature that these cytokines play a major role in the development of T2D or, in the case of adiponectin, its prevention, the best strategy for favourably altering the inflammatory response is still a matter of debate. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMID: 22252015 [PubMed - indexed for MEDLINE] 406. Handb Exp Pharmacol. 2012;(209):111-29. doi: 10.1007/978-3-642-24716-3_5. The central insulin system and energy balance. Begg DP(1), Woods SC. Author information: (1)Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, OH 45237, USA. Insulin acts throughout the body to reduce circulating energy and to increase energy storage. Within the brain, insulin produces a net catabolic effect by reducing food intake and increasing energy expenditure; this is evidenced by the hypophagia and increased brown adipose tissue sympathetic nerve activity induced by central insulin infusion. Reducing the activity of the brain insulin system via administration of insulin antibodies, receptor antisense treatment, or receptor knockdown results in hyperphagia and increased adiposity. However, despite decades of research into the role of central insulin in food intake, many questions remain to be answered, including the underlying mechanism of action. PMID: 22249812 [PubMed - indexed for MEDLINE] 407. Handb Exp Pharmacol. 2012;(209):3-21. doi: 10.1007/978-3-642-24716-3_1. Leptin receptors. Cottrell EC(1), Mercer JG. Author information: (1)Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Scotland, EH16 4TH, UK. The hormone leptin, secreted predominantly from adipose tissue, plays a crucial role in the regulation of numerous neuroendocrine functions, from energy homeostasis to reproduction. Genetic deficiency as a consequence of leptin or leptin receptor mutations, although rare in humans, leads to early onset of chronic hyperphagia and massive obesity. In most human obesity, however, leptin levels are chronically elevated. Under these conditions of persistent hyperleptinaemia, and particularly when obesity is associated with a high-fat diet, leptin resistance develops, and signalling through the leptin receptor is curtailed, fuelling further weight gain. Here, we review the role of leptin receptors in the regulation of feeding and obesity development. Leptin receptors are found in each of the major components of the CNS "feeding" circuitry-the brainstem, hypothalamus and distributed reward centres. Through these receptors, leptin exerts influences on signalling and integration within these circuits to alter feeding behaviours. Although some progress is now being made with peptide analogues, the leptin receptor has not proved to be amenable to small molecule pharmacological intervention to date. Where clinical benefit from recombinant leptin administration has been achieved, this has been under circumstances of complete endogenous leptin deficiency or relative hypoleptinaemia such as in lipodystrophy. PMID: 22249808 [PubMed - indexed for MEDLINE] 408. Int J Obes (Lond). 2012 Dec;36(12):1485-93. doi: 10.1038/ijo.2011.269. Epub 2012 Jan 17. Effect of dairy consumption on weight and body composition in adults: a systematic review and meta-analysis of randomized controlled clinical trials. Abargouei AS(1), Janghorbani M, Salehi-Marzijarani M, Esmaillzadeh A. Author information: (1)Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. BACKGROUND: Although several observational and experimental studies have investigated the effect of dairy consumption on weight and body composition, results are inconsistent. OBJECTIVE: This systematic review and meta-analysis was conducted to summarize the published evidence from randomized controlled clinical trials (RCTs) regarding the effect of dairy consumption on weight, body fat mass, lean mass and waist circumference (WC) in adults. DESIGN: PubMed, ISI Web of Science, SCOPUS, Science Direct and EMBASE were searched from January 1960 to October 2011 for relevant English and non-English publications. Sixteen studies were selected for the systematic review and fourteen studies were included in meta-analysis. RESULTS: Our search led to 14, 12, 6 and 8 eligible RCTs that had data on weight, body fat mass, lean mass and WC, respectively. Overall, mean difference for the effect of dairy on body weight was -0.61 kg (95% confidence interval (CI): -1.29, 0.07, P=0.08). Increased dairy intake resulted in 0.72 kg (95% CI: -1.29, -0.14, P=0.01) greater reduction in fat mass, 0.58 kg (95% CI: 0.18, 0.99, P<0.01) gain in lean mass and 2.19 cm (95% CI: -3.42, -0.96, P-value <0.001) further reduction in WC than that in controls. Subgroup analysis revealed that increasing dairy intake without energy restriction in both intervention and control groups does not significantly affect weight, body fat mass, lean mass and WC; consumption of high-dairy weight loss diets led to 1.29 kg (95% CI: -1.98, -0.6, P<0.001) greater weight loss, 1.11 kg (95% CI: -1.75, -0.47, P=0.001) greater reduction in body fat mass, 0.72 kg (95% CI: 0.12, 1.32, P=0.02) gain in body lean mass and 2.43 cm (95% CI: -3.42, -1.44, P<0.001) additional reduction in WC compared with controls. CONCLUSION: Increased dairy consumption without energy restriction might not lead to a significant change in weight or body composition; whereas inclusion of dairy products in energy-restricted weight loss diets significantly affects weight, body fat mass, lean mass and WC compared with that in the usual weight loss diets. PMID: 22249225 [PubMed - indexed for MEDLINE] 409. Pediatr Endocrinol Diabetes Metab. 2011;17(4):206-13. [Insulin resistance in children]. [Article in Polish] Witek J(1), Witek P, Pańkowska E. Author information: (1)Instytut Matki i Dziecka w Warszawie. joanna.witek@imid.med.pl Insulin resistance is characterized by decreased tissue sensitivity to insulin. The hallmark of insulin resistance is decreased tissue glucose uptake despite normal or elevated insulin concentration. There has been an upward trend in the incidence of insulin resistance in developed countries, although in pediatric population it is difficult to assess. Both genetic and environmental factors play an important role in the etiology of insulin resistance, namely increased diet caloricity and decreased physical activity. Gradually, this leads to adipose tissue build-up. The role of visceral adipose tissue is of particular importance, mainly due to its significant endocrine activity, leading to adverse metabolic effects. The most important consequences of insulin resistance in children include increased incidence of type 2 diabetes, atherogenic dyslipidemia and arterial hypertension, which lead to increased cardiovascular risk. Children with insulin resistance can develop nonalcoholic steatohepatitis and sleep apnea syndrome. In case of female pediatric patients a higher incidence of polycystic ovary syndrome (PCOS) is observed. Furthermore, the authors reviewed opinions on risk factors for insulin resistance, as well as direct and indirect insulin resistance assessment methods. The article presents the principles of primary and secondary prevention of insulin resistance in children, with particular allowance for dietary recommendations and recommendations to increase physical activity, and, in selected cases, current guidelines on pharmacological treatment. PMID: 22248781 [PubMed - indexed for MEDLINE] 410. Int J Food Sci Nutr. 2012 Sep;63(6):749-65. doi: 10.3109/09637486.2011.649250. Epub 2012 Jan 17. Bioactive compounds with effects on inflammation markers in humans. Rosa FT(1), Zulet MÁ, Marchini JS, Martínez JA. Author information: (1)Division of Clinical Nutrition, Department of Internal Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Calle Irunlarrea 1, São Paulo, Brazil. Obesity and other chronic diseases are accompanied by adipose tissue, liver, pancreas, muscle and brain low-grade chronic inflammation. Indeed, the obese condition and metabolic syndrome are characterized by an increased expression of inflammatory cytokines and infiltration of immune cells in adipocytes. The inflammatory response promotes the activation of transcriptional factors and pro-inflammatory cytokines, which can lead to an unresolved inflammatory response associated with an inhibition of insulin signalling and high risk for cardiovascular events. Epidemiological and intervention studies have been carried out to find out dietary patterns, foods and bioactive compounds with protective anti-inflammatory actions. The most studied compounds are polyphenols, especially isoflavone and anthocyanin, but quercertin, catechin and resveratrol have also been investigated. Furthermore, some studies have reported the effects of milk peptides, plant sterol and stanol, l-carnitine and α-lipoic acid on inflammatory processes. This review aimed to collect and discuss those relevant studies reported in the scientific literature following a systematic scientific search about the effect of such bioactive compounds on inflammation in humans. PMID: 22248031 [PubMed - indexed for MEDLINE] 411. Curr Cardiovasc Risk Rep. 2012 Feb;6(1):80-90. Epub 2011 Nov 22. Perivascular Fat and the Microcirculation: Relevance to Insulin Resistance, Diabetes, and Cardiovascular Disease. Houben AJ, Eringa EC, Jonk AM, Serne EH, Smulders YM, Stehouwer CD. Type 2 diabetes and its major risk factor, obesity, are a growing burden for public health. The mechanisms that connect obesity and its related disorders, such as insulin resistance, type 2 diabetes, and hypertension, are still undefined. Microvascular dysfunction may be a pathophysiologic link between insulin resistance and hypertension in obesity. Many studies have shown that adipose tissue-derived substances (adipokines) interact with (micro)vascular function and influence insulin sensitivity. In the past, research focused on adipokines from perivascular adipose tissue (PVAT). In this review, we focus on the interactions between adipokines, predominantly from PVAT, and microvascular function in relation to the development of insulin resistance, diabetes, and cardiovascular disease. PMCID: PMC3251783 PMID: 22247785 [PubMed] 412. Proteomics. 2012 Feb;12(4-5):607-20. doi: 10.1002/pmic.201100355. Epub 2012 Jan 23. Proteomic characterization of adipose tissue constituents, a necessary step for understanding adipose tissue complexity. Peinado JR(1), Pardo M, de la Rosa O, Malagón MM. Author information: (1)Faculty of Medicine, Departament of Medical Sciences, Ciudad Real, Spain. juanramon.peinado@uclm.es The original concept of adipose tissue as an inert storage depot for the excess of energy has evolved over the last years and it is now considered as one of the most important organs regulating body homeostasis. This conceptual change has been supported by the demonstration that adipose tissue serves as a major endocrine organ, producing a wide variety of bioactive molecules, collectively termed adipokines, with endocrine, paracrine and autocrine activities. Adipose tissue is indeed a complex organ wherein mature adipocytes coexist with the various cell types comprising the stromal-vascular fraction (SVF), including preadipocytes, adipose-derived stem cells, perivascular cells, and blood cells. It is known that not only mature adipocytes but also the components of SVF produce adipokines. Furthermore, adipokine production, proliferative and metabolic activities and response to regulatory signals (i.e. insulin, catecholamines) differ between the different fat depots, which have been proposed to underlie their distinct association to specific diseases. Herein, we discuss the recent proteomic studies on adipose tissue focused on the analysis of the separate cellular components and their secretory products, with the aim of identifying the basic features and the contribution of each component to different adipose tissue-associated pathologies. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. PMID: 22246603 [PubMed - indexed for MEDLINE] 413. Trends Endocrinol Metab. 2012 Mar;23(3):133-41. doi: 10.1016/j.tem.2011.12.004. Epub 2012 Jan 13. Insulin resistance in the nervous system. Kim B(1), Feldman EL. Author information: (1)University of Michigan, Department of Neurology, Ann Arbor, MI 48109, USA. bhumsoo@med.umich.edu Metabolic syndrome is a cluster of cardiovascular risk factors including obesity, diabetes and dyslipidemia. Insulin resistance (IR) is at the core of metabolic syndrome. In adipose tissue and muscle, IR results in decreased insulin signaling, primarily affecting downstream phosphatidylinositol 3-kinase (PI3K)/Akt signaling. It was recently proposed that neurons can develop hyperinsulinemia-induced IR, which in turn results in injury to the peripheral and central nervous systems and is probably pathogenic in common neurological disorders such as diabetic neuropathy and Alzheimer's disease (AD). This review presents evidence indicating that, similarly to insulin-dependent metabolically active tissues such as fat and muscle, neurons also develop IR and thus cannot respond to the neurotrophic properties of insulin, resulting in neuronal injury, subsequent dysfunction and disease states. Copyright © 2011 Elsevier Ltd. All rights reserved. PMCID: PMC3392648 PMID: 22245457 [PubMed - indexed for MEDLINE] 414. J Shoulder Elbow Surg. 2012 Feb;21(2):175-80. doi: 10.1016/j.jse.2011.11.017. Mechanisms of fatty degeneration in massive rotator cuff tears. Kang JR(1), Gupta R. Author information: (1)Department of Orthopaedic Surgery, University of California, Irvine, CA, USA. Fatty degeneration of chronically injured muscle is a commonly recognized consequence of massive rotator cuff tears. Current surgical treatments are unable to alter or reverse the progression of fatty degeneration and are associated with poor functional outcomes in these patients. Therefore, a better understanding of the pathophysiology of fatty degeneration is required. As such, recent discoveries in stem cell biology and new animal models have significantly advanced our understanding of the cellular and molecular basis of fatty degeneration. Future studies will facilitate development of novel treatments to prevent the progression of fatty degeneration and improve muscle regeneration in patients with massive rotator cuff tears. Copyright © 2012 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved. PMID: 22244060 [PubMed - indexed for MEDLINE] 415. J Shoulder Elbow Surg. 2012 Feb;21(2):164-74. doi: 10.1016/j.jse.2011.09.027. Muscle degeneration in rotator cuff tears. Laron D(1), Samagh SP, Liu X, Kim HT, Feeley BT. Author information: (1)Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA 94158, USA. Rotator cuff tears are among the most common injuries seen by orthopedic surgeons. Although small- and medium-sized tears do well after arthroscopic and open repair, large and massive tears have been shown to develop marked muscle atrophy and fatty infiltration within the rotator cuff muscles. These pathologic changes have been found to be independent predictors of failed surgical repair with poor functional outcomes. To understand the pathophysiology of rotator cuff disease, we must first develop an understanding of the changes that occur within the cuff muscles themselves. The purpose of this review is to summarize the molecular pathways behind muscular degeneration and emphasize new findings related to the clinical relevance of muscle atrophy and fatty infiltration seen with rotator cuff tears. Understanding these molecular pathways will help guide further research and treatment options that can aim to alter expression of these pathways and improve outcomes after surgical repair of massive rotator cuff tears. Copyright © 2012 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved. PMID: 22244059 [PubMed - indexed for MEDLINE] 416. Biopolymers. 2012 Jun;97(6):455-67. doi: 10.1002/bip.22024. Epub 2012 Jan 12. Invited review nonmulberry silk biopolymers. Kundu SC(1), Kundu B, Talukdar S, Bano S, Nayak S, Kundu J, Mandal BB, Bhardwaj N, Botlagunta M, Dash BC, Acharya C, Ghosh AK. Author information: (1)Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India. kundu@hijli.iitkgp.ernet.in The silk produced by silkworms are biopolymers and can be classified into two types--mulberry and nonmulberry. Mulberry silk of silkworm Bombyx mori has been extensively explored and used for century old textiles and sutures. But for the last few decades it is being extensively exploited for biomedical applications. However, the transformation of nonmulberry silk from being a textile commodity to biomaterials is relatively new. Within a very short period of time, the combination of load bearing capability and tensile strength of nonmulberry silk has been equally envisioned for bone, cartilage, adipose, and other tissue regeneration. Adding to its advantage is its diverse morphology, including macro to nano architectures with controllable degradation and biocompatibility yields novel natural material systems in vitro. Its follow on applications involve sustained release of model compounds and anticancer drugs. Its 3D cancer models provide compatible microenvironment systems for better understanding of the cancer progression mechanism and screening of anticancer compounds. Diversely designed nonmulberry matrices thus provide an array of new cutting age technologies, which is unattainable with the current synthetic materials that lack biodegradability and biocompatibility. Scientific exploration of nonmulberry silk in tissue engineering, regenerative medicine, and biotechnological applications promises advancement of sericulture industries in India and China, largest nonmulberry silk producers of the world. This review discusses the prospective biomedical applications of nonmulberry silk proteins as natural biomaterials. Copyright © 2012 Wiley Periodicals, Inc. PMID: 22241173 [PubMed - indexed for MEDLINE] 417. Curr Opin Nephrol Hypertens. 2012 Mar;21(2):147-56. doi: 10.1097/MNH.0b013e32834fb25b. Extrarenal effects of aldosterone. Nguyen Dinh Cat A(1), Jaisser F. Author information: (1)Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada. cattuong.ndc@gmail.com PURPOSE OF REVIEW: The renal distal tubule has been considered for a long time as the main cellular target of aldosterone, where the hormone enhances sodium reabsorption and potassium secretion. However, other cell types in nonepithelial tissues, such as the heart, the vessels, adipose tissue, and macrophages, are now also recognized as targets for aldosterone. The functions that aldosterone exerts in these nonclassical target tissues are still a matter of debate. This review will highlight the recent findings on the extrarenal effects of aldosterone. RECENT FINDINGS: Numerous studies showed that aldosterone exerts profibrotic and proinflammatory effects, but one or more cofactors such as salt, angiotensin II, and oxidative stress are required. Moreover, inflammation and macrophage infiltration are a prerequisite to aldosterone-induced cardiac fibrosis. This underlines a key role for aldosterone and the mineralocorticoid receptor in macrophages. Inflammatory effects of aldosterone in vascular smooth muscle cells involve trafficking to lipid rafts/caveolae through receptor tyrosine kinases. Finally, a growing body of evidence indicates a prominent role of aldosterone/mineralocorticoid receptor in the metabolic syndrome, in insulin resistance, and in adipocyte biology. SUMMARY: The idiom from Socrates, 'the more we learn, the less we know', can be applied to aldosterone with its different facets and its pleiotropic effects. There is clear evidence for rapid nongenomic effects of aldosterone, mineralocorticoid receptor-dependent and mineralocorticoid receptor-independent signaling, in the heart, the vessels, and other nonepithelial tissues, leading to inflammation, fibrosis, and progression of cardiovascular diseases including hypertension and metabolic syndrome. PMID: 22240440 [PubMed - indexed for MEDLINE] 418. Phys Med Rehabil Clin N Am. 2012 Feb;23(1):67-73, x. doi: 10.1016/j.pmr.2011.11.007. Epub 2011 Dec 11. Regional and whole-body dual-energy X-ray absorptiometry to guide treatment and monitor disease progression in neuromuscular disease. Skalsky AJ(1), Han JJ, Abresch RT, McDonald CM. Author information: (1)Department of Pediatrics, University of California San Diego, Rady Children's Hospital and Health Center, San Diego, CA 92123, USA. askalsky@rchsd.org Dual-energy x-ray absorptiometry (DEXA) is a safe, noninvasive, inexpensive tool for managing patients with neuromuscular diseases. Regional and whole-body DEXA can be used to guide clinical treatments, such as determining body composition to guide nutritional recommendations, as well as to monitor disease progression by assessing regional and whole-body lean tissue mass. DEXA can also be used as an outcome measure for clinical trials. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22239875 [PubMed - indexed for MEDLINE] 419. Obes Rev. 2012 Apr;13(4):381-7. doi: 10.1111/j.1467-789X.2011.00978.x. Epub 2012 Jan 12. Oestradiol is a protective factor for non-alcoholic fatty liver disease in healthy men. Tian GX(1), Sun Y, Pang CJ, Tan AH, Gao Y, Zhang HY, Yang XB, Li ZX, Mo ZN. Author information: (1)Department of Ultrasound, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China. Visceral fat is a risk factor for non-alcoholic fatty liver disease (NAFLD). A reduction in sex hormones is associated with increased abdominal fat. Thus, we investigated whether reduced testosterone (T) or oestradiol (E2) levels in men are associated with NAFLD and central obesity. The study involved a survey of 1,882 men between 20 and 60 years of age. We detected hepatic fat infiltration by ultrasound. Early morning serum was analyzed for total testosterone (TT), E2, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Free testosterone (FT) was calculated using the Vermeulen method. In the studied population, the prevalence of NAFLD, FSH, LH and SHBG increased with age, TT and FT declined with age, and E2 remained stable. However, in the NAFLD group, TT remained stable, FT and E2 declined, and hepatic fat infiltration increased (P < 0.001 for both). Using multivariate analysis, a correlation was found between E2 and NAFLD, with an odds ratio of 0.954 (95% confidence interval: 0.946-0.967). E2 is one of the protective factors against NAFLD in healthy men. T has no significant correlation with NAFLD. Further investigation would be required to assess the clinical consequences of reduced E2 in men with NAFLD, particularly for men whose TT remained stable. © 2012 The Authors. obesity reviews © 2012 International Association for the Study of Obesity. PMID: 22239319 [PubMed - indexed for MEDLINE] 420. J Clin Endocrinol Metab. 2012 Mar;97(3):745-55. doi: 10.1210/jc.2011-2525. Epub 2012 Jan 11. Clinical review: Regulation of food intake, energy balance, and body fat mass: implications for the pathogenesis and treatment of obesity. Guyenet SJ(1), Schwartz MW. Author information: (1)Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington School of Medicine, South Lake Union, 815 Mercer Street, N334, Box 358055, Seattle, Washington 98109, USA. CONTEXT: Obesity has emerged as one of the leading medical challenges of the 21st century. The resistance of this disorder to effective, long-term treatment can be traced to the fact that body fat stores are subject to homeostatic regulation in obese individuals, just as in lean individuals. Because the growing obesity epidemic is linked to a substantial increase in daily energy intake, a key priority is to delineate how mechanisms governing food intake and body fat content are altered in an obesogenic environment. EVIDENCE ACQUISITION: We considered all relevant published research and cited references that represented the highest quality evidence available. Where space permitted, primary references were cited. EVIDENCE SYNTHESIS: The increase of energy intake that has fueled the U.S. obesity epidemic is linked to greater availability of highly rewarding/palatable and energy-dense food. Obesity occurs in genetically susceptible individuals and involves the biological defense of an elevated body fat mass, which may result in part from interactions between brain reward and homeostatic circuits. Inflammatory signaling, accumulation of lipid metabolites, or other mechanisms that impair hypothalamic neurons may also contribute to the development of obesity and offer a plausible mechanism to explain the biological defense of elevated body fat mass. CONCLUSIONS: Despite steady research progress, mechanisms underlying the resistance to fat loss once obesity is established remain incompletely understood. Breakthroughs in this area may be required for the development of effective new obesity prevention and treatment strategies. PMCID: PMC3319208 PMID: 22238401 [PubMed - indexed for MEDLINE] 421. Anat Sci Int. 2012 Mar;87(1):24-44. doi: 10.1007/s12565-011-0128-4. Epub 2012 Jan 12. Mesenchymal cell populations: development of the induction systems for Schwann cells and neuronal cells and finding the unique stem cell population. Kitada M(1). Author information: (1)Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai, Miyagi, 980-8575, Japan. Masaaki.Kitada@gmail.com Mesenchymal cell populations, referred to as mesenchymal stem cells or multipotent stromal cells (MSCs), which include bone marrow stromal cells (BMSCs), umbilical cord stromal cells and adipose stromal cells (ASCs), participate in tissue repair when transplanted into damaged or degenerating tissues. The trophic support and immunomodulation provided by MSCs can protect against tissue damage, and the differentiation potential of these cells may help to replace lost cells. MSCs are easily accessible and can be expanded on a large scale. In addition, BMSCs and ASCs can be harvested from the patient himself. Thus, MSCs are considered promising candidates for cell therapy. In this review, I will discuss recently discovered high-efficiency induction systems for deriving Schwann cells and neurons from MSCs. Other features of MSCs that are important for tissue repair include the self-renewing property of stem cells and their potential for differentiation. Thus, I will also discuss the stemness of MSCs and describe the discovery of a certain stem cell type among adult MSCs that can self-renew and differentiate into cells of all three germ layers. Furthermore, I will explore the prospects of using this cell population for cell therapy. PMID: 22237924 [PubMed - indexed for MEDLINE] 422. Curr Pharm Des. 2012;18(6):789-98. Apelin in the control of body fluid homeostasis and cardiovascular functions. Galanth C(1), Hus-Citharel A, Li B, Llorens-Cortès C. Author information: (1)Center for Interdisciplinary Research in Biology, College de France, 11 Place Marcelin Berthelot, 75231 Paris Cedex 05, France. The discovery of apelin, an endogenous ligand of the orphan APJ receptor is an important advance for fundamental research and clinical medicine. Apelin and its receptor have a wide tissue distribution not only in the brain but also in peripheral organs including kidney, heart, vessels, and adipose tissue. Apelin is implicated in many physiological and pathophysiological processes such as the regulation of body fluid homeostasis, cardiovascular functions, glucose homeostasis, cell proliferation, and angiogenesis. This review focuses on, i) the various signaling cascades evoked upon stimulation of the apelin receptor by the different molecular forms of apelin found in vivo, ii) the distribution of apelin and its receptor in the brain and the cardiovascular system, iii) the opposing actions of vasopressin and apelin in the regulation of water balance at the central and kidney levels, and on the cardiovascular system regarding regulation of arterial blood pressure, vascular tone, and cardiac function. PMID: 22236125 [PubMed - indexed for MEDLINE] 423. ScientificWorldJournal. 2011;11:2509-29. doi: 10.1100/2011/397971. Epub 2011 Dec 28. Macrophages, meta-inflammation, and immuno-metabolism. Shapiro H(1), Lutaty A, Ariel A. Author information: (1)Department of Biology, Faculty of Natural Sciences, University of Haifa, Haifa 31905, Israel. Current research depicts specific modes of immunity and energy metabolism as being interrelated at the molecular, cellular, organ and organism level. Hence, whereas M2 (alternatively-activated) macrophages dominate insulin-sensitive adipose tissue in the lean, M1-skewed (classically-activated) macrophages accumulate in parallel to adiposity in the obese, and promote inflammation and insulin resistance, that is, meta-inflammation. The latest frontier of immuno-metabolism explores the coregulation of energy metabolism and immune function within hematopoietic cells. M1-skewed macrophages are sustained in edematous, hypoxic tissues by anaerobic glycolysis, whereas mitochondrial biogenesis and respiration dominates in M2 cells. We review the underlying mechanisms and the consequences of the transition from M2 to M1 predominance in adipose tissue, as well as the extracellular signals and transcription factors that control macrophage phenotypes and impose distinct metabolic modes. PMCID: PMC3253544 PMID: 22235182 [PubMed - indexed for MEDLINE] 424. Pharmacol Ther. 2012 May;134(2):127-38. doi: 10.1016/j.pharmthera.2011.12.009. Epub 2011 Dec 30. Targeting ASIC3 for pain, anxiety, and insulin resistance. Wu WL(1), Cheng CF, Sun WH, Wong CW, Chen CC. Author information: (1)Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Taipei 115, Taiwan. The acid-sensing ion channel 3 (ASIC3) is a pH sensor that responds to mild extracellular acidification and is predominantly expressed in nociceptors. There is much interest in targeting ASIC3 to relieve pain associated with tissue acidosis, and selective drugs targeting ASIC3 have been used to relieve acid-evoked pain in animal models and human studies. There is accumulating evidence that ASIC3 is widely expressed in many neuronal and non-neuronal cells, such as neurons in the brain and adipose cells, albeit to a lesser extent than in nociceptors. Asic3-knockout mice have reduced anxiety levels and enhanced insulin sensitivity, suggesting that antagonizing ASIC3 has additional benefits. This view is tempered by recent studies suggesting that Asic3-knockout mice may experience cardiovascular disturbances. Due to the development of ASIC3 antagonists as analgesics, we review here the additional benefits, safety, risks, and strategy associated with antagonizing ASIC3 function. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 22233754 [PubMed - indexed for MEDLINE] 425. J Mol Med (Berl). 2012 Aug;90(8):887-93. doi: 10.1007/s00109-012-0858-3. Epub 2012 Jan 10. A new, powerful player in lipoprotein metabolism: brown adipose tissue. Bartelt A(1), Merkel M, Heeren J. Author information: (1)Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. Important causes for modern epidemics such as obesity, diabetes, and cardiovascular disease are over- and malnutrition. Dietary as well as endogenous lipids are transported through the bloodstream in lipoproteins, and disturbances in lipoprotein metabolism are associated with atherosclerosis, heart disease, and diabetes. Recent findings reveal biological principles-how lipoproteins, in particular triglyceride-rich lipoproteins, are metabolized and what factors regulate their processing. The fate of triglycerides delivered by lipoproteins is quite simple: either they can be stored or they can be utilized for combustion or biosynthetic pathways. In the healthy state, fatty acids derived from triglycerides can be burned in the heart, muscle, and other organs for actual work load, or they can be stored in white adipose tissue. The combination of storage and combustion is realized in brown adipose tissue (BAT), a peripheral organ that was long thought to be only of relevance in small mammals: Recent data however prove that BAT plays an important role in human adults. Here, we will review recent insights on how BAT controls triglyceride clearance and the possible implications for the treatment of chronic diseases caused by lipid mishandling. PMID: 22231746 [PubMed - indexed for MEDLINE] 426. Immunol Cell Biol. 2012 Sep;90(8):755-62. doi: 10.1038/icb.2011.110. Epub 2012 Jan 10. The adaptive immune system as a fundamental regulator of adipose tissue inflammation and insulin resistance. Winer S(1), Winer DA. Author information: (1)Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada. Over the past decade, chronic inflammation in visceral adipose tissue (VAT) has gained acceptance as a lead promoter of insulin resistance in obesity. A great deal of evidence has pointed to the role of adipokines and innate immune cells, in particular, adipose tissue macrophages, in the regulation of fat inflammation and glucose homeostasis. However, more recently, cells of the adaptive immune system, specifically B and T lymphocytes, have emerged as unexpected promoters and controllers of insulin resistance. These adaptive immune cells infiltrate obesity expanded VAT and through cytokine secretion and macrophage modulation dictate the extent of the local inflammatory response, thereby directly impacting insulin resistance. The remarkable ability of our adaptive immune system to regulate insulin sensitivity and metabolism has unmasked a novel physiological function of this system, and promises new diagnostic and therapeutic strategies to manage the disease. This review highlights critical roles of adipose tissue lymphocytes in governing glucose homeostasis. PMID: 22231651 [PubMed - indexed for MEDLINE] 427. Nat Rev Neurol. 2012 Jan 10;8(2):70-1. doi: 10.1038/nrneurol.2011.223. Epilepsy in 2011: Insights into epilepsy treatments and biomarkers. Cendes F(1). Author information: (1)Department of Neurology, FCM, University of Campinas, Rua Vital Brasil, 251 Cidade Universitária, Campinas, SP13.083-888, Brazil. fcendes@unicamp.br PMID: 22231197 [PubMed - indexed for MEDLINE] 428. Kardiol Pol. 2011;69 Suppl 3:89-93. [The role of apelin in pathogenesis of cardiovascular diseases and metabolic disorders]. [Article in Polish] Cudnoch Jędrzejewska A(1), Czarzasta K, Gomółka R, Szczepańska Sadowska E. Author information: (1)Katedra i Zakład Fizjologii Doświadczalnej i Klinicznej, Warszawski Uniwersytet Medyczny, Warszawa. agnieszka.cudnoch@wum.edu.pl Apelin is a recently discovered biologically active peptide present in several isoforms that are agonists for orphan receptor APJ. Apelin and APJ receptor were found in the central nervous system and in different peripheral tissues. In the cardiovascular system the peptide is present both in the heart and in the endothelium and smooth muscles cells of the vascular wall. Acting on cardiomyocytes apelin exerts positive inotropic effect, in the endothelium it releases nitric oxide, which mediates its vasodilatory action, while acting directly on smooth muscles cells it causes vasoconstriction. Apelin interacts with other compounds regulating blood pressure; for instance with angiotensin II, vasopressin, and with the sympathetic nervous system. Special attention is focused on the possibility of positive role of apelin in hypertension, initial stages of heart failure and ischaemic heart disease. Synthesis of apelin in adipocytes permits to include this peptide among adipokines. In the adipose tissue its production is increased in obesity and by insulin. It appears that apelin may play essential role in pathogenesis of insulin-resistant obesity. In patients with type 2 diabetes apelin improves glucose tolerance in initial stages of the illness. However, further experimental and clinical studies are required for full evaluation of significance of positive and negative aspects of the role of apelin in the cardiovascular and metabolic diseases. PMID: 22125210 [PubMed - indexed for MEDLINE] 429. Maturitas. 2012 Mar;71(3):227-39. doi: 10.1016/j.maturitas.2011.12.009. Epub 2012 Jan 9. Anti-inflammatory properties of culinary herbs and spices that ameliorate the effects of metabolic syndrome. Jungbauer A(1), Medjakovic S. Author information: (1)Department of Biotechnology and Christian Doppler Laboratory of Receptor Biotechnology, University of Natural Resources and Life Sciences Vienna, Muthgasse 18, 1190 Vienna, Austria. alois.jungbauer@boku.ac.at Obesity and metabolic syndrome are increasing global health problems. In addition to the malnutrition of a sedentary lifestyle, high calorie intake leads to obesity with many negative health consequences. Macrophages infiltrate adipose tissue and induce chronic inflammation by secreting pro-inflammatory cytokines, including COX-2 and iNOS, among other mediators of inflammation. Free fatty acids mediate adipose tissue signalling through toll-like receptor 4 and the expression of these pro-inflammatory mediators via NF-κB or JNK. PPAR γ activators can inhibit the activation of NF-κB, down-regulating the expression of pro-inflammatory cytokines. Here we provide an overview of how different culinary herbs and spices exert anti-inflammatory activities and the extent to which they activate PPAR α and PPAR γ, inhibit the activation of NF-κB, and enhance expression of anti-inflammatory cytokines. Spices can play essential roles as anti-inflammatory agents in our diet, acting as pan PPAR activators and improving insulin sensitivity, counteracting dyslipidaemia and weight gain. The effects of chronic inflammation caused by obesity are counteracted and, consequently, the progression of diseases associated with chronic inflammation slowed. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 22226987 [PubMed - indexed for MEDLINE] 430. Int J Biochem Cell Biol. 2012 Mar;44(3):475-9. doi: 10.1016/j.biocel.2011.12.014. Epub 2011 Dec 31. The transforming growth factor-beta/bone morphogenetic protein signalling pathway in adipogenesis. Margoni A(1), Fotis L, Papavassiliou AG. Author information: (1)Department of Biological Chemistry, University of Athens Medical School, 11527 Athens, Greece. Rising obesity epidemic makes the better understanding of transcription factor networks regulating adipogenesis very challenging. Adipogenesis begins with the commitment of pluripotent mesenchymal stem cells to the adipocyte lineage, followed by terminal differentiation of preadipocytes to mature adipocytes. Among the molecules that influence the decision of progenitor cells to become adipocytes are members of transforming growth factor-beta superfamily and particularly bone morphogenetic proteins. Transforming growth factor-beta and bone morphogenetic proteins exert their biological functions mainly through their downstream molecules, the Smads. Here, we review the role(s) of transforming growth factor-beta/bone morphogenetic protein signalling pathway in adipocyte differentiation. Unravelling the precise mechanism of each molecule/pathway is necessary for developing suitable inhibitors or mimetic agents in order to treat obesity and improve insulin resistance. Current research efforts aim at discovering drugs that reduce fat mass or change the phenotype of adipose tissue into a more thermogenic one. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 22226816 [PubMed - indexed for MEDLINE] 431. Acta Physiol (Oxf). 2012 Jun;205(2):194-208. doi: 10.1111/j.1748-1716.2012.02409.x. Epub 2012 Feb 1. Structural and biochemical characteristics of various white adipose tissue depots. Wronska A(1), Kmiec Z. Author information: (1)Department of Histology, Medical University of Gdansk, Gdansk, Poland. It is now widely accepted that white adipose tissue (WAT) is not merely a fuel storage organ, but also a key component of metabolic homoeostatic mechanisms. Apart from its major role in lipid and glucose metabolism, adipose tissue is also involved in a wide array of other biological processes. The hormones and adipokines, as well as other biologically active agents released from fat cells, affect many physiological and pathological processes. WAT is neither uniform nor inflexible because it undergoes constant remodelling, adapting the size and number of adipocytes to changes in nutrients' availability and hormonal milieu. Fat depots from different areas of the body display distinct structural and functional properties and have disparate roles in pathology. The two major types of WAT are visceral fat, localized within the abdominal cavity and mediastinum, and subcutaneous fat in the hypodermis. Visceral obesity correlates with increased risk of insulin resistance and cardiovascular diseases, while increase of subcutaneous fat is associated with favourable plasma lipid profiles. Visceral adipocytes show higher lipogenic and lipolytic activities and produce more pro-inflammatory cytokines, while subcutaneous adipocytes are the main source of leptin and adiponectin. Moreover, adipose tissue associated with skeletal muscles (intramyocellular and intermuscular fat) and with the epicardium is believed to provide fuels for skeletal and cardiac muscle contraction. However, increased mass of either epicardial or intermuscular adipose tissue correlates with cardiovascular risk, while the presence of the intramyocellular fat is a risk factor for the development of insulin resistance. This review summarizes results of mainly human studies related to the differential characteristics of various WAT depots. © 2012 The Authors Acta Physiologica © 2012 Scandinavian Physiological Society. PMID: 22226221 [PubMed - indexed for MEDLINE] 432. Cell Metab. 2012 Jan 4;15(1):10-8. doi: 10.1016/j.cmet.2011.10.011. The inflammasome puts obesity in the danger zone. Stienstra R(1), Tack CJ, Kanneganti TD, Joosten LA, Netea MG. Author information: (1)Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen 6525 GA, The Netherlands. Obesity-induced inflammation is an important contributor to the induction of insulin resistance. Recently, the cytokine interleukin-1β (IL-1β) has emerged as a prominent instigator of the proinflammatory response in obesity. Several studies over the last year have subsequently deciphered the molecular mechanisms responsible for IL-1β activation in adipose tissue, liver, and macrophages and demonstrated a central role of the processing enzyme caspase-1 and of the protein complex leading to its activation called the inflammasome. These data suggest that activation of the inflammasome represents a crucial step in the road from obesity to insulin resistance and type 2 diabetes. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22225872 [PubMed - indexed for MEDLINE] 433. Annu Rev Immunol. 2012;30:677-706. doi: 10.1146/annurev-immunol-020711-075008. Epub 2012 Jan 6. Cancer and inflammation: an old intuition with rapidly evolving new concepts. Trinchieri G(1). Author information: (1)Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702-1201, USA. trinchig@mail.nih.gov Recent scientific advances have contributed much to the dissection of the complex molecular and cellular pathways involved in the connection between cancer and inflammation. The evidence for this connection in humans is based on the association between infection or chronic sterile inflammation and cancer. The decreased incidence of tumors in individuals who have used nonsteroidal anti-inflammatory drugs is supportive of a role for inflammation in cancer susceptibility. The increased incidence of tumors in overweight patients points to a role for adipose tissue inflammation and energy metabolism in cancer. Energy metabolism, obesity, and genetic instability are regulated in part by the relationship of the organism with commensal bacteria that affect inflammation with both local and systemic effects. Different aspects of inflammation appear to regulate all phases of malignant disease, including susceptibility, initiation, progression, dissemination, morbidity, and mortality. PMID: 22224761 [PubMed - indexed for MEDLINE] 434. Tissue Eng Part B Rev. 2012 Aug;18(4):258-69. doi: 10.1089/ten.TEB.2011.0440. Epub 2012 Mar 23. Bone tissue engineering: current strategies and techniques--part II: Cell types. Szpalski C(1), Barbaro M, Sagebin F, Warren SM. Author information: (1)Department of Plastic Surgery, New York University Langone Medical Center, New York, New York 10016, USA. Bone repair and regeneration is a dynamic process that involves a complex interplay between the (1) ground substance; (2) cells; and (3) milieu. Each constituent is integral to the final product, but it is often helpful to consider each component individually. While bone tissue engineering has capitalized on a number of breakthrough technologies, one of the most valued advancements is the incorporation of mesenchymal stem cells (SCs) into bone tissue engineering applications. With this new idea, however, came new found problems of guiding SC differentiation. Moreover, investigators are still working to understand which SCs source produces optimal bone formation in vitro and in vivo. Bone marrow-derived mesenchymal SCs and adipose-derived SCs have been researched most extensively, but other SC sources, including dental pulp, blood, umbilical cord blood, epithelial cells reprogrammed to become induced pluripotent SCs, among others, are being investigated. In Part II of this review series, we discuss the variety of cell types (e.g., osteocytes, osteoblasts, osteoclasts, chondrocytes, mesenchymal SCs, and vasculogenic cells) important in bone tissue engineering. PMID: 22224439 [PubMed - indexed for MEDLINE] 435. ScientificWorldJournal. 2011;11:1568-81. doi: 10.1100/tsw.2011.146.. Epub 2011 Aug 16. Current status of human adipose-derived stem cells: differentiation into hepatocyte-like cells. Al Battah F(1), De Kock J, Vanhaecke T, Rogiers V. Author information: (1)Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel (VUB), Brussels, Belgium. falbatta@vub.ac.be The shortage of human organ donors and the low cell quality of available liver tissues represent major obstacles for the clinical application of orthotropic liver transplantation and hepatocyte transplantation, respectively. Therefore, worldwide research groups are investigating alternative extrahepatic cell sources. Recent in vitro studies have demonstrated that mesenchymal stem cells (MSCs) from various sources, including human bone marrow, adipose tissue, and umbilical cord, can be differentiated into hepatocyte-like cells when appropriate conditions are used. In particular, interest exists for human adipose-derived stems cells (hASCs) as an attractive cell source for generating hepatocyte-like cells. The hASCs are multipotent MSCs that reside in adipose tissue, with the ability to self-renew and differentiate into multiple cell lineages. Moreover, these cells can secrete multiple growth factors and cytokines that exert beneficial effects on organ or tissue injury. In this review, we will not only present recent data regarding hASC biology, their isolation, and differentiation capability towards hepatocytes, but also the potential application of hASC-derived hepatocytes to study drug toxicity. Additionally, this review will discuss the therapeutic potential of hASCs as undifferentiated cells in liver regeneration. PMCID: PMC3201629 PMID: 22224071 [PubMed - indexed for MEDLINE] 436. Int J Biochem Cell Biol. 2012 Mar;44(3):435-40. doi: 10.1016/j.biocel.2011.12.011. Epub 2011 Dec 28. White adipocytes: more than just fat depots. Henry SL(1), Bensley JG, Wood-Bradley RJ, Cullen-McEwen LA, Bertram JF, Armitage JA. Author information: (1)Department of Anatomy and Developmental Biology, Monash University, Australia. Globally 30% of adults are overweight or obese. The white adipocyte is a major component of adipose tissue, and as the obesity epidemic increases it is critically important to understand the factors determining adipocyte development and function. Adipogenesis has two distinct phases; determination of the adipocyte from a multipotent stem cell, and terminal differentiation of a pre-adipocyte into a mature adipocyte. The environment encountered in early life can alter adipocyte number and size and potentially impact upon adipocyte endocrine function in adulthood. These alterations may contribute to the pathophysiology of chronic diseases and thus targeted therapy of the adipocyte has great potential for treating the current obesity epidemic. Copyright © 2012 Elsevier Ltd. All rights reserved. PMID: 22222895 [PubMed - indexed for MEDLINE] 437. J Pharm Pharmacol. 2012 Feb;64(2):161-71. doi: 10.1111/j.2042-7158.2011.01366.x. Epub 2011 Oct 13. Role of PPARg2 transcription factor in thiazolidinedione-induced insulin sensitization. Saraf N(1), Sharma PK, Mondal SC, Garg VK, Singh AK. Author information: (1)Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut (UP), India. saraf.140588@gmail.com OBJECTIVES: Adipose tissue is the key regulator of energy balance, playing an active role in lipid storage and metabolism and may be a dynamic buffer to control fatty acid flux. Peroxisome proliferator-activated receptor gamma isoform-2 (PPARg2), an isoform of the nuclear hormone receptor superfamily, has been implicated in almost all aspects of human metabolic alterations such as obesity, insulin resistance, type-2 diabetes and dyslipidaemia. The PPARg2 isoform is highly present in adipose tissue where it functions as a thrifty phenotype, which promotes adipocyte differentiation and triglyceride storage. Thiazolidinediones, antidiabetic drugs, induce insulin sensitivity by controlling adipokines. The thiazolidinediones bind with PPARg2 in adipocytes and exert an agonist effect by enhancing adipogenesis and fatty acid uptake. Thiazolidinediones stimulate PPARg2, by which they down-regulate tumour necrosis factor-α, leptin, interleukin-6 and plasminogen and also enhance insulin sensitivity. The aim of this work is to define role of PPARg2 transcription factor in thiazolidinedione-induced insulin sensitization. KEY FINDINGS: The PPARg2 alters the transcription of the target gene. This altered gene transcription results in the up-regulation of insulin-sensitizing factors and down-regulation of insulin-resistant factors. The variant Pro12Ala of the PPARg2 gene is an important modulator in metabolic control in the body. Thiazolidinediones stimulate PPARg2 transcription factor by which PPARg2 binds to responsive elements located in the promoter regions of many genes and modulates their transcriptive activity. There is a strong mutual relationship between receptor binding and agonism, which is evidence of the insulin-sensitizing target of thiazolidinediones in PPARg2. This evidently increases the biological potency of the glucose-lowering effect of thiazolidinediones in vivo as well as their antidiabetic activity. CONCLUSIONS: PPARg2 transcription factor plays an important role in treatment of type-2 diabetes with thiazolidindiones. The variant Pro12Ala of the PPARg2 gene promotes the activity of thiazolidinediones in minimizing insulin resistance. Transcriptional activity of Pro12Ala variant improves the activity of insulin. Thus thiazolidinediones promote the phosphorylation of PPARg2 to induce insulin sensitivity. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society. PMID: 22221092 [PubMed - indexed for MEDLINE] 438. Nihon Rinsho Meneki Gakkai Kaishi. 2011;34(6):464-75. [Topics of glucocorticoids--centered on therapy for rheumatoid arthritis]. [Article in Japanese] Akama H(1). Author information: (1)Japan/Asia Clinical Research Product Creation Unit, Eisai Product Creation Systems, Eisai Co., Ltd, Japan. Glucocorticoids (steroids) have been widely used for the treatment of patients with rheumatoid arthritis (RA) since Hench had attempted to administer cortisone (Kendall's compound E) to an active RA patient in 1948. Rheumatologists even in the 21st century can learn a lot from the history of steroid. In this feature article on steroid, a brief outline of 11β-hydroxysteroid dehydrogenase type 1, a tissue-specific regulator of steroid response, is presented. The isozyme re-activates inactive cortisone (compound E) to active cortisol (compound F), and seems to play an important role particularly in adipose tissue. In addition, I give an account of non-genomic mechanisms of steroid, which might be relevant to early and rapid effects during methylprednisolone pulse therapy. As for the field of practical rheumatology, rates and dosages of steroid administration for RA in Japan are shown, by looking into 3 large observational cohort researches and post-marketing surveillance programs for several biologics. The definition or an appropriate interpretation of medical/technical terms such as 'effectiveness' in the clinical setting and 'low-dose' steroid is also described. PMID: 22214807 [PubMed - indexed for MEDLINE] 439. Proteomics Clin Appl. 2012 Jan;6(1-2):91-101. doi: 10.1002/prca.201100052. Epub 2011 Dec 27. Adipokines: a treasure trove for the discovery of biomarkers for metabolic disorders. Lehr S(1), Hartwig S, Sell H. Author information: (1)Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Duesseldorf, Germany. stefan.lehr@ddz.uni-duesseldorf.de Adipose tissue is a major endocrine organ, releasing signaling and mediator proteins, termed adipokines, via which adipose tissue communicates with other organs. Expansion of adipose tissue in obesity alters adipokine secretion which may contribute to the development of metabolic diseases. Consequently, this correlation has emphasized the importance to further characterize the adipocyte secretion profile, and several attempts have been made to characterize the complex nature of the adipose tissue secretome by utilizing diverse proteomic profiling approaches. Although the entirety of human adipokines is still incompletely characterized, to date more than 600 potentially secretory proteins were identified providing a rich source to identify putative novel biomarkers associated with metabolic diseases. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. PMID: 22213627 [PubMed - indexed for MEDLINE] 440. Ann N Y Acad Sci. 2011 Dec;1243:30-46. doi: 10.1111/j.1749-6632.2011.06246.x. Interactions between metabolism and circadian clocks: reciprocal disturbances. Delezie J(1), Challet E. Author information: (1)Department of Neurobiology of Rhythms, Institute of Cellular and Integrative Neurosciences, Centre National de la Recherche Scientifique, UPR3212, University of Strasbourg, Strasbourg, France. Obesity is a medical condition of excess body fat, recognized as a global epidemic. Besides genetic factors, overconsumption of high-energy food and a sedentary lifestyle are major obesogenic causes. A newly identified determinant is altered circadian rhythmicity. To anticipate and adapt to daily changes in the environment, organisms have developed an endogenous circadian timing system, comprising a main circadian clock, located in the suprachiasmatic nucleus (SCN) of the hypothalamus, principally synchronized to the light-dark cycle. Secondary peripheral clocks are found in various tissues, such as the liver, pancreas, and adipose tissue. These clocks control the rhythmic patterns of myriad metabolic processes. We will review the evidence that metabolic dysfunction is associated with circadian disturbances at both central and peripheral levels and, conversely, that disruption of circadian clock functioning can lead to obesity. The roots of these reciprocal interactions will be illustrated by transcriptional crosstalk between metabolic and circadian systems. Chronotherapeutic approaches of dieting to maintain or restore a proper circadian alignment could be useful to limit the magnitude of metabolic risks. © 2011 New York Academy of Sciences. PMID: 22211891 [PubMed - indexed for MEDLINE] 441. Am J Physiol Heart Circ Physiol. 2012 Mar 15;302(6):H1231-40. doi: 10.1152/ajpheart.00765.2011. Epub 2011 Dec 30. Adiponectin and adipocyte fatty acid binding protein in the pathogenesis of cardiovascular disease. Xu A(1), Vanhoutte PM. Author information: (1)Department of Pharmacology and Pharmacy, the University of Hong Kong, Hong Kong. The heart and blood vessels are surrounded by epicardial and perivascular adipose tissues, respectively, which play important roles in maintaining cardiovascular homeostasis by secreting a number of biologically active molecules, termed "adipokines." Many of these adipokines function as an important component of the 'adipo-cardiovascular axis' mediating the cross talk between adipose tissues, the heart, and the vasculature. On the one hand, most adipokines [including tumor necrosis factor-α, resistin, adipocyte fatty acid binding protein (A-FABP), and lipocalin-2] are proinflammatory and causally associated with endothelial and cardiac dysfunction by their endocrine/paracrine actions. On the other hand, adiponectin is one of the few adipokines that possesses multiple salutary effects on the prevention of cardiovascular disease, because of its pleiotropic actions on the heart and the blood vessels. The discordant production of adipokines in dysfunctional adipose tissue is a key contributor to obesity-related cardiovascular disease. This review provides an update in understanding the roles of adipokines in the pathogenesis of cardiovascular disorders associated with obesity and diabetes and focuses on the two most abundant adipokines, adiponectin and A-FABP. Indeed, data from both animal studies and clinical investigations imply that these two adipokines are prognostic biomarkers for cardiovascular disease and even promising therapeutic targets for its treatment. PMID: 22210749 [PubMed - indexed for MEDLINE] 442. Expert Opin Biol Ther. 2012 Feb;12(2):155-63. doi: 10.1517/14712598.2012.644533. Epub 2011 Dec 31. Adipose stem cell-based soft tissue regeneration. Philips BJ(1), Marra KG, Rubin JP. Author information: (1)University of Pittsburgh, Division of Plastic Surgery, Department of Surgery, Pittsburgh, PA 15261, USA. INTRODUCTION: Since their isolation and characterization nearly a decade ago, adipose-derived stem cells (ASCs) have become one of the most popular adult stem cell populations for research in soft tissue engineering and regenerative medicine applications. Compared with other stem cell sources, ASCs offer several advantages including an abundant autologous source, minor invasive harvesting (liposuction), significant proliferative capacity in culture and multi-lineage potential. Numerous preclinical studies have been pursued, with early clinical data appearing in the literature. AREAS COVERED: Autologous fat grafting has gained tremendous momentum in clinical practice over the past several years due to its potential applications in trauma and reconstructive surgery. This review focuses on the published clinical and pre-clinical (i.e., animal) data to date using ASCs for soft tissue reconstruction, with particular attention to experimental models and methodologies. Future directions for rendering soft tissue reconstructive therapies more effective are discussed. EXPERT OPINION: Although standardization of ASC harvesting and processing techniques, as well as long-term results of existing clinical studies, remains to be addressed, the known biological properties of ASCs suggest a potential role in enhancing fat graft retention and facilitating minimally invasive reconstructive treatments. While clinical applications are being reported, well controlled clinical studies are needed to demonstrate safety and efficacy. PMID: 22208874 [PubMed - indexed for MEDLINE] 443. Nutrition. 2012 Feb;28(2):113-7. doi: 10.1016/j.nut.2011.09.009. Visceral fat and gut inflammation. Drouet M(1), Dubuquoy L, Desreumaux P, Bertin B. Author information: (1)Université Lille Nord de France, Lille, France. The etiology of inflammatory bowel disease and, in particular, Crohn's disease involves a deregulated mucosal immune system under the influence of intestinal flora and environmental factors in genetically susceptible individuals. A new hypothesis has focused on mesenteric fat hypertrophy and the presence of ectopic fat surrounding inflamed bowel, the so-called creeping fat, which are hallmarks of Crohn's disease. Mesenteric adipose tissue is currently recognized as an active actor in immunity with a capacity for mediator secretion. These mediators include classic pro- and anti-inflammatory cytokines or chemokines and hormone-like adipokines with multiple effects. Mesenteric fat participates in the course of Crohn's disease and may play an active role in the regulation of intestinal inflammation. However, little is known about the origin and role of mesenteric fat in Crohn's disease, essentially because of a lack of experimental models that develop creeping fat. The purpose of this review is to present the recent data describing the immune properties of mesenteric fat and the recent advances in animal models, which have suggested a new hypothesis about the role of creeping fat in Crohn's disease. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22208553 [PubMed - indexed for MEDLINE] 444. Scientifica (Cairo). 2012;2012:525374. doi: 10.6064/2012/525374. Epub 2012 Aug 30. The prothrombotic tendency in metabolic syndrome: focus on the potential mechanisms involved in impaired haemostasis and fibrinolytic balance. Russo I(1). Author information: (1)Internal Medicine and Metabolic Disease Unit, Department of Clinical and Biological Sciences of the Turin University, San Luigi Gonzaga Hospital, 10043 Orbassano, Italy. The metabolic syndrome is a clinical disorder characterized by impairment of glucose metabolism, increased arterial blood pressure, and abdominal obesity. The presence of these clinical features exposes patients to a high risk of atherothrombotic cardiovascular events. The pathogenesis of atherothrombosis in the metabolic syndrome is multifactorial, requiring a close relationship among the main components of the metabolic syndrome, including insulin resistance, alterations of glycaemic and lipid pattern, haemodynamic impairment, and early appearance of endothelial dysfunction. Furthermore, haemostatic alterations involving coagulation balance, fibrinolysis, and platelet function play a relevant role both in the progression of the arterial wall damage and in acute vascular events. The mechanisms linking abdominal obesity with prothrombotic changes in the metabolic syndrome have been identified and partially elucidated on the basis of alterations of each haemostatic variable and defined through the evidence of peculiar dysfunctions in the endocrine activity of adipose tissue responsible of vascular impairment, prothrombotic tendency, and low-grade chronic inflammation. This paper will focus on the direct role of adipose tissue on prothrombotic tendency in patients affected by metabolic syndrome, with adipocytes being able to produce and/or release cytokines and adipokines which deeply influence haemostatic/fibrinolytic balance, platelet function, and proinflammatory state. PMCID: PMC3820496 PMID: 24278711 [PubMed] 445. Adipocyte. 2012 Jan 1;1(1):13-24. Brown adipose tissue: Recent insights into development, metabolic function and therapeutic potential. Townsend K(1), Tseng YH. Author information: (1)Joslin Diabetes Center and Harvard Medical School; Boston, MA USA. Obesity is currently a global pandemic, and is associated with increased mortality and co-morbidities including many metabolic diseases. Obesity is characterized by an increase in adipose mass due to increased energy intake, decreased energy expenditure, or both. While white adipose tissue is specialized for energy storage, brown adipose tissue has a high concentration of mitochondria and uniquely expresses uncoupling protein 1, enabling it to be specialized for energy expenditure and thermogenesis. Although brown fat was once considered only necessary in babies, recent morphological and imaging studies have provided evidence that, contrary to prior belief, this tissue is present and active in adult humans. In recent years, the topic of brown adipose tissue has been reinvigorated with many new studies regarding brown adipose tissue differentiation, function and therapeutic promise. This review summarizes the recent advances, discusses the emerging questions and offers perspective on the potential therapeutic applications targeting this tissue. PMCID: PMC3661118 PMID: 23700507 [PubMed] 446. Vopr Onkol. 2012;58(4):464-72. [Heterogeneity of obesity and cancer: the potential role of brown adipose tissue]. [Article in Russian] Bershteĭn LM. PMID: 23607199 [PubMed - indexed for MEDLINE] 447. Vopr Onkol. 2012;58(6):744-7. [Ursolic acid as antitumor agent and inductor of PTEN and brown fat]. [Article in Russian] Bershteĭn LM. In this mini-review the basic evidence about anticancer properties of ursolic acid (UA), the compound belonging to the class of triterpenoids, is given. Beside inhibiting tumor cell growth in vitro and in vivo and activating of apoptosis, UA (as well as some other related and not related compounds) is capable to induce PTEN (a tumor suppressor mutation of which is rather often discovered in human tumors including endometrial cancer type I) and amount/activity of brown fat. The latter action may explain obesity-preventing capacity of UA that also may lead to an additional antiblastomogenic effect. PMID: 23600297 [PubMed - indexed for MEDLINE] 448. J Long Term Eff Med Implants. 2012;22(3):181-93. Factors influencing the long-term behavior of extracellular matrix-derived scaffolds for musculoskeletal soft tissue repair. Rowland CR(1), Little D, Guilak F. Author information: (1)Department of Orthopaedic Surgery and Biomedical Engineering, Duke University Medical Center, Durham, NC 27710, USA. Musculoskeletal connective tissues such as tendon, ligament, and cartilage possess a limited ability for self-repair. Tissue engineering seeks to use combinations of cells, bioactive molecules, and biomaterials to develop new treatment options for the repair or replacement of damaged tissues. The use of native extracellular matrix as scaffold material for tissue engineering has become increasingly attractive because such tissues can not only provide structural support, but also regulate cell behavior. Although demineralized bone matrix has long been recognized for its osteoinductive abilities, recent studies have identified the ability of cartilage and tendon extracellular matrices to stimulate the differentiation of mesenchymal or adipose-derived adult stem cells toward chondrogenic or tenogenic lineages, respectively. This review discusses the motivation for fabricating scaffolds from musculoskeletal tissues, the in vitro and in vivo efficacy of these tissue-derived scaffolds, and various processing techniques such as decellularization or cross-linking that can mitigate immunogenic responses, moderate the degradation profile, and enhance the mechanical properties of these constructs following long-term implantation in vivo. PMCID: PMC3633148 PMID: 23582110 [PubMed - indexed for MEDLINE] 449. J Stem Cells. 2012;7(2):87-95. The characterisation of mesenchymal stem cells: a stem cell is not a stem cell is not a stem cell. Khan WS(1), Hardingham TE. Author information: (1)University College London Institute of Orthopaedics and Musculoskeletal Sciences, Royal National Orthopaedic Hospital, Stanmore, London HA7 4LP, UK. wasimkhan@doctors.org.uk There has been an increasing interest in stem cell applications and tissue engineering approaches in surgical practice to deal with damaged or lost tissue. Although there have been developments in almost all surgical disciplines, the greatest advances are being made in orthopaedics. This is due to many factors including the familiarity with bone marrow derived mesenchymal stem cells. Unfortunately significant hurdles remain to be overcome in many areas before tissue engineering becomes more routinely used in clinical practice. Stem cells have been identified in a number of adult tissues, albeit in small numbers. In addition to bone marrow, mesenchymal stem cells have been identified in a number of tissues including adipose tissue and fat pad. The mesenchymal stem cells are generally isolated from the tissue and expanded in culture. These cells are characterised or defined using a set of cell surface markers; mesenchymal stem cells are generally positive for CD44, CD90 and CD105, and are negative for haematopoetic markers CD34 and CD45, and the neurogenic marker CD56. In this paper the characterisation of stem cells is discussed followed by preliminary evidence suggesting that pericytes may be a candidate stem cell. PMID: 23550347 [PubMed - indexed for MEDLINE] 450. Nutr Diabetes. 2012 Mar 5;2:e29. doi: 10.1038/nutd.2012.1. Getting 'Smad' about obesity and diabetes. Tan CK(1), Chong HC, Tan EH, Tan NS. Author information: (1)School of Biological Sciences, Nanyang Technological University, Singapore, Singapore. Recent findings on the role of transforming growth factor (TGF)-β/Smad3 signaling in the pathogenesis of obesity and type 2 diabetes have underscored its importance in metabolism and adiposity. Indeed, elevated TGF-β has been previously reported in human adipose tissue during morbid obesity and diabetic neuropathy. In this review, we discuss the pleiotropic effects of TGF-β/Smad3 signaling on metabolism and energy homeostasis, all of which has an important part in the etiology and progression of obesity-linked diabetes; these include adipocyte differentiation, white to brown fat phenotypic transition, glucose and lipid metabolism, pancreatic function, insulin signaling, adipocytokine secretion, inflammation and reactive oxygen species production. We summarize the recent in vivo findings on the role of TGF-β/Smad3 signaling in metabolism based on the studies using Smad3(-/-) mice. Based on the presence of a dual regulatory effect of Smad3 on peroxisome proliferator-activated receptor (PPAR)β/δ and PPARγ2 promoters, we propose a unifying mechanism by which this signaling pathway contributes to obesity and its associated diabetes. We also discuss how the inhibition of this signaling pathway has been implicated in the amelioration of many facets of metabolic syndromes, thereby offering novel therapeutic avenues for these metabolic conditions. PMCID: PMC3341711 PMID: 23449528 [PubMed] 451. Horm Metab Res. 2012 Jan;44(1):6-14. doi: 10.1055/s-0031-1295491. Epub 2011 Dec 28. The metabolic role of retinol binding protein 4: an update. Christou GA(1), Tselepis AD, Kiortsis DN. Author information: (1)Laboratory of Physiology, Medical School, University of Ioannina, Ioannina, Greece. Retinol binding protein 4 (RBP(4)) is regarded as a novel cardiometabolic risk factor, which is secreted mainly by the hepatocytes and also by the adipose tissue. RBP(4) has been shown to induce insulin resistance, and plasma RBP(4) values are increased in type 2 diabetes mellitus, obesity, metabolic syndrome, and cardiovascular disease. Moreover, it has been found that circulating RBP(4) decreases during medical interventions that result in amelioration of the metabolic profile, such as diet, exercise, oral antidiabetic drugs, and hypolipidemic agents. However, only few of the RBP(4)-related studies have investigated whether RBP(4) constitutes a causal factor of the above-mentioned metabolic conditions. Importantly, circulating RBP(4) is influenced by some nonmetabolic conditions, such as renal failure, acute illness, injury, and liver failure. Thus, further studies investigating the metabolic roles of RBP(4) should be carefully planned, taking into account the effects of nonmetabolic conditions on circulating RBP(4). © Georg Thieme Verlag KG Stuttgart · New York. PMID: 22205567 [PubMed - indexed for MEDLINE] 452. Curr Pharm Des. 2011 Dec;17(37):4121-31. Inflammation in hypertension: current therapeutic approaches. Androulakis E(1), Tousoulis D, Papageorgiou N, Latsios G, Siasos G, Tsioufis C, Giolis A, Stefanadis C. Author information: (1)1st Cardiology Unit, Hippokration Hospital, Athens University Medical School, Greece. The role of inflammation as crucial underlying process contributing to the initiation and the progression of atherosclerosis as well as its clinical manifestations is well established. Recent data have demonstrated also a strong association between essential hypertension and inflammatory process. In addition, several studies have shown that tissue expression and plasma concentrations of several inflammatory biomarkers/mediators are related to increased risk of hypertension. The determination of markers such as acute phase proteins (C-reactive protein), adhesion molecules such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and chemokines is crucial in determining therapeutic responses and clinical outcomes of hypertensive patients. In addition, several therapeutic approaches targeting blood pressure may have also beneficial effects in terms of inflammation and thus further clinical benefits. Although the available data are encouraging, further large scale studies are required to evaluate the reported anti-inflammatory effects in management and treatment of arterial hypertension. PMID: 22204373 [PubMed - indexed for MEDLINE] 453. Exp Diabetes Res. 2012;2012:103063. doi: 10.1155/2012/103063. Epub 2011 Dec 8. The pathophysiology of HIV-/HAART-related metabolic syndrome leading to cardiovascular disorders: the emerging role of adipokines. Palios J(1), Kadoglou NP, Lampropoulos S. Author information: (1)2nd Department of Cardiology, Attikon University Hospital of Athens, Haidari 12462, Greece. Individuals infected with human immunodeficiency virus (HIV) frequently demonstrate metabolic syndrome (MS) associated with increased incidence of cardiovascular disorders. Characteristics of HIV infection, such as immunodeficiency, viral load, and duration of the disease, in addition to the highly active antiretroviral therapy (HAART) have been suggested to induce MS in these patients. It is well documented that MS involves a number of traditional cardiovascular risk factors, like glucose, lipids, and arterial blood pressure abnormalities, leading to extensive atherogenic arterial wall changes. Nevertheless, the above traditional cardiovascular risk factors merely explain the exacerbated cardiovascular risk in MS. Nowadays, the adipose-tissue derivatives, known as adipokines, have been suggested to contribute to chronic inflammation and the MS-related cardiovascular disease. In view of a novel understanding on how adipokines affect the pathogenesis of HIV/HAART-related MS and cardiovascular complications, this paper focuses on the interaction of the metabolic pathways and the potential cardiovascular consequences. Based on the current literature, we suggest adipokines to have a role in the pathogenesis of the HIV/HAART-related MS. It is crucial to understand the pathophysiology of the HIV/HAART-related MS and apply therapeutic strategies in order to reduce cardiovascular risk in HIV patients. PMCID: PMC3235775 PMID: 22203832 [PubMed - indexed for MEDLINE] 454. Front Biosci (Schol Ed). 2012 Jan 1;4:916-31. Insulin resistance, metabolic stress, and atherosclerosis. Pansuria M(1), Xi H, Li L, Yang XF, Wang H. Author information: (1)Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA. Atherosclerosis, a pathological process that underlies the development of cardiovascular disease, is the primary cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). T2DM is characterized by hyperglycemia and insulin resistance (IR), in which target tissues fail to respond to insulin. Systemic IR is associated with impaired insulin signaling in the metabolic tissues and vasculature. Insulin receptor is highly expressed in the liver, muscle, pancreas, and adipose tissue. It is also expressed in vascular cells. It has been suggested that insulin signaling in vascular cells regulates cell proliferation and vascular function. In this review, we discuss the association between IR, metabolic stress, and atherosclerosis with focus on 1) tissue and cell distribution of insulin receptor and its differential signaling transduction and 2) potential mechanism of insulin signaling impairment and its role in the development of atherosclerosis and vascular function in metabolic disorders including hyperglycemia, hypertension, dyslipidemia, and hyperhomocysteinemia. We propose that insulin signaling impairment is the foremost biochemical mechanism underlying increased cardiovascular morbidity and mortality in atherosclerosis, T2DM, and metabolic syndrome. PMCID: PMC3319745 PMID: 22202099 [PubMed - indexed for MEDLINE] 455. Front Biosci (Elite Ed). 2012 Jan 1;4:768-78. Role of sirtuins, calorie restriction and physical activity in aging. Corbi G(1), Conti V, Scapagnini G, Filippelli A, Ferrara N. Author information: (1)Department of Health Sciences, Faculty of Medicine and Surgery, University of Molise, via Giovanni Paolo II -Localita Tappino, 86100 Campobasso, Italy. graziamaria.corbi@unimol.it Recently it has been discovered that Sirtuins represent pivotal regulators of lifespan. Caloric restriction (CR) enhances longevity from yeast to mammals. Whereas the relationship between Sirt-1 and CR is clear, the molecular mechanisms by which Sir2 increases longevity are still unknown. In mammals, CR induces physiological and behavioral changes, and many studies have shown that CR decreases production of reactive oxygen species production thus minimizing oxidative damage, leading to the hypothesis that CR by reducing oxidative stress extends the lifespan by counteraction of aging. In fact, the pathophysiology of aging and age-related diseases involves oxidative stress as an early stage in its development. Recently we found that in aged rats the SIRT1 activity was decreased in heart and adipose tissue, showing as aging is characterized in vivo by a reduced efficiency of this key-regulator of longevity. Whereas several studies have reported that increased physical activity can improve mean life span presumably by reducing mortality risk from many age-related diseases, exercise and longevity studies have failed to document an exercise effect on maximum life span. However, in aged rats a moderate prolonged exercise training is able to induce increase in SIRT1 activity, suggesting that this tool could counteract age-related dysfunctions. PMID: 22201912 [PubMed - indexed for MEDLINE] 456. Front Biosci (Landmark Ed). 2012 Jan 1;17:892-908. The biology of equine mesenchymal stem cells: phenotypic characterization, cell surface markers and multilineage differentiation. Penny J(1), Harris P, Shakesheff KM, Mobasheri A. Author information: (1)Musculoskeletal Research Group, Division of Veterinary Medicine, School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Sutton Bonington Campus, College Road, Sutton Bonington, Leicestershire, LE12 5RD, United Kingdom. Mesenchymal stem cells (MSCs) are multipotent stem cells that can give rise to a range of connective tissue cells including osteoblasts, chondrocytes and adipocytes. MSCs have been isolated from humans and a variety of animal species including rodents, dogs, horses and rabbits. There is currently no consensus on how these cells are identified and characterized. This is partly due to the lack of standardized specific cell surface markers for MSCs. The aim of this review is to examine the literature on equine MSCs and establish whether there is a well-defined phenotype for these cells. Equine MSCs have been obtained from four main sources, bone marrow, adipose tissue, umbilical cord (blood and matrix) and peripheral blood. MSCs from these tissue sources have been shown to undergo chondrogenic, adipogenic and osteogenic differentiation. However the markers used to identify these cells vary significantly in the literature. Despite this, CD90 and CD34 seem to be reliable positive and negative markers respectively. Our understanding of the biology of equine MSCs will benefit from better reagents for their phenotypic characterization. The antibodies and molecular probes needed for the reliable identification of equine MSCs are not standardized and this is a high priority for future research. PMID: 22201780 [PubMed - indexed for MEDLINE] 457. Neuropharmacology. 2012 Jul;63(1):57-75. doi: 10.1016/j.neuropharm.2011.12.010. Epub 2011 Dec 17. The adipocyte as an endocrine organ in the regulation of metabolic homeostasis. Harwood HJ Jr(1). Author information: (1)Delphi BioMedical Consultants, LLC, 10 Eska Drive, Ledyard, CT 06339, USA. h.james.harwood@gmail.com Over the past decade and a half it has become increasingly clear that adipose tissue is a much more complex organ than was initially considered and that its metabolic functions extend well beyond the classical actions of thermoregulation and of storage and release of fatty acids. In fact, it is now well established that adipose tissue plays a critical role in maintenance of energy homeostasis through secretion of a large number of adipokines that interact with central as well as peripheral organs such as the brain, liver, pancreas, and skeletal muscle to control diverse processes, such as food intake, energy expenditure, carbohydrate and lipid metabolism, blood pressure, blood coagulation, and inflammation. While many of these adipokines are adipocyte-derived and have a variety of endocrine functions, others are produced by resident macrophages and interact in a paracrine fashion to control adipocyte metabolism. It is also abundantly clear that the dysregulation of adipokine secretion and action that occurs in obesity plays a fundamental role in the development of a variety of cardiometabolic disorders, including the metabolic syndrome, type 2 diabetes, inflammatory disorders, and vascular disorders, that ultimately lead to coronary heart disease. Described herein are the traditional as well as endocrine roles of adipose tissue in controlling energy metabolism and their dysregulation in obesity that leads to development of cardiometabolic disorders, with a focus on what is currently known regarding the characteristics and roles in both health and disease of the adipocyte-derived adipokines, adiponectin, leptin, resistin, and retinol binding protein 4, and the resident macrophage-derived adipokines, tumor necrosis factor-α and interleukin-6. This article is part of a Special Issue entitled 'Central Control of Food Intake'. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 22200617 [PubMed - indexed for MEDLINE] 458. J Ren Nutr. 2012 Jan;22(1):81-5. doi: 10.1053/j.jrn.2011.10.029. Adipokines as uremic toxins. Teta D(1). Author information: (1)Service of Nephrology, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. daniel.teta@chuv.ch The adipose tissue has pleiotropic functions far beyond the mere storage of energy, and it secretes a number of hormones and cytokines, called adipokines, which have biological effects that impact heath and disease. Adipokines are markedly elevated in the plasma of uremic patients, mainly due to decreased renal excretion. They have pluripotent signaling effects on inflammation/oxidative stress (leptin, adiponectin, resistin), protein-energy wasting (leptin, adiponectin), insulin signaling (adiponectin, leptin, visfatin), endothelial dysfunction (visfatin), and vascular damage (adiponectin, leptin, resistin), which are prevalent in uremic patients. Obesity superimposed to uremia may further aggravate hyperadipokinemia, with the exception of adiponectinemia, which is mitigated by adiposity. Among adipokines and until more data become available, only leptin may be considered as a full uremic toxin owing to adverse effects on protein-energy wasting, cardiovascular damage, inflammation, and the immune system, which have been documented both clinically and experimentally. Resistin and visfatin display some features of uremic toxins, but more data are needed to consider these adipokines as true uremic toxins. In contrast, high levels of adiponectin and chemerin seen in uremia appear to be beneficial. Further research is needed to investigate whether selective removal of leptin, resistin, and visfatin and increments of adiponectin and chemerin levels may have clinical relevance in uremic patients. Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. PMID: 22200420 [PubMed - indexed for MEDLINE] 459. ScientificWorldJournal. 2011;11:1932-47. doi: 10.1100/2011/290142. Epub 2011 Oct 25. Beyond fat mass: exploring the role of adipokines in rheumatic diseases. Scotece M(1), Conde J, Gómez R, López V, Lago F, Gómez-Reino JJ, Gualillo O. Author information: (1)Laboratory of Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases, SERGAS, Institute of Medical Research IDIS, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain. The cloning of leptin in 1994 by Zhang et al. introduced a novel concept about white adipose tissue (WAT) as a very dynamic organ that releases a plethora of immune and inflammatory mediators, such as adipokines and cytokines, which are involved in multiple diseases. Actually, adipokines exert potent modulatory actions on target tissues involved in rheumatic diseases including cartilage, synovial, bone and immune cells. The goal of this paper is to elucidate the recent findings concerning the involvement of adipokines in rheumatic diseases, such as rheumatoid arthritis (RA), osteoarthritis (OA), and systemic lupus erythematosus (SLE). PMCID: PMC3236382 PMID: 22194660 [PubMed - indexed for MEDLINE] 460. Ageing Res Rev. 2012 Apr;11(2):220-9. doi: 10.1016/j.arr.2011.12.003. Epub 2011 Dec 13. "Is obesity linked to aging?": adipose tissue and the role of telomeres. Tzanetakou IP(1), Katsilambros NL, Benetos A, Mikhailidis DP, Perrea DN. Author information: (1)Laboratory for Experimental Surgery and Surgical Research "N. S. Christeas", University of Athens Medical School, Greece. itzanetakoy@yahoo.gr Obesity is a condition in which excess or abnormal fat accumulation may present with adverse effects on health and decreased life expectancy. Increased body weight and adipose tissue accumulation amplifies the risk of developing various age-related diseases, such as cardiovascular disease, type 2 diabetes mellitus, musculoskeletal disorders, respiratory diseases and certain types of cancer. This imbalance in body composition and body weight is now recognized as a state of increased oxidative stress and inflammation for the organism. Increasing oxidative stress and inflammation affect telomeres. Telomeres are specialized DNA-protein structures found at the ends of eukaryotic chromosomes and serve as markers of biological aging rate. They also play a critical role in maintaining genomic integrity and are involved in age-related metabolic dysfunction. Erosion of telomeres is hazardous to healthy cells, as it is a known mechanism of premature cellular senescence and loss of longevity. The association of telomeres and oxidative stress is evident in cultured somatic cells in vitro, where oxidative stress enhances the process of erosion with each cycle of replication. Shorter telomeres have been associated with increasing body mass index, increased adiposity, and more recently with increasing waist to hip ratio and visceral excess fat accumulation. Furthermore, many of the metabolic imbalances of obesity (e.g. glycemic, lipidemic, etc.) give rise to organ dysfunction in a way that resembles the accelerated aging process. This article is a non-systematic review of the evidence linking obesity and accelerated aging processes as they are regulated by telomeres. Copyright © 2011 Elsevier B.V. All rights reserved. PMID: 22186032 [PubMed - indexed for MEDLINE] 461. Am J Physiol Endocrinol Metab. 2012 Jun 1;302(11):E1315-28. doi: 10.1152/ajpendo.00561.2011. Epub 2011 Dec 20. Lipid metabolism in skeletal muscle: generation of adaptive and maladaptive intracellular signals for cellular function. Watt MJ(1), Hoy AJ. Author information: (1)Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia. matthew.watt@monash.edu Fatty acids derived from adipose tissue lipolysis, intramyocellular triacylglycerol lipolysis, or de novo lipogenesis serve a variety of functions in skeletal muscle. The two major fates of fatty acids are mitochondrial oxidation to provide energy for the myocyte and storage within a variety of lipids, where they are stored primarily in discrete lipid droplets or serve as important structural components of membranes. In this review, we provide a brief overview of skeletal muscle fatty acid metabolism and highlight recent notable advances in the field. We then 1) discuss how lipids are stored in and mobilized from various subcellular locations to provide adaptive or maladaptive signals in the myocyte and 2) outline how lipid metabolites or metabolic byproducts derived from the actions of triacylglycerol metabolism or β-oxidation act as positive and negative regulators of insulin action. We have placed an emphasis on recent developments in the lipid biology field with respect to understanding skeletal muscle physiology and discuss unanswered questions and technical limitations for assessing lipid signaling in skeletal muscle. PMID: 22185843 [PubMed - indexed for MEDLINE] 462. Crit Rev Eukaryot Gene Expr. 2011;21(4):363-77. Mesenchymal stem cells in the aging and osteoporotic population. Veronesi F(1), Torricelli P, Borsari V, Tschon M, Rimondini L, Fini M. Author information: (1)Preclinical and Surgical Studies Laboratory, Codivilla-Putti Research Institute--Rizzoli Orthopedica Institute, Bologna-Italy. Because of their ability to self-renew and differentiate, mesenchymal stem cells (MSCs) are the in vivo source for replacing lost cells in high-turnover tissues during the life of an organism. MSCs have osteogenic potential and can be eligible for the repair and maintenance of the skeleton, thus they are very attractive for tissue engineering and regenerative medicine approaches. However, many changes in their behavior, caused by aging and bone disease, have been reported in the literature. These changes, which affect MSC self-renewal ability and differentiation potentiality, are related to cell proliferation, differentiation, cell cycle phases (depending on gene modification), and cytokine and growth factor production. This review summarizes the literature related to intrinsic and extrinsic characteristics of human bone marrow or adipose tissue MSCs during aging and osteoporosis. Although some studies reveal contrasting results, the results of this review suggest that the cellular modifications due to aging and osteoporosis should be carefully considered in relation to the use of MSCs for therapeutic application. PMID: 22181705 [PubMed - indexed for MEDLINE] 463. J Med Food. 2012 Mar;15(3):223-30. doi: 10.1089/jmf.2011.0072. Epub 2011 Dec 19. Dietary fiber, gut peptides, and adipocytokines. Sánchez D(1), Miguel M, Aleixandre A. Author information: (1)Department of Pharmacology, Faculty of Medicine, Complutense University, Madrid, Spain. The consumption of dietary fiber (DF) has increased since it was related to the prevention of a range of illnesses and pathological conditions. DF can modify some gut hormones that regulate satiety and energy intake, thus also affecting lipid metabolism and energy expenditure. Among these gut hormones are ghrelin, glucagon-like peptide 1, peptide YY, and cholecystokinin. Adipose tissue is known to express and secrete a variety of products known as "adipocytokines," which are also affected by DF. Some of the most relevant adipocytokines include adiponectin, leptin, tumor necrosis factor-α, and interleukin-6. The release of adipocytokines, by either adipocytes or macrophage-infiltrated adipose tissue, leads to a chronic subinflammatory state that could play a central role in the development of insulin resistance and type 2 diabetes, therefore increasing the risk of cardiovascular disease associated with obesity. DF modulation of these molecules could also have positive effects on obesity, insulin resistance, and hyperlipidemia. This review is focused on the effects of DF on the above-mentioned gut peptides and adipocytokines. PMID: 22181071 [PubMed - indexed for MEDLINE] 464. Steroids. 2012 Mar 10;77(4):300-5. doi: 10.1016/j.steroids.2011.12.003. Epub 2011 Dec 8. Inflammation in Polycystic Ovary Syndrome: underpinning of insulin resistance and ovarian dysfunction. González F(1). Author information: (1)Indiana University School of Medicine, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Indianapolis, IN 46202, USA. gonzalef@iupui.edu Chronic low-grade inflammation has emerged as a key contributor to the pathogenesis of Polycystic Ovary Syndrome (PCOS). A dietary trigger such as glucose is capable of inciting oxidative stress and an inflammatory response from mononuclear cells (MNC) of women with PCOS, and this phenomenon is independent of obesity. This is important because MNC-derived macrophages are the primary source of cytokine production in excess adipose tissue, and also promote adipocyte cytokine production in a paracrine fashion. The proinflammatory cytokine tumor necrosis factor-α (TNFα) is a known mediator of insulin resistance. Glucose-stimulated TNFα release from MNC along with molecular markers of inflammation are associated with insulin resistance in PCOS. Hyperandrogenism is capable of activating MNC in the fasting state, thereby increasing MNC sensitivity to glucose; and this may be a potential mechanism for promoting diet-induced inflammation in PCOS. Increased abdominal adiposity is prevalent across all weight classes in PCOS, and this inflamed adipose tissue contributes to the inflammatory load in the disorder. Nevertheless, glucose ingestion incites oxidative stress in normal weight women with PCOS even in the absence of increased abdominal adiposity. In PCOS, markers of oxidative stress and inflammation are highly correlated with circulating androgens. Chronic suppression of ovarian androgen production does not ameliorate inflammation in normal weight women with the disorder. Furthermore, in vitro studies have demonstrated the ability of pro-inflammatory stimuli to upregulate the ovarian theca cell steroidogenic enzyme responsible for androgen production. These findings support the contention that inflammation directly stimulates the polycystic ovary to produce androgens. Copyright © 2011 Elsevier Inc. All rights reserved. PMCID: PMC3309040 PMID: 22178787 [PubMed - indexed for MEDLINE] 465. Cytotherapy. 2012 May;14(5):555-62. doi: 10.3109/14653249.2011.638914. Epub 2011 Dec 16. Fibrin glue as the cell-delivery vehicle for mesenchymal stromal cells in regenerative medicine. Wu X(1), Ren J, Li J. Author information: (1)Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China. The use of tissue-engineering techniques such as stem-cell therapy to renew injured tissues is a promising strategy in regenerative medicine. As a cell-delivery vehicle, fibrin glues (FG) facilitate cell attachment, growth and differentiation and, ultimately, tissue formation and organization by its three-dimensional structure. Numerous studies have provided evidence that stromal cells derived from bone marrow (bone marrow stromal cells; BMSC) and adipose tissue (adipose-derived stromal cells; ADSC) contain a population of adult multipotent mesenchymal stromal cells (MSC) and endothelial progenitor cells that can differentiate into several lineages. By combining MSC with FG, the implantation could take advantage of the mutual benefits. Researchers and physicians have pinned their hopes on stem cells for developing novel approaches in regenerative medicine. This review focuses on the therapeutic potential of MSC with FG in bone defect reconstruction, cartilage and tendon injury repair, ligament, heart and nerve regeneration, and, furthermore, wound healing. PMID: 22175911 [PubMed - indexed for MEDLINE] 466. Ann N Y Acad Sci. 2011 Dec;1240:70-6. doi: 10.1111/j.1749-6632.2011.06309.x. Pathogenesis of diabetic neuropathy: bad to the bone. Chan L(1), Terashima T, Urabe H, Lin F, Kojima H. Author information: (1)Diabetes and Endocrinology Research Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA. lchan@bcm.edu Insulin and proinsulin are normally produced only by the pancreas and thymus. We detected in diabetic rodents the presence of extra pancreatic proinsulin-producing bone marrow-derived cells (PI-BMDCs) in the BM, liver, and fat. In mice and rats with diabetic neuropathy, we also found proinsulin-producing cells in the sciatic nerve and neurons of the dorsal root ganglion (DRG). BM transplantation experiments using genetically marked donor and recipient mice showed that the proinsulin-producing cells in the DRG, which morphologically resemble neurons, are actually polyploid proinsulin-producing fusion cells formed between neurons and PI-BMDCs. Additional experiments indicate that diabetic neuropathy is not simply the result of nerve cells being damaged directly by hyperglycemia. Rather, hyperglycemia induces fusogenic PI-BMDCs that travel to the peripheral nervous system, where they fuse with Schwann cells and DRG neurons, causing neuronal dysfunction and death, the sine qua non for diabetic neuropathy. Poorly controlled diabetes is indeed bad to the bone. © 2011 New York Academy of Sciences. PMCID: PMC3636709 PMID: 22172042 [PubMed - indexed for MEDLINE] 467. Int J Surg Pathol. 2012 Aug;20(4):390-5. doi: 10.1177/1066896911428735. Epub 2011 Dec 14. Neuroendocrine tumor of the pancreas in a patient with tuberous sclerosis: a case report and review of the literature. Díaz Díaz D(1), Ibarrola C, Goméz Sanz R, Pérez Hurtado B, Salazar Tabares J, Colina Ruizdelgado F. Author information: (1)Pathology Service, Hospital Universitario 12 de Octubre, Madrid, Spain. delissadiaz@gmail.com A rare case of pancreatic neuroendocrine neoplasm in a patient with tuberous sclerosis complex is described. The patient was a 31-year-old man who had multiple congenital subependymal nodules, bilateral cortical tubers, and seizures of difficult control. A 2.3 cm × 2 cm well-delimitated solid tumor in the tail of the pancreas was discovered during a monitoring abdominal computed tomography. A distal pancreatectomy was performed. Histologically, the tumor was formed by uniform cells with moderated cytoplasm arranged in a combined trabecular and nested pattern. The nuclear features were bland, and mitosis was infrequent. There was no vascular invasion. Immunoreactivity for cytokeratine AE1/AE3, chromogranin A, and synaptophysin confirmed the neuroendocrine nature of this neoplasia. Pancreatic hormones were negatives. One of the 5 lymph nodes isolated from the peripancreatic adipose tissue was positive for metastases. Small series and case reports have documented that in tuberous sclerosis many endocrine system alterations might occur, affecting the function of the pituitary, parathyroid, and other neuroendocrine tissue, including islet cells of the pancreas. However, the true association of these pathological conditions remains uncertain. As far as we know, there are 10 cases reported of pancreatic neuroendocrine tumors in a setting of tuberous sclerosis complex, in which 2 cases resulted in malignant, nonfunctioning pancreatic neuroendocrine tumors. PMID: 22169969 [PubMed - indexed for MEDLINE] 468. Trends Endocrinol Metab. 2012 Feb;23(2):83-9. doi: 10.1016/j.tem.2011.10.003. Epub 2011 Dec 12. Aromatase, breast cancer and obesity: a complex interaction. Bulun SE(1), Chen D, Moy I, Brooks DC, Zhao H. Author information: (1)Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Obesity has been associated with abnormally high expression of the enzyme aromatase in the breast, increased local estrogen production, and predisposition to breast hyperplasia and cancer. Increased adiposity in postmenopausal women may trigger signaling pathways that induce aromatase expression. In breast adipose fibroblasts, increased TNF production may induce the distal aromatase promoter, whereas increased local PGE(2) production may induce the proximal promoter region. We review here the mechanisms that control aromatase gene expression in breast adipose tissue, and the paracrine interactions between malignant breast epithelial cells and the surrounding adipose fibroblasts. Systematic characterization of these signaling pathways will facilitate the identification of potential drug targets to selectively reduce aromatase expression and excessive estrogen production, with therapeutic benefit. Copyright © 2011 Elsevier Ltd. All rights reserved. PMCID: PMC3428377 PMID: 22169755 [PubMed - indexed for MEDLINE] 469. Zhonghua Xin Xue Guan Bing Za Zhi. 2011 Aug;39(8):772-5. [Adipose tissue-derived stem cells-a novel option for cardiac regenerative]. [Article in Chinese] Yin QX, Zhao YS. PMID: 22169431 [PubMed - indexed for MEDLINE] 470. Gen Comp Endocrinol. 2012 Jul 1;177(3):296-304. doi: 10.1016/j.ygcen.2011.11.039. Epub 2011 Dec 7. Peptidergic Edinger-Westphal neurons and the energy-dependent stress response. Xu L(1), Scheenen WJ, Roubos EW, Kozicz T. Author information: (1)Department of Cellular Animal Physiology, Faculty of Science, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, P.O. Box 9010, 6500 GL Nijmegen, The Netherlands. The continuously changing environment demands for adequate stress responses to maintain the internal dynamic equilibrium of body and mind. A successful stress response requires energy, in an amount matching the severity of the stressor and the type of response ('fight, flight or freeze'). The stress response is generated by the central nervous system, which needs to be informed about both the threatening stressor and the availability of energy. In this review, evidence is considered for a role of the midbrain Edinger-Westphal centrally projecting neuron population (EWcp; synonym: non-preganglionic Edinger-Westphal nucleus) in the energy-dependent stress adaptation response. It deals with studies on the neurochemical organization of the EWcp with particular reference to the neuropeptides urocortin-1 and cocaine- and amphetamine-regulated transcript peptide, on the EWcp responses to different types of stressor (e.g., acute and chronic) and a changed energy state (e.g., fasting and leptin change), and on the sex-specificity of these responses. Finally, a model is presented for the way the EWcp might contribute to the coordination of the energy-dependent stress adaptation response. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 22166814 [PubMed - indexed for MEDLINE] 471. Immunol Res. 2012 Jun;52(3):182-99. doi: 10.1007/s12026-011-8261-7. Immunomodulation at epithelial sites by obesity and metabolic disease. Cheung KP(1), Taylor KR, Jameson JM. Author information: (1)The Department of Immunology and Microbiology, The Scripps Research Institute, 10550 North Torrey Pines Road, Imm-25, La Jolla, CA, 92037, USA. Obesity and related type 2 diabetes are increasing at epidemic proportions globally. It is now recognized that inflammatory responses mediated within the adipose tissue in obesity are central to the development of disease. Once initiated, chronic inflammation associated with obesity leads to the modulation of immune cell function. This review will focus specifically on the impact of obesity on γδ T cells, a T-cell subset that is found in high concentrations in epithelial tissues such as the skin, intestine, and lung. Epithelial γδ T cell function is of particular concern in obesity as they are the guardians of the epithelial barrier and mediate repair. A breakdown in their function, and subsequently the deterioration of the epithelium can result in dire consequences for the host. Obese patients are more prone to non-healing injuries, infection, and disease. The resulting inflammation from these pathologies further perpetuates the disease condition already present in obese hosts. Here we will provide insight into the immunomodulation of γδ T cells that occurs in the epithelial barrier during obesity and discuss current therapeutic options. PMID: 22160809 [PubMed - indexed for MEDLINE] 472. Mol Biol Rep. 2012 May;39(5):5367-71. doi: 10.1007/s11033-011-1336-7. Epub 2011 Dec 13. Role of NYGGF4 in insulin resistance. Chen X(1), Huang Z, Chen D, Jia G, Mao X, Wu X. Author information: (1)Institute of Animal Nutrition, Sichuan Agricultural University, Yaan, 625014, Sichuan, People's Republic of China. chenxlh@hotmail.com Insulin resistance is a clinical condition that is characterized by reducing glucose uptake in response to insulin. A major factor in the development of insulin resistance syndrome is obesity. NYGGF4 is a novel gene that is abundantly expressed in the adipose tissue of obese subjects. NYGGF4 induced the secretion of FFAs and TNF-α and caused mitochondrial dysfunction, which may cause insulin resistance. This review will summarize the effect of NYGGF4 on the adipogenesis, glucose uptake and mitochondrial dysfunction in vitro, and the possible mechanism and signal pathway of NYGGF4 for insulin resistance. PMID: 22160469 [PubMed - indexed for MEDLINE] 473. Pediatr Emerg Care. 2011 Dec;27(12):1167-9. doi: 10.1097/PEC.0b013e31823b0186. Traumatic pediatric olecranon injury: a report of suture fixation and review of the literature. Rath NK(1), Carpenter EC, Thomas DP. Author information: (1)Department of Paediatric Orthopaedics and Trauma, University Hospital of Wales, Cardiff, UK. rath.narendra@gmail.com Elbow injuries make up to 3% to 4% of all emergency department presentations and are often difficult to diagnose. These injuries are often missed on radiographs because of the large cartilaginous component of the pediatric elbow resulting in malunion. Fractures around the elbow joint are one of the leading causes of litigation claim, and awareness of the pitfalls in diagnosis of these subtle injuries is necessary for a prompt diagnosis. Fracture of the olecranon epiphysis is rare and often being described around puberty and in association with osteogenesis imperfecta. Management using K-wire tension band fixation has been described in the past, which can lead to growth arrest in younger patients.We hereby present a missed rare sleeve-type open olecranon epiphyseal fracture in a young child, highlighting the pitfalls in the diagnosis of these injuries. This article also reviews various options to manage such a rare fracture and also suggests an alternative method of transosseous suture fixation with an excellent result. PMID: 22158276 [PubMed - indexed for MEDLINE] 474. Ann Saudi Med. 2012 Jan-Feb;32(1):68-77. Human stromal (mesenchymal) stem cells: basic biology and current clinical use for tissue regeneration. Aldahmash A(1), Zaher W, Al-Nbaheen M, Kassem M. Author information: (1)Stem Cell Unit, King Saud University, Riyadh, Saudi Arabia. mkassem@health.sdu.dk Human stromal (mesenchymal) stem cells (hMSC) represent a group of non-hematopoietic stem cells present in the bone marrow stroma and the stroma of other organs including subcutaneous adipose tissue, placenta, and muscles. They exhibit the characteristics of somatic stem cells of self-renewal and multi-lineage differentiation into mesoderm-type of cells, e.g., to osteoblasts, adipocytes, chondrocytes and possibly other cell types including hepatocytes and astrocytes. Due to their ease of culture and multipotentiality, hMSC are increasingly employed as a source for cells suitable for a number of clinical applications, e.g., non-healing bone fractures and defects and also non-skeletal degenerative diseases like heart failure. Currently, the numbers of clinical trials that employ MSC are increasing. However, several biological and biotechnological challenges need to be overcome to benefit from the full potential of hMSC. In this current review, we present some of the most important and recent advances in understanding of the biology of hMSC and their current and potential use in therapy. PMID: 22156642 [PubMed - indexed for MEDLINE] 475. Circulation. 2011 Dec 13;124(24):e837-41. doi: 10.1161/CIRCULATIONAHA.111.077602. Ectopic fat depots and cardiovascular disease. Britton KA(1), Fox CS. Author information: (1)Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. PMID: 22156000 [PubMed - indexed for MEDLINE] 476. Georgian Med News. 2011 Oct;(199):81-5. [Role of the adipose derived adult stem cell in cartilage regeneration, features and brief history (review)]. [Article in Russian] Salmanov A. Regeneration of the cartilage is one of the difficult and uncertain solved problems of reconstructive surgery. Lot of successfully experiments was done about regeneration of cartilage defects with ADAS cells. Use of stem cells promise new decisons in this direction at the near future. Little information about ADAS cells and their use in regeneration of cartilage defects was revealed. PMID: 22155811 [PubMed - indexed for MEDLINE] 477. Sports Med. 2012 Jan 1;42(1):51-67. doi: 10.2165/11595680-000000000-00000. Evaluation and treatment of disorders of the infrapatellar fat pad. Dragoo JL(1), Johnson C, McConnell J. Author information: (1)Department of Orthopaedic Surgery, Stanford University, Palo Alto, CA, USA. jdragoo@stanford.edu The infrapatellar fat pad (IFP), also known as Hoffa's fat pad, is an intracapsular, extrasynovial structure that fills the anterior knee compartment, and is richly vascularized and innervated. Its degree of innervation, the proportion of substance-P-containing fibres and close relationship to its posterior synovial lining implicates IFP pathologies as a source of infrapatellar knee pain. Though the precise function of the IFP is unknown, studies have shown that it may play a role in the biomechanics of the knee or act as a store for reparative cells after injury. Inflammation and fibrosis within the IFP, caused by trauma and/or surgery can lead to a variety of arthrofibrotic lesions including Hoffa's disease, anterior interval scarring and infrapatellar contracture syndrome. Lesions or mass-like abnormalities rarely occur within the IFP, but their classification can be narrowed down by radiographical appearance. Clinically, patients with IFP pathology present with burning or aching infrapatellar anterior knee pain that can often be reproduced on physical exam with manoeuvres designed to produce impingement. Sagittal MRI is the most common imaging technique used to assess IFP pathology including fibrosis, inflammation, oedema, and mass-like lesions. IFP pathology is often successfully managed with physical therapy. Passive taping is used to unload or shorten an inflamed IFP, and closed chain quadriceps exercises can improve lower limb control and patellar congruence. Training of the gluteus medius and stretching the anterior hip may help to decrease internal rotation of the hip and valgus force at the knee. Gait training and avoiding hyperextension can also be used for long-term management. Injections within the IFP of local anaesthetic plus corticosteroids and IFP ablation with ultrasound guided alcohol injections have been successfully explored as treatments for IFP pain. IFP pathology refractory to physical therapy can be approached through a variety of operative treatments. Arthroscopic partial resection for IFP impingement and Hoffa's disease has showed favourable results; however, total excision of the IFP performed concomitantly with total knee arthroplasty (TKA) resulted in worse results when compared with TKA alone. Arthroscopic debridement of IFP fibrosis has been successfully used to treat extension block following anterior cruciate ligament reconstruction, and arthroscopic anterior interval release has been an effective treatment for pain associated with anterior interval scarring. Arthroscopic resection of infrapatellar plicae and denervation of the inferior pole of the patella have also been shown to be effective treatments for refractory infrapatellar pain. PMID: 22149697 [PubMed - indexed for MEDLINE] 478. Benef Microbes. 2011 Dec 1;2(4):305-18. doi: 10.3920/BM2011.0020. Prebiotics to manage the microbial control of energy homeostasis. Grootaert C(1), Marzorati M, Van den Abbeele P, Van de Wiele T, Possemiers S. Author information: (1)Laboratory of Microbial Ecology and Technology (LabMET), Ghent University, Coupure Links 653, 9000 Ghent, Belgium. The prevalence of obesity is continuously growing and has reached epidemic proportions. It is clear that current methods to combat obesity are not effective enough to reduce the problem. Therefore, further investigation is needed to develop new strategies. Recent research pointed out a potential role of the microbial community associated to the human host in controlling and influencing the energy homeostasis. According to the concept of Gastrointestinal Resource Management, this microbiota and its metabolic potential can be steered with the aim of improving host health. This review therefore focuses on the modulation of the intestinal microbiota through prebiotics with the aim to control several aspects of metabolic homeostasis. In a first part, the importance of host-microbe cross-talk at the intestinal epithelium is discussed. Yet, energy metabolism, which includes both lipid and glucose metabolism, is also regulated by several key organs including the adipose tissue, brain, liver, muscles, pancreas and gut. Therefore, in a second part, we will discuss the microbial factors that are involved in the communication between these different tissues, and their potential management. Finally, we will give some future prospects of the use of prebiotics in an individualised treatment of metabolic disorders. PMID: 22146690 [PubMed - indexed for MEDLINE] 479. Metabolism. 2012 May;61(5):611-9. doi: 10.1016/j.metabol.2011.10.005. Epub 2011 Dec 5. Metabolic consequences of stress during childhood and adolescence. Pervanidou P(1), Chrousos GP. Author information: (1)First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, 11527 Athens, Greece. ppervanid@med.uoa.gr Comment in Metabolism. 2012 May;61(5):e1; author reply e3-4. Stress, that is, the state of threatened or perceived as threatened homeostasis, is associated with activation of the stress system, mainly comprised by the hypothalamic-pituitary-adrenal axis and the arousal/sympathetic nervous systems. The stress system normally functions in a circadian manner and interacts with other systems to regulate a variety of behavioral, endocrine, metabolic, immune, and cardiovascular functions. However, the experience of acute intense physical or emotional stress, as well as of chronic stress, may lead to the development of or may exacerbate several psychologic and somatic conditions, including anxiety disorders, depression, obesity, and the metabolic syndrome. In chronically stressed individuals, both behavioral and neuroendocrine mechanisms promote obesity and metabolic abnormalities: unhealthy lifestyles in conjunction with dysregulation of the stress system and increased secretion of cortisol, catecholamines, and interleukin-6, with concurrently elevated insulin concentrations, lead to development of central obesity, insulin resistance, and the metabolic syndrome. Fetal life, childhood, and adolescence are particularly vulnerable periods of life to the effects of intense acute or chronic stress. Similarly, these life stages are crucial for the later development of behavioral, metabolic, and immune abnormalities. Developing brain structures and functions related to stress regulation, such as the amygdala, the hippocampus, and the mesocorticolimbic system, are more vulnerable to the effects of stress compared with mature structures in adults. Moreover, chronic alterations in cortisol secretion in children may affect the timing of puberty, final stature, and body composition, as well as cause early-onset obesity, metabolic syndrome, and type 2 diabetes mellitus. The understanding of stress mechanisms leading to metabolic abnormalities in early life may lead to more effective prevention and intervention strategies of obesity-related health problems. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22146091 [PubMed - indexed for MEDLINE] 480. J Sex Med. 2012 Feb;9(2):385-403. doi: 10.1111/j.1743-6109.2011.02556.x. Epub 2011 Dec 6. Multipotent stromal cell therapy for cavernous nerve injury-induced erectile dysfunction. Albersen M(1), Kendirci M, Van der Aa F, Hellstrom WJ, Lue TF, Spees JL. Author information: (1)Laboratory of Experimental Urology, University Hospitals Leuven, Leuven, Belgium. INTRODUCTION: Erectile dysfunction (ED) following radical prostatectomy (RP) is a result of inadvertent damage to the cavernous nerves that run close to the prostate capsula. The mechanisms behind the development of post-RP ED are increasingly recognized and include cavernosal fibrosis and cavernosal smooth muscle apoptosis, resulting from cavernous nerve degeneration due to neuropraxia. In recent years, cell-based therapies have received increasing attention regarding their potential for recovery of erectile function following cavernous nerve injury (CNI). Multipotent stromal cells (MSCs) are an attractive cell source for this application based on their regenerative potential and their clinical applicability. AIM: To review available evidence on the efficacy and mechanisms of action of MSC application for the treatment of ED, with an emphasis on ED following CNI. METHODS: A nonsystematic review was conducted on the available English literature between 1966 and 2011 on the search engines SciVerse-sciencedirect, SciVerse-scopus, Google Scholar, and PubMed. RESULTS: MSCs from both bone marrow and adipose tissue have shown beneficial effects in a variety of animal models for ED. While MSC application in chronic disease models such as diabetes, aging, and hyperlipidemia may result in cell engraftment and possibly MSC differentiation, this observation has not been made in the acute CNI rat model. In the latter setting, MSC effects seem to be established by cell recruitment toward the major pelvic ganglion and local paracrine interaction with the host neural tissue. CONCLUSIONS: While the type of model may influence the mechanisms of action of this MSC-based therapy, MSCs generally display efficacy in various animal models for ED. Before translation to the clinic is established, various hurdles need to be overcome. © 2011 International Society for Sexual Medicine. PMID: 22145667 [PubMed - indexed for MEDLINE] 481. Ann Nutr Metab. 2011;59(2-4):176-86. doi: 10.1159/000334071. Epub 2011 Dec 2. Effects of monounsaturated fatty acids on cardiovascular risk factors: a systematic review and meta-analysis. Schwingshackl L(1), Strasser B, Hoffmann G. Author information: (1)University for Health Sciences, Medical Informatics and Technology, Institute for Nutritional Sciences and Physiology, Hall in Tirol, Austria. lukas.schwingshackl@umit.at The appropriate pattern of macronutrient distribution for dietary protocols aimed at treating or preventing obesity and its associated cardiovascular diseases is still a controversial topic of discussion. Recommendations considering a specific percentage or range for monounsaturated fatty acids (MUFA) are rare. It was the aim of this study to analyze long-term, randomized, controlled dietary intervention trials and to investigate the effects of MUFA on the biomarkers of obesity and cardiovascular risk factors. Dietary regimens with a high amount of MUFA (>12%) were compared to those with ≤12%. The biomarkers taken into account were weight, waist circumference, fat mass, total cholesterol, LDL cholesterol, HDL cholesterol, triacylglycerols, systolic and diastolic blood pressure, as well as C-reactive protein. A total of 12 studies met the inclusion criteria. Data analysis was performed using the Review Manager 5.0.25 software. Significant differences between high- and low-MUFA protocols could be observed with respect to fat mass [-1.94 kg (confidence interval -3.72, -0.17), p = 0.03], systolic blood pressure [-2.26 mm Hg (confidence interval -4.28, -0.25), p = 0.03] and diastolic blood pressure [-1.15 mm Hg (confidence interval -1.96, -0.34), p = 0.005] favoring the dietary protocols with >12% MUFA. Therefore, MUFA might represent a useful tool in the design of dietary regimens for obesity and cardiovascular disease. Copyright © 2011 S. Karger AG, Basel. PMID: 22142965 [PubMed - indexed for MEDLINE] 482. Dan Med Bull. 2011 Dec;58(12):B4368. Glucose-dependent Insulinotropic Polypeptide (GIP): From prohormone to actions in endocrine pancreas and adipose tissue. Ugleholdt R(1). Author information: (1)Department of Biomedical Sciences, Cellular and Metabolic Research Section, University of Copenhagen, Faculty of Health Sciences, Blegdamsvej 3B build. 12.2, 2200 Copenhagen N, Denmark. randi@ugleholdt.com The present thesis consists of one published article and one draft manuscript. Interest in the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) was reignited by the discovery that GIP receptor deficient mice were unable to gain weight in response to high fat feeding. However, the path from processing of the prohormone to regulation of secretion and establishment of its role in the complicated network of mediators involved in energy mobilization is not fully understood. The biologically active GIP1-42 was found in vivo to be dependent on processing from the immature prohormone by proprotein convertase 1/3 (PC1/3) in the intestinal K-cell. Even so, ~50% of GIP immunoreactive cells do not express PC1/3 raising the possibility that subsets of K-cells exist in which the precursor may be cleaved at alternative sites. Cell line studies did demonstrate that another convertase in endocrine cell types, PC2, mediated cleavage at alternative sites liberating larger and smaller GIP fragments. It was possible to detect fragments of similar size in gel filtration extracts of murine upper jejunum, but the identity, mechanism of processing and function of these immunoreactivities remains uncertain. Once correctly processed GIP1-42 is secreted in response to food intake. The K-cell is believed to directly sense and respond to nutrients in the intestine, but as the molecular profiling of this cell type has just begun, the nutrient sensing machinery and possible feedback regulation are still poorly characterized. When secreted to the blood stream, GIP acts as a mediator of energy mobilization in a complex network with other hormones. An acute and established function of GIP is to exert its incretin function thereby enhancing glucose stimulated insulin secretion necessary for prompt disposal of nutrients, yet GIP also stimulates glucagon secretion to increase blood glucose. In the diabetic state the insulinotropic effect of GIP is impaired and an early inexpedient glucagon stimulation in response to a meal further counteracts effects of insulin and worsens glycaemic control. A demonstration that GIP receptor deficient mice were resistant to diet induced obesity let to the categorization of GIP as a fat promoting hormone and direct insulin-mimetic effects in adipose tissue has been proposed. We were able to demonstrate a redundancy for the GIP receptor in incorporation of lipids into adipocytes. We also observed that GIP receptor deficient mice could respond normally to high fat feeding with increased fat mass, but failed to increase lean mass. Mice with rescue of the GIP receptor in adipose tissue normalized the body composition in response to high fat diet, but the mice had a lower total body weight. In contrast, the GIP receptor expressed in the pancreatic beta-cell was able to promote lean mass gain on a low fat diet, but not on a high fat diet. Overall, we have established principal requirements for GIP maturation. Furthermore, we have demonstrated that neither beta-cell nor adipocyte GIP receptor expression can replace the endogenous GIP receptor in regulation of body weight and body composition. PMID: 22142579 [PubMed - indexed for MEDLINE] 483. J Lipid Res. 2012 Feb;53(2):227-46. doi: 10.1194/jlr.R021089. Epub 2011 Dec 2. Adipose tissue stem cells meet preadipocyte commitment: going back to the future. Cawthorn WP(1), Scheller EL, MacDougald OA. Author information: (1)Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. White adipose tissue (WAT) is perhaps the most plastic organ in the body, capable of regeneration following surgical removal and massive expansion or contraction in response to altered energy balance. Research conducted for over 70 years has investigated adipose tissue plasticity on a cellular level, spurred on by the increasing burden that obesity and associated diseases are placing on public health globally. This work has identified committed preadipocytes in the stromal vascular fraction of adipose tissue and led to our current understanding that adipogenesis is important not only for WAT expansion, but also for maintenance of adipocyte numbers under normal metabolic states. At the turn of the millenium, studies investigating preadipocyte differentiation collided with developments in stem cell research, leading to the discovery of multipotent stem cells within WAT. Such adipose tissue-derived stem cells (ASCs) are capable of differentiating into numerous cell types of both mesodermal and nonmesodermal origin, leading to their extensive investigation from a therapeutic and tissue engineering perspective. However, the insights gained through studying ASCs have also contributed to more-recent progress in attempts to better characterize committed preadipocytes in adipose tissue. Thus, ASC research has gone back to its roots, thereby expanding our knowledge of preadipocyte commitment and adipose tissue biology. PMCID: PMC3269153 PMID: 22140268 [PubMed - indexed for MEDLINE] 484. Endocrine. 2012 Apr;41(2):176-82. doi: 10.1007/s12020-011-9572-0. Epub 2011 Dec 3. Vaspin in obesity and diabetes: pathophysiological and clinical significance. Blüher M(1). Author information: (1)Department of Medicine, University of Leipzig, Liebigstr. 20, 04103 Leipzig, Germany. bluma@medizin.uni-leipzig.de Vaspin (visceral adipose tissue-derived serpin; serpinA12) was originally identified as an adipokine, which is predominantly secreted from visceral adipose tissue in Otsuka Long-Evans Tokushima fatty (OLETF), an animal model of obesity and type 2 diabetes. Consistent with that higher vaspin serum concentrations and increased vaspin mRNA expression in human adipose tissue were found to be associated with obesity, insulin resistance, and type 2 diabetes in humans. However, the mechanisms how vaspin secretion may be linked to deterioration of glucose metabolism and insulin sensitivity are not entirely understood. Vaspin serum concentrations show a food intake-related diurnal variation. Vaspin is also expressed in the skin, hypothalamus, pancreatic islets, and stomach. Administration of vaspin to obese mice improves glucose tolerance, insulin sensitivity, and reduces food intake. Until now molecular target(s) of vaspin and its mode of action are unknown. Thus, identification of the proteases, which are inhibited by vaspin may lead to the development of novel strategies in the treatment of obesity, diabetes and insulin resistance. This review discusses the clinical relevance of vaspin in the pathophysiology of obesity and type 2 diabetes. PMID: 22139797 [PubMed - indexed for MEDLINE] 485. Proc Nutr Soc. 2012 Feb;71(1):27-37. doi: 10.1017/S0029665111003375. Epub 2011 Dec 5. Musculoskeletal phenotype through the life course: the role of nutrition. Ward K(1). Author information: (1)MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge CB1 9NL, UK. kate.ward@mrc-hnr.cam.ac.uk This review considers the definition of a healthy bone phenotype through the life course and the modulating effects of muscle function and nutrition. In particular, it will emphasise that optimal bone strength (and how that is regulated) is more important than simple measures of bone mass. The forces imposed on bone by muscle loading are the primary determinants of musculoskeletal health. Any factor that changes muscle loading on the bone, or the response of bone to loading results in alterations of bone strength. Advances in technology have enhanced the understanding of a healthy bone phenotype in different skeletal compartments. Multiple components of muscle strength can also be quantified. The critical evaluation of emerging technologies for assessment of bone and muscle phenotype is vital. Populations with low and moderate/high daily Ca intakes and/or different vitamin D status illustrate the importance of nutrition in determining musculoskeletal phenotype. Changes in mass and architecture maintain strength despite low Ca intake or vitamin D status. There is a complex interaction between body fat and bone which, in addition to protein intake, is emerging as a key area of research. Muscle and bone should be considered as an integrative unit; the role of body fat requires definition. There remains a lack of longitudinal evidence to understand how nutrition and lifestyle define musculoskeletal health. In conclusion, a life-course approach is required to understand the definition of healthy skeletal phenotype in different populations and at different stages of life. PMID: 22137032 [PubMed - indexed for MEDLINE] 486. Br J Nutr. 2011 Dec;106 Suppl 3:S5-78. doi: 10.1017/S0007114511005460. Dietary factors and low-grade inflammation in relation to overweight and obesity. Calder PC(1), Ahluwalia N, Brouns F, Buetler T, Clement K, Cunningham K, Esposito K, Jönsson LS, Kolb H, Lansink M, Marcos A, Margioris A, Matusheski N, Nordmann H, O'Brien J, Pugliese G, Rizkalla S, Schalkwijk C, Tuomilehto J, Wärnberg J, Watzl B, Winklhofer-Roob BM. Author information: (1)School of Medicine, University of Southampton, Southampton, UK. Low-grade inflammation is a characteristic of the obese state, and adipose tissue releases many inflammatory mediators. The source of these mediators within adipose tissue is not clear, but infiltrating macrophages seem to be especially important, although adipocytes themselves play a role. Obese people have higher circulating concentrations of many inflammatory markers than lean people do, and these are believed to play a role in causing insulin resistance and other metabolic disturbances. Blood concentrations of inflammatory markers are lowered following weight loss. In the hours following the consumption of a meal, there is an elevation in the concentrations of inflammatory mediators in the bloodstream, which is exaggerated in obese subjects and in type 2 diabetics. Both high-glucose and high-fat meals may induce postprandial inflammation, and this is exaggerated by a high meal content of advanced glycation end products (AGE) and partly ablated by inclusion of certain antioxidants or antioxidant-containing foods within the meal. Healthy eating patterns are associated with lower circulating concentrations of inflammatory markers. Among the components of a healthy diet, whole grains, vegetables and fruits, and fish are all associated with lower inflammation. AGE are associated with enhanced oxidative stress and inflammation. SFA and trans-MUFA are pro-inflammatory, while PUFA, especially long-chain n-3 PUFA, are anti-inflammatory. Hyperglycaemia induces both postprandial and chronic low-grade inflammation. Vitamin C, vitamin E and carotenoids decrease the circulating concentrations of inflammatory markers. Potential mechanisms are described and research gaps, which limit our understanding of the interaction between diet and postprandial and chronic low-grade inflammation, are identified. PMID: 22133051 [PubMed - indexed for MEDLINE] 487. Obes Rev. 2012 Apr;13(4):368-80. doi: 10.1111/j.1467-789X.2011.00957.x. Epub 2011 Dec 1. Importance of metabolic changes induced by chemotherapy on prognosis of early-stage breast cancer patients: a review of potential mechanisms. Gadéa E(1), Thivat E, Planchat E, Morio B, Durando X. Author information: (1)Clinical Research Medical Oncology, Centre Jean Perrin INRA/UdA, Clermont-Ferrand, France.emilie.gadea@hotmail.fr Weight variation has been reported as a side effect of chemotherapy treatment in early breast cancer patients and has been identified as a factor of poor prognosis. Causes of weight variation during chemotherapy and mechanisms involved in the poor prognosis have been little studied. Here is reviewed the current knowledge about the main causes and mechanisms involved in body weight change. Special emphasis is placed on factors associated with weight variation which could potentially be involved in the risk of relapse in breast cancer survivors. In recent decades, some studies have investigated the causes of weight variation by studying energy balance of breast cancer patients during chemotherapy. Weight gain or loss may be the consequence of energy imbalance through different factors linked with chemotherapy, such as poor treatment tolerance, decreased muscle mass and function, or hormonal alterations. This results in body composition modifications in favour of fat gain and/or lean body mass loss. Increased adipose tissue, especially in the abdominal region, could induce metabolic disturbances such as insulin resistance, through various pathways involving adipokines. These molecules have growth properties and could therefore play a role in cancer relapse. Understanding such mechanisms is key to developing preventive strategies for improving the prognosis of early-stage breast cancer patients. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 22133030 [PubMed - indexed for MEDLINE] 488. Clin Exp Immunol. 2012 Jan;167(1):40-6. doi: 10.1111/j.1365-2249.2011.04501.x. Immunology in the Clinic Review Series; focus on metabolic diseases: development of islet autoimmune disease in type 2 diabetes patients: potential sequelae of chronic inflammation. Brooks-Worrell B(1), Palmer JP. Author information: (1)Department of Medicine, University of Washington, Seattle, WA, USA. bbrooks@u.washington.edu Historically, the development of type 2 diabetes has been considered not to have an autoimmune component, in contrast to the autoimmune pathogenesis of type 1 diabetes. In this review we will discuss the accumulating data supporting the concept that islet autoreactivity and inflammation is present in type 2 diabetes pathogenesis, and the islet autoimmunity appears to be one of the factors associated with the progressive nature of the type 2 diabetes disease process. Published 2011. This article is a U.S. Government work and is in the public domain in the USA. PMCID: PMC3248085 PMID: 22132883 [PubMed - indexed for MEDLINE] 489. Am J Kidney Dis. 2012 Feb;59(2):276-83. doi: 10.1053/j.ajkd.2011.10.013. Epub 2011 Nov 29. Tuberous sclerosis complex-associated angiomyolipomas: focus on mTOR inhibition. Budde K(1), Gaedeke J. Author information: (1)Department of Nephrology, Charité Universitätsmedizin Berlin, Germany. klemens.budde@charite.de Tuberous sclerosis complex (TSC) is an autosomal dominant disorder promoting the development of benign tumors in multiple organ systems, including the skin, brain, and kidneys. In contrast to asymptomatic spontaneous angiomyolipomas, angiomyolipomas in patients with TSC are mostly bilateral and are accompanied by other typical clinical features of TSC. Kidney angiomyolipomas are benign tumors composed of blood vessels, adipose tissue, and smooth muscle and are associated with spontaneous bleeding and potential life-threatening hemorrhage if >4 cm. Current treatment options for angiomyolipoma are focused on conserving kidney function and limiting potentially fatal hemorrhage. TSC is caused by mutations in either TSC1 or TSC2 suppressor genes, resulting in increased mammalian target of rapamycin (mTOR) activity. Preclinical studies have shown the efficacy of mTOR inhibitors in inhibiting the growth of patient-derived cell lines and suppressing tumors in animal models of TSC. In the clinical setting, mTOR inhibitors have shown promising efficacy in patients with TSC-associated angiomyolipomas and subependymal giant cell astrocytomas. This review explores the diagnosis and current management of TSC-associated angiomyolipomas, the relevance of the mTOR pathway in the pathogenesis of TSC, and the potential promise of mTOR-inhibitor therapy as a systemic therapeutic approach to treat the underlying cause of TSC. Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. PMID: 22130643 [PubMed - indexed for MEDLINE] 490. Med Sci (Paris). 2011 Nov;27(11):993-9. doi: 10.1051/medsci/20112711016. Epub 2011 Nov 30. [Adipose tissue, a new playground for immune cells]. [Article in French] Dalmas E(1), Tordjman J, Guerre-Millo M, Clément K. Author information: (1)Université Pierre et Marie Curie-Paris 6, Centre de recherche des Cordeliers, F-75006 Paris, France. Adipose tissue has been under focus in the last decade and pivotal concepts have emerged from the studies of its complex biology. Low-grade inflammation both at the systemic level and in adipose tissue itself characterizes obesity. Among the different cell types contributing to inflammation, this review focuses on the mechanisms and consequences of macrophage accumulation in obese adipose tissue. Mechanisms for monocyte recruitment to adipose tissue, and how macrophages' phenotypes are modified in this environment in response to increasing fat mass, are considered. We review recent studies addressing the complex and versatile phenotype of adipose tissue macrophages that contribute to inflammatory and metabolic alterations, but could also help to maintain adipose tissue homeostasis in the setting of obesity both in mouse and human situations. A newly discovered consequence of adipose tissue inflammation is fibrosis. Whether macrophages and/or other immune cells exert a pro-fibrotic effect in adipose tissue is still unclear. This wealth of new information will hopefully help to design new ways to control adipose tissue inflammation and its deleterious sequels. © 2011 médecine/sciences – Inserm / SRMS. PMID: 22130027 [PubMed - indexed for MEDLINE] 491. Annu Rev Food Sci Technol. 2011;2:237-57. doi: 10.1146/annurev-food-022510-133656. Food components with anti-obesity effect. Kim KH(1), Park Y. Author information: (1)Department of Food Science, Purdue University, West Lafayette, Indiana 47907, USA. keehong@purdue.edu Although many food components are reportedly beneficial to body-weight management, lack of understanding of molecular mechanisms and their function in overall adiposity under physiological conditions hinders successful and safe development of antiobesity functional foods. A positive energy balance resulting from an increase in food intake, a reduced energy expenditure, and/or dysfunction of adipose biology is associated with the development of obesity. This article provides an overview of the components involved in energy balance and adipose development and function. There is evidence that numerous ingredients found in foods can modulate energy balance and adipose biology, thereby potentially lowering adiposity. PMID: 22129382 [PubMed - indexed for MEDLINE] 492. Adv Clin Chem. 2011;55:61-79. Adipokine actions on cartilage homeostasis. Dozio E(1), Corsi MM, Ruscica M, Passafaro L, Steffani L, Banfi G, Magni P. Author information: (1)Department of Human Morphology and Biomedical Sciences "Città Studi," Chair of Clinical Pathology, School of Medicine, Università degli Studi di Milano, Milan, Italy. Epidemiological studies have shown an intriguing correlation between obesity and articular cartilage disease. An increase in mechanical forces across weight-bearing joints has long been considered the primary factor leading to joint degeneration. However, emerging data suggest that additional soluble factors such as the adipocyte-derived molecules "adipokines" may also play an important role in the onset and progression of weight-associated cartilage degradative process. Adipokines are pleiotropic secretory molecules mainly produced by white adipose tissue. Adipokines exert their actions through endocrine, paracrine, autocrine, or juxtacrine cross talk in a wide variety of physiological or pathophysiological processes. In particular, they are mainly involved in the regulation of food intake and energy metabolism, in both health and disease states, and in the inflammatory response. Recent observations have shown that, among adipokines, leptin, adiponectin, resistin, visfatin, and apelin may also participate to the complex mechanisms that regulate skeleton biology, both at bone and cartilage level. Herein, we review the present knowledge about the role of these adipokines in cartilage function as well as in inflammatory and degenerative joint diseases. Moreover, we describe some methodological approaches which can be utilized in the measurement of these adipokines in different biological matrices, like plasma and synovial fluid (SF), and may be helpful to better clarify the involvement of these molecules in cartilage disease. PMID: 22126024 [PubMed - indexed for MEDLINE] 493. Curr Mol Pharmacol. 2012 Jun;5(2):272-81. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists on glycemic control, lipid profile and cardiovascular risk. Derosa G(1), Maffioli P. Author information: (1)Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy. giuseppe.derosa@unipv.it Peroxisome proliferator-activated receptor (PPAR) is involved in the pathology of numerous diseases including obesity, diabetes, and atherosclerosis, because of its role in decreasing insulin resistance and inflammation. Type 2 diabetes mellitus and obesity are the most frequent endocrine-metabolic diseases and their pathogenic basis are characterized by insulin resistance and insulin secretion defects that can be demonstrated through several alterations in carbohydrates, lipids, and protein metabolism. For that reason a class of compounds, called thiazolidinediones, has been developed for the management of type 2 diabetes mellitus. Thiazolidinediones are PPAR-γ agonists regulating the expression of several genes involved in the regulation of glucose, lipid and protein metabolism, enhancing the action of insulin in insulin-sensitive tissue by increasing glucose uptake in skeletal muscle and adipose tissue, and decreasing hepatic glucose production. Pioglitazone is the only available PPAR-γ agonist for the treatment of type 2 diabetes after rosiglitazone withdrawal from several countries. This review discusses the safety and effectiveness of pioglitazone in the clinical practice for the treatment of type 2 diabetes mellitus. PMID: 22122457 [PubMed - indexed for MEDLINE] 494. Curr Mol Pharmacol. 2012 Jun;5(2):224-40. The involvement of PPARs in the causes, consequences and mechanisms for correction of cardiac lipotoxicity and oxidative stress. Sugden MC(1), Warlow MP, Holness MJ. Author information: (1)Centre for Diabetes, Blizard Institute, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary University of London, London, UK. m.c.sugden@qmul.ac.uk Chronically-elevated plasma lipid concentrations, particularly when combined with high glucose, elicit a plethora of effects that cause the progressive deterioration of insulin sensitivity and ultimately cellular malfunction or death. This review addresses how metabolic abnormalities in white adipose tissue leading to excessive lipid or abnormal adipokine release can be modified by PPARγ activation. It also discusses the etiology of cardiac lipotoxicity and oxidative stress, in relation to imbalanced lipid delivery and clearance and how PPARα activation can be used to correct some of these effects. PMID: 22122452 [PubMed - indexed for MEDLINE] 495. Zentralbl Chir. 2011 Oct;136(5):399-403. [Stem cell therapy in vascular medicine]. [Article in German] Nikol S(1). Author information: (1)Chefärztin Klinische und Interventionelle Angiologie, Asklepios Klinik St. Georg, Lohmühlenstr. 5, 20099 Hamburg. s.nikol@asklepios.com PMID: 22121537 [PubMed - indexed for MEDLINE] 496. J Innate Immun. 2012;4(3):260-72. doi: 10.1159/000332435. Epub 2011 Nov 22. The role of complement in the development and manifestation of murine atherogenic inflammation: novel avenues. Francescut L(1), Steiner T, Byrne S, Cianflone K, Francis S, Stover C. Author information: (1)Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK. Atherosclerosis is a chronic progressive inflammatory disease which manifests in the arterial vascular tree. It is a major cause of cardiovascular morbidity and contributes significantly to mortality in the developed world. Triggers for this inflammatory process are elevated levels of cholesterol, bacterial infection and obesity. The immune response in atherosclerosis is essentially pro-atherogenic, leading to lipid accumulation and cellular changes within the arterial wall. Small-animal models of atherosclerosis are used to study the relevance of candidate factors (cells, genes, diets) in the development and progression of lesions. From a multidisciplinary viewpoint, there are challenges and limitations to this approach. Activation of complement determines or modifies the outcome of acute and chronic inflammation. This review dissects the role of complement in the early development as well as the progressive manifestation of murine atherosclerosis and the advances in knowledge provided by the use of specific mouse models. It gives a critical overview of existing models, analyses seemingly conflicting results obtained with complement-deficient mouse models, highlights the importance of interrelationships between pro-coagulpant activity, adipose tissue, macrophages and complement, and uncovers exciting avenues of topical research. Copyright © 2011 S. Karger AG, Basel. PMID: 22116497 [PubMed - indexed for MEDLINE] 497. J Biomech. 2012 Jan 3;45(1):1-8. doi: 10.1016/j.jbiomech.2011.10.023. Epub 2011 Nov 21. Mechanotransduction in adipocytes. Shoham N(1), Gefen A. Author information: (1)Department of Biomedical Engineering, Tel Aviv University, Tel Aviv 69978, Israel. Obesity is widely recognized as a major public health problem due to its strong association with a number of serious chronic diseases including hyperlipidemia, hypertension, type II diabetes and coronary atherosclerotic heart disease. During the development of obesity, the positive energy balance involves recruitment of new adipocytes from preadipocytes in adipose tissue, which have proliferated and differentiated. Given that cells in adipose tissues are physiologically exposed to compound mechanical loading: tensile, compressive and shear strains/stresses, which are caused by bodyweight loads as well as by weight-bearing, it is important to determine whether the adipose conversion process is influenced by mechanical stimulations. In this article we provide a comprehensive review of the experimental studies addressing mechanotransduction in adipocytes, as well as of mathematical and computational models that are useful for studying mechanotransduction in adipocytes or for quantifying the responsiveness of adipocytes to different types of mechanical loading. The new understanding that adipogenesis is influenced by mechanical stimulations has the potential to open new and important research paths, driven by mechanotransduction, to explore mechanisms as well as treatment approaches in obesity and related conditions. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 22112919 [PubMed - indexed for MEDLINE] 498. Exp Diabetes Res. 2012;2012:716425. doi: 10.1155/2012/716425. Epub 2011 Oct 26. Role of transcription factor modifications in the pathogenesis of insulin resistance. Kim MY(1), Bae JS, Kim TH, Park JM, Ahn YH. Author information: (1)Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea. Non-alcoholic fatty liver disease (NAFLD) is characterized by fat accumulation in the liver not due to alcohol abuse. NAFLD is accompanied by variety of symptoms related to metabolic syndrome. Although the metabolic link between NAFLD and insulin resistance is not fully understood, it is clear that NAFLD is one of the main cause of insulin resistance. NAFLD is shown to affect the functions of other organs, including pancreas, adipose tissue, muscle and inflammatory systems. Currently efforts are being made to understand molecular mechanism of interrelationship between NAFLD and insulin resistance at the transcriptional level with specific focus on post-translational modification (PTM) of transcription factors. PTM of transcription factors plays a key role in controlling numerous biological events, including cellular energy metabolism, cell-cycle progression, and organ development. Cell type- and tissue-specific reversible modifications include lysine acetylation, methylation, ubiquitination, and SUMOylation. Moreover, phosphorylation and O-GlcNAcylation on serine and threonine residues have been shown to affect protein stability, subcellular distribution, DNA-binding affinity, and transcriptional activity. PTMs of transcription factors involved in insulin-sensitive tissues confer specific adaptive mechanisms in response to internal or external stimuli. Our understanding of the interplay between these modifications and their effects on transcriptional regulation is growing. Here, we summarize the diverse roles of PTMs in insulin-sensitive tissues and their involvement in the pathogenesis of insulin resistance. PMCID: PMC3205681 PMID: 22110478 [PubMed - indexed for MEDLINE] 499. Steroids. 2012 Jan;77(1-2):27-35. doi: 10.1016/j.steroids.2011.10.013. Epub 2011 Nov 13. Tissue physiology and pathology of aromatase. Stocco C(1). Author information: (1)Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, United States. costocco@uic.edu Aromatase is expressed in multiple tissues, indicating a crucial role for locally produced oestrogens in the differentiation, regulation and normal function of several organs and processes. This review is an overview of the role of aromatase in different tissues under normal physiological conditions and its contribution to the development of some oestrogen-related pathologies. Copyright © 2011 Elsevier Inc. All rights reserved. PMCID: PMC3286233 PMID: 22108547 [PubMed - indexed for MEDLINE] 500. Curr Opin Clin Nutr Metab Care. 2012 Jan;15(1):12-22. doi: 10.1097/MCO.0b013e32834dd297. Chronic low-grade inflammation and age-related sarcopenia. Beyer I(1), Mets T, Bautmans I. Author information: (1)Geriatrics Department, Universitair Ziekenhuis Brussel, Brussels, Belgium. PURPOSE OF REVIEW: Age-related chronic low-grade inflammatory profile (CLIP) has been recognized as an important causative factor for sarcopenia. Here, we report the recent evidence concerning CLIP and sarcopenia. RECENT FINDINGS: Twenty-one studies were included (12 observational, five interventional studies and four randomized controlled trials). Observational studies strengthen the association between CLIP and sarcopenia in cross-sectional and longitudinal designs. Interleukin (IL)-6 and tumour necrosis factor-α are the most reported inflammatory parameters. Biopsy studies confirm the role of oxidative mechanisms, protein kinase B and nuclear factor kappa-light-chain-enhancer of activated B cells pathways and implicate stress response mechanisms and heat shock protein. Adipose tissue as source of inflammatory cytokines remains unclear and correction for fat mass is advisable in new research. Exercise interventions (both aerobic and resistance training) demonstrate beneficial effects on CLIP even in the absence of decreases in weight, BMI or fat mass. IL-6 is also released during exercise, in hormone-like fashion unrelated to inflammation, and exercise-induced IL-6 changes require careful interpretation. Soy supplementation in one study showed no influence on CLIP and no recent pharmacological trials were retrieved. SUMMARY: Associations between CLIP and sarcopenia are observed quite consistently and underlying mechanisms become apparent. Exercise remains the mainstay intervention to lower CLIP and counter sarcopenia. More research is warranted to unravel the exact dose-response relationship. PMID: 22108098 [PubMed - indexed for MEDLINE] 501. Curr Opin Clin Nutr Metab Care. 2012 Jan;15(1):49-57. doi: 10.1097/MCO.0b013e32834d199f. Cysteine and obesity: consistency of the evidence across epidemiologic, animal and cellular studies. Elshorbagy AK(1), Kozich V, Smith AD, Refsum H. Author information: (1)Department of Pharmacology, University of Oxford, Oxford, UK. amany.elshorbagy@pharm.ox.ac.uk PURPOSE OF REVIEW: The concentrations of several plasma amino acids increase in obesity. Notably, plasma total concentrations of the sulphur amino acid cysteine (tCys) are linearly associated with fat mass in large population studies. Animal and cellular experiments support the concept that cysteine may be obesogenic. Here we review experimental and epidemiologic findings linking cysteine and related compounds with fat regulation and obesity. RECENT FINDINGS: tCys, and to a lesser extent cystathionine, are the only plasma sulphur amino acids consistently associated with human obesity, whereas glutathione is inversely associated with BMI. Supplementing cyste(i)ne in rodents decreases energy expenditure and promotes adiposity, whereas defects of cysteine-synthesizing enzymes decrease body weight. In adipocytes, cysteine inhibits lipolysis and promotes lipogenesis via H2O2 production. Unlike most plasma amino acids, tCys levels do not decrease with gastric bypass-induced weight loss, further supporting the concept that elevated cysteine may be a cause, not a consequence of obesity. Although cysteine products (glutathione, taurine and H2S) are altered in obesity, they do not appear to explain cysteine's effects on body weight. SUMMARY: Cellular, animal and epidemiologic data are consistent with the view that cysteine is obesogenic. Targeted research linking in-vitro and in-vivo findings is needed to elucidate mechanisms involved. PMID: 22108094 [PubMed - indexed for MEDLINE] 502. J Tissue Eng Regen Med. 2012 Nov;6(10):e1-e11. doi: 10.1002/term.502. Epub 2011 Nov 21. Can one generate stable hyaline cartilage from adult mesenchymal stem cells? A developmental approach. Hellingman CA(1), Koevoet W, van Osch GJ. Author information: (1)Department of Otorhinolaryngology, Head and Neck Surgery, Erasmus MC, University Medical Centre Rotterdam, PO Box 2040, 3000, CA, Rotterdam, The Netherlands. Chondrogenically differentiating bone marrow-derived mesenchymal stem cells (BMSCs) display signs of chondrocyte hypertrophy, such as production of collagen type X, MMP13 and alkaline phosphatase (ALPL). For cartilage reconstructions this is undesirable, as terminally differentiated cartilage produced by BMSCs mineralizes when implanted in vivo. Terminal differentiation is not restricted to BMSCs but is also encountered in chondrogenic differentiation of adipose-derived mesenchymal stem cells (MSCs) as well as embryonic stem cells, which by definition should be able to generate all types of tissues, including stable cartilage. Therefore, we propose that the currently used culture conditions may drive the cells towards terminal differentiation. In this manuscript we aim to review the literature, supplemented by our own data to answer the question, is it possible to generate stable hyaline cartilage from adult MSCs? We demonstrate that recently published methods for inhibiting terminal differentiation (through PTHrP, MMP13 or blocking phosphorylation of Smad1/5/8) result in cartilage formation with reduction of hypertrophic markers, although this does not reach the low level of stable chondrocytes. A set of hypertrophy markers should be included in future studies to characterize the phenotype more precisely. Finally, we used what is currently known in developmental biology about the differential development of hyaline and terminally differentiated cartilage to provide thought and insights to change current culture models for creating hyaline cartilage. Inhibiting terminal differentiation may not result in stable hyaline cartilage if the right balance of signals has not been created from the start of culture onwards. Copyright © 2011 John Wiley & Sons, Ltd. PMID: 22106029 [PubMed - indexed for MEDLINE] 503. J Endocrinol Invest. 2011 Dec;34(11):869-75. doi: 10.3275/8108. Epub 2011 Nov 21. Application of proteomics to the study of polycystic ovary syndrome. Insenser M(1), Escobar-Morreale HF. Author information: (1)Diabetes, Obesity and Human Reproduction Research Group, Hospital Universitario Ramon y Cajal & Universidad de Alcalá & Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain. BACKGROUND: Clinical proteomics consists of qualitative and quantitative profiling of proteins present in clinical specimens such as body fluids or tissues, with the aim of discovering novel proteins and cellular pathways associated with the disease of interest. AIM: To review the proteomic studies conducted to date that addressed different aspects of the pathogenesis of polycystic ovary syndrome (PCOS). METHODS: Descriptive review of studies that applied proteomic techniques to the study of PCOS. Published articles were identified using the Entrez-PubMed online search facilities. RESULTS: Most studies conducted to date focused on protein variations in plasma and different target tissues. Plasma proteomics analysis revealed that PCOS associates changes in protein expression in several acute-phase response proteins. Moreover, some of these molecules play major roles in iron metabolism and low-grade chronic inflammation. Studies using omental adipose tissue from morbidly obese women with or without PCOS revealed differences in abundance of proteins that may be involved in lipid and glucose metabolism, oxidative stress processes, and adipocyte differentiation. Moreover, identification of differentially expressed proteins in ovarian tissue, granulosa cells or T lymphocites may help to characterize more clearly some aspects of this disorder. CONCLUSIONS: Although the application of proteomic techniques to the study of PCOS is in its early infancy, studies conducted to date highlight its heterogeneous nature. Aside from androgen excess, several pathways related to intermediate metabolism, oxidative stress processes, inflammation and iron metabolism appear to be involved in the pathophysiology of PCOS. PMID: 22104628 [PubMed - indexed for MEDLINE] 504. Expert Rev Cardiovasc Ther. 2011 Dec;9(12):1557-64. doi: 10.1586/erc.11.167. Adiposity assessment: explaining the association between obesity, hypertension and stroke. Rhéaume C(1), Leblanc MÈ, Poirier P. Author information: (1)Institut Universitaire de Cardiologie et de pneumologie de Québec, 2725 ch Sainte-Foy, Québec, QC, G1V 4G5, Canada. Obesity is associated with a greater prevalence of cardiovascular risk factors and a higher risk of cardiovascular events, and contributes to the rise in cardiovascular morbidity and mortality worldwide. Increased BMI is established as an independent risk factor for cardiovascular disease (CVD). Attention has recently been drawn to alternate measures of adiposity/obesity, such as waist circumference, waist-to-hip ratio and waist-to-height ratio, that provide information regarding body fat distribution. Although BMI is the established clinical measurement to estimate CVD risk associated with excess bodyweight, there is evidence suggesting that abdominal obesity could represent a better marker of CVD risk than BMI. It is now recognized that abdominally obese individuals tend to have higher blood pressure. A major cardiovascular risk factor associated with stroke is systemic hypertension followed closely by obesity. Clinical adiposity indices used to describe obesity linked with systemic hypertension and stroke incidence are reviewed in this article. In summary, BMI, waist circumference, waist-to-hip ratio and waist-to-height ratio measurements are all useful tools for assessing adiposity/obesity in clinical practice, and should be evaluated with other cardiometabolic risk factors to refine cardiovascular risk stratification. PMID: 22103875 [PubMed - indexed for MEDLINE] 505. Biochem Soc Trans. 2011 Dec;39(6):1752-7. doi: 10.1042/BST20110675. LMNA-linked lipodystrophies: from altered fat distribution to cellular alterations. Bidault G(1), Vatier C, Capeau J, Vigouroux C, Béréziat V. Author information: (1)UMPC Université Paris 6, UMR S938, F-75005 Paris, France. Mutations in the LMNA gene, encoding the nuclear intermediate filaments the A-type lamins, result in a wide variety of diseases known as laminopathies. Some of them, such as familial partial lipodystrophy of Dunnigan and metabolic laminopathies, are characterized by lipodystrophic syndromes with altered fat distribution and severe metabolic alterations with insulin resistance and dyslipidaemia. Metabolic disturbances could be due either to the inability of adipose tissue to adequately store triacylglycerols or to other cellular alterations linked to A-type lamin mutations. Indeed, abnormal prelamin A accumulation and farnesylation, which are clearly involved in laminopathic premature aging syndromes, could play important roles in lipodystrophies. In addition, gene expression alterations, and signalling abnormalities affecting SREBP1 (sterol-regulatory-element-binding protein 1) and MAPK (mitogen-activated protein kinase) pathways, could participate in the pathophysiological mechanisms leading to LMNA (lamin A/C)-linked metabolic alterations and lipodystrophies. In the present review, we describe the clinical phenotype of LMNA-linked lipodystrophies and discuss the current physiological and biochemical hypotheses regarding the pathophysiology of these diseases. PMID: 22103520 [PubMed - indexed for MEDLINE] 506. Biochem Soc Trans. 2011 Dec;39(6):1698-704. doi: 10.1042/BST20110657. Prelamin A-mediated nuclear envelope dynamics in normal and laminopathic cells. Lattanzi G(1). Author information: (1)National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR, Unit of Bologna c/o IOR, Via di Barbiano 1/10, I-40136 Bologna, Italy. giovanna.lattanzi@cnr.it Prelamin A is the precursor protein of lamin A, a major constituent of the nuclear lamina in higher eukaryotes. Increasing attention to prelamin A processing and function has been given after the discovery, from 2002 to 2004, of diseases caused by prelamin A accumulation. These diseases, belonging to the group of laminopathies and mostly featuring LMNA mutations, are characterized, at the clinical level, by different degrees of accelerated aging, and adipose tissue, skin and bone abnormalities. The outcome of studies conducted in the last few years consists of three major findings. First, prelamin A is processed at different rates under physiological conditions depending on the differentiation state of the cell. This means that, for instance, in muscle cells, prelamin A itself plays a biological role, besides production of mature lamin A. Secondly, prelamin A post-translational modifications give rise to different processing intermediates, which elicit different effects in the nucleus, mostly by modification of the chromatin arrangement. Thirdly, there is a threshold of toxicity, especially of the farnesylated form of prelamin A, whose accumulation is obviously linked to cell and organism senescence. The present review is focused on prelamin A-mediated nuclear envelope modifications that are upstream of chromatin dynamics and gene expression mechanisms regulated by the lamin A precursor. PMID: 22103510 [PubMed - indexed for MEDLINE] 507. Biochem Soc Trans. 2011 Dec;39(6):1687-92. doi: 10.1042/BST20110670. Clinical and genetic heterogeneity in laminopathies. Bertrand AT(1), Chikhaoui K, Yaou RB, Bonne G. Author information: (1)Inserm, U974, Paris, France. Mutations in the LMNA gene encoding lamins A/C are responsible for more than ten different disorders called laminopathies which affect various tissues in an isolated (striated muscle, adipose tissue or peripheral nerve) or systemic (premature aging syndromes) fashion. Overlapping phenotypes are also observed. Associated with this wide clinical variability, there is also a large genetic heterogeneity, with 408 different mutations being reported to date. Whereas a few hotspot mutations emerge for some types of laminopathies, relationships between genotypes and phenotypes remain poor for laminopathies affecting the striated muscles. In addition, there is important intrafamilial variability, explained only in a few cases by digenism, thus suggesting an additional contribution from modifier genes. In this regard, a chromosomal region linked to the variability in the age at onset of myopathic symptoms in striated muscle laminopathies has recently been identified. This locus is currently under investigation to identify modifier variants responsible for this variability. PMID: 22103508 [PubMed - indexed for MEDLINE] 508. Endocrinol Nutr. 2012 Jan;59(1):50-61. doi: 10.1016/j.endonu.2011.08.002. Epub 2011 Nov 18. [Chronobiological aspects of obesity and metabolic syndrome]. [Article in Spanish] Gómez-Abellán P(1), Madrid JA, Ordovás JM, Garaulet M. Author information: (1)Departamento de Fisiología, Facultad de Biología, Universidad de Murcia, Murcia, España. Circadian rhythms (approximately 24h) are widely characterized at molecular level and their generation is acknowledged to originate from oscillations in expression of several clock genes and from regulation of their protein products. While general entrainment of organisms to environmental light-dark cycles is mainly achieved through the master clock of the suprachiasmatic nucleus in mammals, this molecular clockwork is functional in several organs and tissues. Some studies have suggested that disruption of the circadian system (chronodisruption (CD)) may be causal for manifestations of the metabolic syndrome. This review summarizes (1) how molecular clocks coordinate metabolism and their specific role in the adipocyte; (2) the genetic aspects of and scientific evidence for obesity as a chronobiological illness; and (3) CD and its causes and pathological consequences. Finally, ideas about use of chronobiology for the treatment of obesity are discussed. Copyright © 2011 SEEN. Published by Elsevier Espana. All rights reserved. PMID: 22100640 [PubMed - indexed for MEDLINE] 509. Cytokine. 2012 Jan;57(1):9-16. doi: 10.1016/j.cyto.2011.10.008. Epub 2011 Nov 17. Adipose tissue inflammation and cancer cachexia: possible role of nuclear transcription factors. Batista ML Jr(1), Peres SB, McDonald ME, Alcantara PS, Olivan M, Otoch JP, Farmer SR, Seelaender M. Author information: (1)Laboratory of Adipose Tissue Biology, Center for Integrated Biotechnology, University of Mogi das Cruzes, Mogi das Cruzes, Sao Paulo, Brazil. miguelj@umc.br Cancer cachexia is a multifaceted syndrome whose aetiology is extremely complex and is directly related to poor patient prognosis and survival. Changes in lipid metabolism in cancer cachexia result in marked reduction of total fat mass, increased lipolysis, total oxidation of fatty acids, hyperlipidaemia, hypertriglyceridaemia, and hypercholesterolaemia. These changes are believed to be induced by inflammatory mediators, such as tumour necrosis factor-α (TNF-α) and other factors. Attention has recently been drawn to the current theory that cachexia is a chronic inflammatory state, mainly caused by the host's reaction to the tumour. Changes in expression of numerous inflammatory mediators, notably in white adipose tissue (WAT), may trigger several changes in WAT homeostasis. The inhibition of adipocyte differentiation by PPARγ is paralleled by the appearance of smaller adipocytes, which may partially account for the inhibitory effect of PPARγ on inflammatory gene expression. Furthermore, inflammatory modulation and/or inhibition seems to be dependent on the IKK/NF-κB pathway, suggesting that a possible interaction between NF-κB and PPARγ is required to modulate WAT inflammation induced by cancer cachexia. In this article, current literature on the possible mechanisms of NF-κB and PPARγ regulation of WAT cells during cancer cachexia are discussed. This review aims to assess the role of a possible interaction between NF-κB and PPARγ in the setting of cancer cachexia as well as its significant role as a potential modulator of chronic inflammation that could be explored therapeutically. Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved. PMID: 22099872 [PubMed - indexed for MEDLINE] 510. Plast Reconstr Surg. 2011 Dec;128(6):1236-40. doi: 10.1097/PRS.0b013e318230c7b8. Panniculectomy in preparation for renal transplantation: a new indication for an old procedure to reduce renal transplantation-associated wound complications. Kuo JH(1), Troppmann C, Perez RV, Wong MS. Author information: (1)University of California, Davis, CA, USA. End-stage renal disease patients who have lost a significant amount of weight are increasingly being evaluated for kidney transplantation. An abdominal panniculus, almost uniformly observed, creates an area predisposed to wound complications. Consequently, a panniculus may limit a patient's candidacy for transplantation. The authors describe their preliminary experience utilizing panniculectomy as a prophylactic procedure to reduce wound complications following kidney transplantation in patients whose panniculus would exclude them from renal transplantion. A single-institution chart review was conducted of nine patients with end-stage renal disease who underwent a panniculectomy in preparation for transplantation. Clinical outcomes and complications were reviewed. The nine patients included three men and six women with a mean age of 54.5 years and a mean body mass index of 28.3 kg/m. Four patients had diabetes. All patients underwent an uncomplicated panniculectomy, with a mean resected weight of 3.0 kg, and a mean length of hospital stay of 1.75 days. No one required blood transfusions. All patients were followed postoperatively for 3 months. Complications included an abscess and a skin dehiscence treated with local wound care. After recovery, patients were referred to the transplant center for re-evaluation for kidney transplantation. Thus far, four of these nine patients have undergone transplantation. This case series suggests that panniculectomy can be performed safely in patients with end-stage renal disease. Furthermore, panniculectomy gives these otherwise unsuitable kidney transplant candidates access to a life-saving operation. PMID: 22094742 [PubMed - indexed for MEDLINE] 511. Diabetes Obes Metab. 2012 Jun;14(6):493-9. doi: 10.1111/j.1463-1326.2011.01538.x. Epub 2011 Dec 27. Controversies surrounding the clinical potential of cinnamon for the management of diabetes. Rafehi H(1), Ververis K, Karagiannis TC. Author information: (1)Epigenomic Medicine Laboratory, Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia. Obesity levels have increased significantly in the past five decades and are predicted to continue rising, resulting in important health implications. In particular, this has translated to an increase in the occurrence of type II diabetes mellitus (T2D). To alleviate associated problems, certain nutraceuticals have been considered as potential adjuncts or alternatives to conventional prescription drugs. Cinnamon, a commonly consumed spice originating from South East Asia, is currently being investigated as a potential preventative supplement and treatment for insulin resistance, metabolic syndrome and T2D. Extensive in vitro evidence has shown that cinnamon may improve insulin resistance by preventing and reversing impairments in insulin signalling in skeletal muscle. In adipose tissue, it has been shown that cinnamon increases the expression of peroxisome proliferator-activated receptors including, PPARγ. This is comparable to the action of commonly used thiazolinediones, which are PPAR agonists. Studies have also shown that cinnamon has potent anti-inflammatory properties. However, numerous human clinical trials with cinnamon have been conducted with varying findings. While some studies have showed no beneficial effect, others have indicated improvements in cholesterol levels, systolic blood pressure, insulin sensitivity and postprandial glucose levels with cinnamon. However, the only measurement consistently improved by cinnamon consumption is fasting glucose levels. While it is still premature to suggest the use of cinnamon supplementation based on the evidence, further investigation into mechanisms of action is warranted. Apart from further characterization of genetic and epigenetic changes in model systems, systematic large-scale clinical trials are required. In this study, we discuss the mechanisms of action of cinnamon in the context of T2D and we highlight some of the associated controversies. © 2011 Blackwell Publishing Ltd. PMID: 22093965 [PubMed - indexed for MEDLINE] 512. Am J Clin Nutr. 2011 Dec;94(6 Suppl):2036S-2043S. doi: 10.3945/ajcn.111.018903. Epub 2011 Nov 16. Programming research: where are we and where do we go from here? Koletzko B(1), Symonds ME, Olsen SF; Early Nutrition Programming Project; Early Nutrition Academy. Author information: (1)Division of Metabolic and Nutritional Medicine, Department of Pediatrics, Dr von Hauner Children's Hospital, University of Munich Medical Center, Munich, Germany. office.koletzko@med.uni-muenchen.de Convincing evidence has accumulated to show that both pre- and postnatal nutrition preprogram long-term health, well-being, and performance until adulthood and old age. There is a very large potential in the application of this knowledge to promote public health. One of the prerequisites for translational application is to strengthen the scientific evidence. More extensive knowledge is needed (eg, on effect sizes of early life programming in contemporary populations, on specific nutritional exposures, on sensitive time periods in early life, on precise underlying mechanisms, and on potential effect differences in subgroups characterized by, eg, genetic predisposition or sex). Future programming research should aim at filling the existing gaps in scientific knowledge, consider the entire lifespan, address socioeconomic issues, and foster innovation. Research should aim at results suitable for translational application (eg, by leading to health-promoting policies and evidence-based dietary recommendations in the perinatal period). International collaboration and a close research partnership of academia, industry, and small and medium enterprises may strengthen research and innovative potential enhancing the likelihood of translational application. The scientific know-how and methodology available today allow us to take major steps forward in the near future; hence, research on nutritional programming deserves high priority. PMID: 22089444 [PubMed - indexed for MEDLINE] 513. Curr Med Chem. 2011;18(34):5267-80. Determinants of increased cardiovascular disease in obesity and metabolic syndrome. Vazzana N(1), Santilli F, Sestili S, Cuccurullo C, Davi G. Author information: (1)Center of Excellence on Aging, "G. D'Annunzio" University Foundation, Via Colle dell'Ara, 66013 Chieti, Italy. Obesity is associated with an increased mortality and morbidity for cardiovascular disease (CVD) and adipose tissue is recognised as an important player in obesity-mediated CVD. The diagnosis of the metabolic syndrome (MS) appears to identify substantial additional cardiovascular risk above and beyond the individual risk factors, even though the pathophysiology underlying this evidence is still unravelled. The inflammatory response related to fat accumulation may influence cardiovascular risk through its involvement not only in body weight homeostasis, but also in coagulation, fibrinolysis, endothelial dysfunction, insulin resistance (IR) and atherosclerosis. Moreover, there is evidence that oxidative stress may be a mechanistic link between several components of MS and CVD, through its role in inflammation and its ability to disrupt insulin-signaling. The cross-talk between impaired insulin-signaling and inflammatory pathways enhances both metabolic IR and endothelial dysfunction, which synergize to predispose to CVD. Persistent platelet hyperreactivity/activation emerges as the final pathway driven by intertwined interactions among IR, adipokine release, inflammation, dyslipidemia and oxidative stress and provides a pathophysiological explanation for the excess risk of atherothrombosis in this setting. Despite the availability of multiple interventions to counteract these metabolic changes, including appropriate diet, regular exercise, antiobesity drugs and bariatric surgery, relative failure to control the incidence of MS and its complications reflects both the multifactorial nature of these diseases as well as the scarce compliance of patients to established strategies. Evaluation of the impact of these therapeutic strategies on the pathobiology of atherothrombosis, as discussed in this review, will translate into an optimized approach for cardiovascular prevention. PMID: 22087824 [PubMed - indexed for MEDLINE] 514. Rev Bras Cir Cardiovasc. 2011 Jul-Sep;26(3):440-6. Absence of arteriosclerosis in intramyocardial coronary arteries: a mystery to be solved? Ramalli EL Jr(1), Braga LH, Evora PM, Albuquerque AA, Celotto AC, Mota AL, Evora PR. Author information: (1)Surgery and Anatomy Department, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil. Several studies show that portions of intramyocardial coronary arteries are spared of arteriosclerosis, involving morphological, embryological, biochemical and pathophysiological aspects. Endothelial function is significantly affected in the segment of transition, as estimated by the vasoactive response to Ach. These findings suggest that myocardial bridge can provide protection against arteriosclerosis by counteracting the negative effects of endothelial dysfunction. The intramyocardial portion's protection phenomenon deserves further scientific research on all research fronts. Improved morphological, biomechanical and especially physiological and embryological knowledge may be the key to a future window of opportunity for chronic arterial disease therapy and prevention. In addition, this review discusses possible therapeutic approaches for symptomatic coronary ischemia caused by myocardial bridges. PMID: 22086582 [PubMed - indexed for MEDLINE] 515. Nat Rev Endocrinol. 2011 Nov 15;8(5):263-75. doi: 10.1038/nrendo.2011.184. The multifactorial role of leptin in driving the breast cancer microenvironment. Andò S(1), Catalano S. Author information: (1)Department of Cell Biology and Centro Sanitario, University of Calabria, via Pietro Bucci, 87036 Arcavacata di Rende, Italy. sebastiano.ando@ unical.it Adipose-tissue-derived signaling molecules, including the adipokines, are emerging as key candidate molecules that link obesity with cancer. Peritumoral, stromal, adipose tissue and secreted adipokines, particularly leptin, have important roles in breast cancer biology. For example, leptin signaling contributes to the metabolic features associated with breast cancer malignancy, such as switching the cells' energy balance from mitochondrial β-oxidation to the aerobic glycolytic pathway. Leptin also shapes the tumor microenvironment, mainly through its ability to potentiate both migration of endothelial cells and angiogenesis, and to sustain the recruitment of macrophages and monocytes, which in turn secrete vascular endothelial growth factor and proinflammatory cytokines. This article presents an overview of current knowledge on the involvement of leptin in the pathogenesis and progression of breast cancer, highlighted by human, in vitro and animal studies. Data are presented on the functional crosstalk between leptin and estrogen signaling, which further contributes to promotion of breast carcinogenesis. Finally, future perspectives and clinical applications in which leptin and the leptin receptor are considered as potential therapeutic targets for breast cancer are reviewed. PMID: 22083089 [PubMed - indexed for MEDLINE] 516. Amyloid. 2011 Dec;18(4):177-82. doi: 10.3109/13506129.2011.630762. Proteomic typing of amyloid deposits in systemic amyloidoses. Lavatelli F(1), Vrana JA. Author information: (1)Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Italy. francesca.lavatelli@unipv.it Comment in Amyloid. 2011 Dec;18(4):175-6. Amyloidoses are characterized by the presence of extracellular amyloid deposits, constituted by fibrillar aggregates of misfolded proteins. Despite the similar morphologic appearance of fibrils, at least 28 different proteins have been detected as causative agents of human amyloidoses, 14 of which associated with systemic forms. Unequivocal typing of the amyloid deposits is a key step in the management of these diseases. Existing drawbacks of traditional, immunohistochemistry-based techniques have driven the search for alternative solutions for direct amyloid typing. Proteomics indicates the comprehensive study of the proteins in a biological sample, centered on analysis by mass spectrometry. The great potential of this approach in describing the composition of amyloid deposits and in studying the molecular features of the amyloidogenic precursors has become immediately clear and the introduction of proteomics in the clinical practice has revolutionized the field of amyloid typing. This review provides a critical overview of the various approaches that have been proposed in this specific context, along with a brief description of the proteomic methods for assessment of the circulating amyloidogenic proteins. PMID: 22080761 [PubMed - indexed for MEDLINE] 517. Joint Bone Spine. 2012 Mar;79(2):129-33. doi: 10.1016/j.jbspin.2011.08.004. Epub 2011 Nov 12. Bone tissue and muscle dystrophin deficiency in mdx mice. Nakagaki WR(1), Camilli JA. Author information: (1)Department of Anatomy, Cell Biology and Physiology and Biophysics, Institute of Biology, State University of Campinas (UNICAMP), Campinas, SP, Brazil. Erratum in Joint Bone Spine. 2013 Oct;80(5):557-8. Duchenne muscular dystrophy is a neuromuscular disease caused by the lack of dystrophin that affects skeletal muscles, causing degeneration of muscle fibers and replacing them with fibrous and adipose tissue, events that gradually lead to functional loss. Patients with Duchenne muscular dystrophy have shown that bones become more fragile with age and with advancement of the disease. Muscle weakness and reduced mobility have been suggested to be the factors that promote bone deterioration. However, it seems that this does not occur in mdx mice. It has been identified in mdx mice the existence of a factor related or not to the lack of dystrophin that also participates in the impairment of bone quality. Mdx mice also exhibit muscle degeneration, but unlike human, it is compensated by muscle regeneration. In consequence, there is an increase in the muscle mass, but not necessarily of muscle contractile strength. The accommodation of this increased muscle mass promotes bone formation at specific sites, such as at tendo-osseous junctions. In addition, the inflammatory response to muscle injury may be responsible for the increase in angiogenesis and regeneration observed in mdx mice, inducing the release of cytokines and chemokines that play an important role in the recruitment of leukocytes and macrophages. Then, mdx mice may possess compensatory mechanisms in bone in response to a genetic defect. Copyright © 2011 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved. PMID: 22079415 [PubMed - indexed for MEDLINE] 518. Thromb Res. 2012 Mar;129(3):285-9. doi: 10.1016/j.thromres.2011.10.021. Epub 2011 Nov 9. Thrombosis and obesity: cellular bases. Lorenzet R(1), Napoleone E, Cutrone A, Donati MB. Author information: (1)Laboratori di Ricerca, Fondazione di Ricerca e Cura Giovanni Paolo II, Largo Gemelli, 1, 86100 Campobasso, Italy. roberto.lorenzet@rm.unicatt.it The prevalence of obesity has dramatically increased during the past two decades. Epidemiological studies suggest that obesity is an independent, modifiable risk factor for coronary heart disease, possibly due, at least in part, to the development of a pro-inflammatory and a pro-thrombotic state in obese subjects. In addition, numerous cohort studies have shown a link between obesity and different types of cancer. Accordingly, the regulation of body weight is becoming a serious concern for public health experts and scientists. Although the mechanisms responsible for these associations are still to be fully elucidated, a key role has been assigned to adipokines, a family of hormones which act as modulators of metabolism or inflammation, secreted by adipocytes. Tissue factor, the major physiological trigger of the blood coagulation cascade in vivo, which plays a central role in atherothrombosis and tumor biology, has also been proposed as one of the key molecules responsible for these associations. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 22078462 [PubMed - indexed for MEDLINE] 519. Crit Rev Eukaryot Gene Expr. 2011;21(2):131-42. Inflammatory mediators: tracing links between obesity and osteoarthritis. Rai MF(1), Sandell LJ. Author information: (1)Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA. Osteoarthritis (OA), the most common form of arthritis, is associated with joint malfunction and chronic disability in the aged population. It is a multifactorial disorder to which several factors-such as age, sex, trauma, and obesity-contribute significantly. Obesity is one of the most influential but modifiable risk factors because it exerts an increased mechanical stress on the tibiofemoral cartilage. However, the high prevalence of OA in obese individuals in non-weightbearing areas, like finger joints, suggests that the link between being overweight and OA lies with factors other than simple biomechanics. An important correlation has been made between obesity and inflammation. Adipose tissues (and the infrapatellar fat pad) play an important role in this context because they are the major source of cytokines, chemokines, and metabolically active mediators called adipokines (or adipocytokines). These metabolic factors are known to possess catabolic and proinflammatory properties and to orchestrate the pathophysiological processes in OA. This review provides information on the relationship between obesity and OA through biomechanical and biochemical factors and highlights the functions of important obesity-related inflammatory products in the initiation and progression of OA. This information will broaden our thinking in identifying the targets for both prevention and intervention for OA. PMID: 22077152 [PubMed - indexed for MEDLINE] 520. Nihon Yakurigaku Zasshi. 2011 Nov;138(5):182-6. [Role of chronic inflammation in the pathogenesis of atherosclerosis]. [Article in Japanese] Sata M(1). Author information: (1)sata@clin.med.tokushima-u.ac.jp PMID: 22075459 [PubMed - indexed for MEDLINE] 521. Nihon Yakurigaku Zasshi. 2011 Nov;138(5):178-81. [Obesity and homeostatic inflammation]. [Article in Japanese] Ogawa Y(1). Author information: (1)ogawa.mmm@mri.tmd.ac.jp PMID: 22075458 [PubMed - indexed for MEDLINE] 522. Obes Rev. 2012 Mar;13(3):234-57. doi: 10.1111/j.1467-789X.2011.00948.x. Epub 2011 Nov 10. Role of the hypothalamus in the neuroendocrine regulation of body weight and composition during energy deficit. Sainsbury A(1), Zhang L. Author information: (1)Neuroscience Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia. a.sainsbury-salis@garvan.org.au Energy deficit in lean or obese animals or humans stimulates appetite, reduces energy expenditure and possibly also decreases physical activity, thereby contributing to weight regain. Often overlooked in weight loss trials for obesity, however, is the effect of energy restriction on neuroendocrine status. Negative energy balance in lean animals and humans consistently inhibits activity of the hypothalamo-pituitary-thyroid, -gonadotropic and -somatotropic axes (or reduces circulating insulin-like growth factor-1 levels), while concomitantly activating the hypothalamo-pituitary-adrenal axis, with emerging evidence of similar changes in overweight and obese people during lifestyle interventions for weight loss. These neuroendocrine changes, which animal studies show may result in part from hypothalamic actions of orexigenic (e.g. neuropeptide Y, agouti-related peptide) and anorexigenic peptides (e.g. alpha-melanocyte-stimulating hormone, and cocaine and amphetamine-related transcript), can adversely affect body composition by promoting the accumulation of adipose tissue (particularly central adiposity) and stimulating the loss of lean body mass and bone. As such, current efforts to maximize loss of excess body fat in obese people may inadvertently be promoting long-term complications such as central obesity and associated health risks, as well as sarcopenia and osteoporosis. Future weight loss trials would benefit from assessment of the effects on body composition and key hormonal regulators of body composition using sensitive techniques. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 22070225 [PubMed - indexed for MEDLINE] 523. Diabetes Metab Res Rev. 2011 Nov;27(8):913-8. doi: 10.1002/dmrr.1279. 'Sensing' the link between type 1 and type 2 diabetes. Tsui H(1), Paltser G, Chan Y, Dorfman R, Dosch HM. Author information: (1)The Research Institute, Hospital For Sick Children, University of Toronto, Neuroscience and Mental Health Program, Toronto, ON M5G 1X8, Canada. hubert.tsui@utoronto.ca Obesity-associated insulin resistance is a core element of metabolic syndrome and type 2 diabetes (T2D). Notably, insulin resistance is also a feature of type 1 diabetes (T1D), where findings in the non-obese diabetic mouse model have implicated transient receptor potential vanilloid-1 (TRPV1+) sensory neurons in local islet inflammation and glucose metabolism. Here, we briefly review the role of TRPV1 in non-obese diabetic (NOD) T1D pathogenesis, highlighting commonalities that suggest TRPV1 may contribute to obesity and T2D as well. With the recently discovered importance of adipose infiltrating lymphocytes in the metabolic disturbances of obesity and T2D, sensory innervation of fat may thus play an analogous role to sensory neurons in the islet--modulating neuroendocrine homeostasis and inflammation. In such a scenario, TRPV1+ sensory nerves would provide the pathoaetiological link connecting the shared metabolic and immunologic features of type 1 diabetes and T2D. Copyright © 2011 John Wiley & Sons, Ltd. PMID: 22069284 [PubMed - indexed for MEDLINE] 524. Circ J. 2011;75(12):2739-48. Epub 2011 Nov 8. Chronic inflammation links cardiovascular, metabolic and renal diseases. Manabe I(1). Author information: (1)Department of Cardiovascular Medicine and Global COE, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. manabe-tky@umin.ac.jp Chronic inflammation appears to underlie most, if not all, the chronic diseases of today, including cardiovascular disease, type 2 diabetes, chronic kidney disease, Alzheimer's disease and cancer. We have demonstrated that obesity induces chronic local inflammation in adipose tissue. We also found that chronic inflammation is crucially involved in the development of heart failure and chronic kidney disease. In this article, I review recent findings reported by my group and others regarding the mechanisms underlying the chronic inflammatory processes commonly observed in adipose tissue, heart and kidney. I then discuss the key features of the chronic inflammation seen in chronic diseases. PMID: 22067929 [PubMed - indexed for MEDLINE] 525. Int J Immunopathol Pharmacol. 2011 Oct;24(4 Suppl):13-6. Adipokines and their role in allergies. Ciprandi G(1), Caimmi D, Raschetti R, Miraglia Del Giudice M, Salpietro C, Caimmi S, Castellazzi AM. Author information: (1)Department of Internal Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino, Genoa, Italy. gio.cip@libero.it Both allergic disorders and obesity keep increasing in industrialized countries. Even though a strong association between obesity and allergy- related diseases has been reported in several studies, no published data show a scientific and firm link in-between the two conditions. In general, obesity and weight gain have been associated with an increased risk of asthma and allergic rhinitis. Asthma, allergic rhinitis and obesity have a common inflammatory pattern that could therefore justify their association. In fact, the chronic inflammation that characterizes the increase in white adipose tissue typically pushes the immune system toward a Th2 pattern. Such a polarization might, consequentially, worsen a pre-existing allergic disease or even stimulate the evolution from a sensitization to a respiratory form of allergy. Several studies have been published on the role of different adipokines on allergic diseases. We focus our review on the role of adipokines on asthma and allergic rhinitis. PMID: 22032780 [PubMed - indexed for MEDLINE] 526. Dis Model Mech. 2011 Nov;4(6):733-45. doi: 10.1242/dmm.008698. Set points, settling points and some alternative models: theoretical options to understand how genes and environments combine to regulate body adiposity. Speakman JR(1), Levitsky DA, Allison DB, Bray MS, de Castro JM, Clegg DJ, Clapham JC, Dulloo AG, Gruer L, Haw S, Hebebrand J, Hetherington MM, Higgs S, Jebb SA, Loos RJ, Luckman S, Luke A, Mohammed-Ali V, O'Rahilly S, Pereira M, Perusse L, Robinson TN, Rolls B, Symonds ME, Westerterp-Plantenga MS. Author information: (1)Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, Scotland, AB39 2PN, UK. J.Speakman@abdn.ac.uk The close correspondence between energy intake and expenditure over prolonged time periods, coupled with an apparent protection of the level of body adiposity in the face of perturbations of energy balance, has led to the idea that body fatness is regulated via mechanisms that control intake and energy expenditure. Two models have dominated the discussion of how this regulation might take place. The set point model is rooted in physiology, genetics and molecular biology, and suggests that there is an active feedback mechanism linking adipose tissue (stored energy) to intake and expenditure via a set point, presumably encoded in the brain. This model is consistent with many of the biological aspects of energy balance, but struggles to explain the many significant environmental and social influences on obesity, food intake and physical activity. More importantly, the set point model does not effectively explain the 'obesity epidemic'--the large increase in body weight and adiposity of a large proportion of individuals in many countries since the 1980s. An alternative model, called the settling point model, is based on the idea that there is passive feedback between the size of the body stores and aspects of expenditure. This model accommodates many of the social and environmental characteristics of energy balance, but struggles to explain some of the biological and genetic aspects. The shortcomings of these two models reflect their failure to address the gene-by-environment interactions that dominate the regulation of body weight. We discuss two additional models--the general intake model and the dual intervention point model--that address this issue and might offer better ways to understand how body fatness is controlled. PMCID: PMC3209643 PMID: 22065844 [PubMed - indexed for MEDLINE] 527. Prog Neurobiol. 2012 May;97(2):152-72. doi: 10.1016/j.pneurobio.2011.10.003. Epub 2011 Nov 2. Cell-autonomous and non-cell-autonomous toxicity in polyglutamine diseases. Sambataro F(1), Pennuto M. Author information: (1)Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova 16163, Italy. Polyglutamine diseases are neurodegenerative disorders caused by expansion of polyglutamine tracts in the coding regions of specific genes. One of the most important features of polyglutamine diseases is that, despite the widespread and in some cases ubiquitous expression of the polyglutamine proteins, specific populations of neurons degenerate in each disease. This finding has led to the idea that polyglutamine diseases are cell-autonomous diseases, in which selective neuronal dysfunction and death result from damage caused by the mutant protein within the targeted neuronal population itself. Development of animal models for conditional expression of polyglutamine proteins, along with new pharmacologic manipulation of polyglutamine protein expression and toxicity, has led to a remarkable change of the current view of polyglutamine diseases as cell-autonomous disorders. It is becoming evident that toxicity in the neighboring non-neuronal cells contributes to selective neuronal damage. This observation implies non-cell-autonomous mechanisms of neurodegeneration in polyglutamine diseases. Here, we describe cell-autonomous and non-cell-autonomous mechanisms of polyglutamine disease pathogenesis, including toxicity in neurons, skeletal muscle, glia, germinal cells, and other cell types. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 22061202 [PubMed - indexed for MEDLINE] 528. Clin Chim Acta. 2012 Jan 18;413(1-2):81-7. doi: 10.1016/j.cca.2011.10.028. Epub 2011 Oct 26. ESR1 in myocardial infarction. Puzianowska-Kuźnicka M(1). Author information: (1)Department of Human Epigenetics, Mossakowski Medical Research Centre, Warsaw, Poland. mpuzianowska@wum.edu.pl Women live longer than men; this can be attributed in part to the function of estrogens. In premenopausal women 17β-estradiol (E2) is produced mainly by the ovaries. Extra-ovarian sources of this hormone comprise adipose tissue, breast tissue, bone, leukocytes, heart, testes, prostate, adrenal tissues, and some brain structures. E2 exerts the majority of its biological functions by interacting with the nuclear receptors ERα and ERβ, encoded by the ESR1 and ESR2 genes, respectively. The genomic mechanism of ER action is the regulation of the activity of target genes. In addition, E2 induces rapid cellular effects in transcription-independent, non-genomic mechanisms, acting via receptors localized in the plasma membrane, in the cytoplasm, and in the mitochondria. Notably, ERα commonly serves as an extra-nuclear receptor of E2. In wild type animal models of cardiac ischemia ERα activation reduces infarct size, apoptosis of cardiomyocytes, inflammation, and oxidative stress, induces vasodilatation and increases neovascularization. The cardioprotective role of ERα in human is not fully elucidated. An individual with disruptive ESR1 mutation had dysfunctional epithelium and suffered from early cardiovascular disease. An association of the common ESR1 -397T>C and -351A>G polymorphisms and of other polymorphisms with cardiovascular disease and with myocardial infarction is still not firmly established. Copyright © 2011 Elsevier B.V. All rights reserved. PMID: 22061094 [PubMed - indexed for MEDLINE] 529. Transl Res. 2011 Dec;158(6):369-84. doi: 10.1016/j.trsl.2011.08.004. Epub 2011 Sep 3. Oxidant mechanisms in childhood obesity: the link between inflammation and oxidative stress. Codoñer-Franch P(1), Valls-Bellés V, Arilla-Codoñer A, Alonso-Iglesias E. Author information: (1)Department of Pediatrics, Dr. Peset University Hospital, Valencia, Spain. pilar.codoner@uv.es Evidence of obesity-induced oxidative stress in adults has emerged in the past several years, and similar evidence has been demonstrated in children more recently. The reactive species of oxygen or nitrogen can chemically alter all major classes of biomolecules by modifying their structure and function. Organisms have developed mechanisms to protect biomolecules from the deleterious effects of free radicals. These include the enzymes superoxide dismutase, catalase, and glutathione peroxidase, as well as water and lipid-soluble antioxidants, such as glutathione, ascorbate (vitamin C), α-tocopherol (vitamin E), and β-carotene. Obesity creates oxidant conditions that favor the development of comorbid diseases. Energy imbalances lead to the storage of excess energy in adipocytes, resulting in both hypertrophy and hyperplasia. These processes are associated with abnormalities of adipocyte function, particularly mitochondrial stress and disrupted endoplasmic reticulum function. In this sense, oxidative stress can also be induced by adipocyte associated inflammatory macrophages. There is a close link among obesity, a state of chronic low-level inflammation, and oxidative stress. In addition, the dysregulation of adipocytokines, which are secreted by adipose tissue and promoted by oxidative stress, act synergistically in obesity-related metabolic abnormalities. Adipocytokines link the local and systemic inflammation responses in the context of obesity. It is thought that the evaluation of oxidative status may allow for the identification of patients at an increased risk of complications. Decreasing the levels of chronic inflammation and oxidative stress in childhood may decrease cardiovascular morbidity and mortality in adulthood. Copyright © 2011 Mosby, Inc. All rights reserved. PMID: 22061044 [PubMed - indexed for MEDLINE] 530. Scand J Clin Lab Invest. 2012 Feb;72(1):1-13. doi: 10.3109/00365513.2011.626868. Epub 2011 Nov 7. Soluble CD163. Møller HJ(1). Author information: (1)Department of Clinical Biochemistry, Aarhus University Hospital, Nørrebrogade 44, Aarhus C, Denmark. holgmoel@rm.dk CD163 is an endocytic receptor for haptoglobin-hemoglobin complexes and is expressed solely on macrophages and monocytes. As a result of ectodomain shedding, the extracellular portion of CD163 circulates in blood as a soluble protein (sCD163) at 0.7-3.9 mg/l in healthy individuals. The function of sCD163 is unknown, but during inflammation and macrophage activation, sCD163 levels increase acutely due to metalloproteinase-mediated cleavage near the cell membrane. It is now evident that sCD163 is very useful as a biomarker of macrophage activation in various inflammatory diseases, such as macrophage activation syndrome, sepsis, and liver disease. Moreover, sCD163 is a general risk marker of comorbidity and mortality in several chronic inflammatory disease states. Recently, sCD163 has been shown to be strongly associated with later development of type 2 diabetes in both lean and obese subjects, likely due to macrophage infiltration of adipose tissue and the liver. This review summarizes the current knowledge on the regulation of sCD163 in normal and pathological states and also deals with analytical aspects of sCD163 measurements in biological samples. PMID: 22060747 [PubMed - indexed for MEDLINE] 531. Regen Med. 2011 Nov;6(6):757-65. doi: 10.2217/rme.11.91. Urologic applications of engineered tissue. Kollhoff DM(1), Cheng EY, Sharma AK. Author information: (1)Loyola University Medical Center, Maywood, IL 60153, USA. Many congenital and acquired anomalies affect the genitourinary tract, necessitating surgical intervention. Among these are bladder exstrophy, hypospadias, epispadias, posterior urethral valves, myelomeningocele, bladder carcinoma, urethral stricture disease, stress urinary incontinence, pelvic organ prolapse, vesicoureteral reflux and traumatic injuries of the urinary tract. Surgical repair of these conditions often utilizes skin, oral mucosa or bowel autograft or xenograft material to replace missing tissue or to augment inadequate tissues. These materials are often sufficient to restore the basic anatomy of the organ to which they are being grafted, but they usually do not completely restore normal function. In addition, postoperative complications are common, especially in the case of bladder augmentation or neobladder creation with autologous bowel. The complications and inherent limitations of these procedures may be mitigated by the availability of alternative tissue sources. Therefore, there has been a great deal of interest in developing tissues engineered from autologous materials, such as mature bladder cells, bone marrow-derived stem cells and adipose tissue. Ideally, an engineered tissue would restore or preserve the normal function of the organ it is augmenting or replacing. In addition, the engineered tissue should be nonimmunogenic to minimize rejection or foreign-body reactions. For the purposes of this article, we will focus on selection of scaffolding materials, selection of cell sources, and the current applications and potential future roles of tissue engineering in urology. PMID: 22050527 [PubMed - indexed for MEDLINE] 532. BioDrugs. 2011 Dec 1;25(6):405-8. doi: 10.2165/11208290-000000000-00000. Spotlight on tesamorelin in HIV-associated lipodystrophy. Dhillon S(1). Author information: (1)Adis, a Wolters Kluwer Business, Auckland, New Zealand. demail@adis.co.nz Tesamorelin (Egrifta™) is a synthetic analog of human growth hormone-releasing hormone (also known as growth hormone-releasing factor) that stimulates the synthesis and release of endogenous growth hormone. It is the first and, so far, only treatment indicated for the reduction of excess abdominal fat in patients with HIV-associated lipodystrophy. This article reviews the pharmacological properties, clinical efficacy and tolerability of tesamorelin in patients with HIV-associated central fat accumulation. Subcutaneous tesamorelin was effective in reducing visceral adipose tissue (VAT), but did not affect subcutaneous adipose tissue to a clinically significant extent in two 26-week, well designed, clinical trials in patients with HIV-associated central fat accumulation. This reduction in VAT was maintained in the longer term in patients who continued to receive tesamorelin until week 52 in the extension phases of the two trials. However, discontinuation of therapy during this period resulted in the reaccumulation of VAT. Tesamorelin therapy was also associated with significant improvements in other body composition measures (e.g. trunk fat and waist circumference) and improvements were generally seen in some body image parameters (e.g. belly image distress). Tesamorelin was generally well tolerated, with treatment-emergent serious adverse events occurring in <4% of patients during 26 weeks of therapy. Most of these events were injection-site reactions or events known to be associated with growth hormone therapy (e.g. arthralgia, headache and peripheral edema). Although long-term clinical experience is needed to further assess the benefits and risks of therapy, current evidence suggests that tesamorelin may be useful for reducing visceral adiposity in patients with HIV-associated lipodystrophy, thereby potentially improving self image. PMID: 22050344 [PubMed - indexed for MEDLINE] 533. Arthritis. 2011;2011:203901. doi: 10.1155/2011/203901. Epub 2011 Aug 18. Adipokines and osteoarthritis: novel molecules involved in the pathogenesis and progression of disease. Conde J(1), Scotece M, Gómez R, Lopez V, Gómez-Reino JJ, Gualillo O. Author information: (1)SERGAS, NEIRID Lab (Laboratory of NeuroEndocrine Interaction in Rheumatology and Inflammatory Diseases), Institute of Medical Research (IDIS), Santiago University Clinical Hospital Building C, Level-2, 15706 Santiago de Compostela, Spain. Obesity has been considered a risk factor for osteoarthritis and it is usually accepted that obesity contributes to the development and progression of osteoarthritis by increasing mechanical load of the joints. Nevertheless, recent advances in the physiology of white adipose tissue evidenced that fat cells produce a plethora of factors, called adipokines, which have a critical role in the development of ostearthritis, besides to mechanical effects. In this paper, we review the role of adipokines and highlight the cellular and molecular mechanisms at play in osteoarthritis elicited by adipokines. We also emphasize how defining the role of adipokines has broadned our understanding of the diversity of factors involved in the genesis and progression of osteoarthritis in the hope of modifying it to prevent and treat diseases. PMCID: PMC3200120 PMID: 22046513 [PubMed] 534. Clin Ter. 2011;162(5):e145-53. [The ketogenic diet: an underappreciated therapeutic option?]. [Article in Italian] Paoli A(1), Canato M, Toniolo L, Bargossi AM, Neri M, Mediati M, Alesso D, Sanna G, Grimaldi KA, Fazzari AL, Bianco A. Author information: (1)Dipartimento di Anatomia e Fisiologia Umana, Università di Padova, Italy. antonio.paoli@unipd.it Obesity is reaching epidemic proportions in Western countries and is a strong risk factor for cardiovascular disease. Despite the constant recommendations of health care organizations regarding the importance of weight control, this goal often fails. Although there is a common agreement about the concept that exercise and diet are two key factors for the control of body weight, the ideal amount and type of exercise and also the ideal diet for weight control are still under debate. A widely accepted nutritional regime is the Mediterranean diet that has evident health benefits although less attention has been paid to see if the effects are due to other lifestyle factors which may contribute to the health benefits perhaps as much as specific food choices. There are several other options available to the physician that may produce good weight loss results in the short/medium term and also for maintenance of the goal achieved. One of these strategies is the ketogenic diet or VLCKD (very low carbohydrate ketogenic diet) that has been widely studied in recent years. Most studies show that this diet has a solid physiological and biochemical basis which is able to induce effective weight loss and improvement of several parameters of cardiovascular risk. This review discusses the physiological basis of VLCKD and the main applications together with its strengths and weaknesses compared to common dietary recommendations. PMID: 22041813 [PubMed - indexed for MEDLINE] 535. Yakugaku Zasshi. 2011;131(11):1557-62. [Novel therapeutic approach based on recent understanding of the development of metabolic syndrome]. [Article in Japanese] Hosoi T(1). Author information: (1)Department of Pharmacotherapy, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. toruh@hiroshima-u.ac.jp Obesity is associated with metabolic syndrome, a cluster of symptoms including diabetes, hyperlipidemia, hypertension and arteriosclerosis, which can cause serious health problems. Accumulating evidence suggests that endoplasmic reticulum stress (ER stress) is associated with metabolic syndrome. Leptin is an anti-obesity hormone, which is secreted from adipose tissue. Circulating leptin acts at the brain hypothalamus and reduces food intake. As most forms of obesity indicate a state of leptin resistance, elucidation of the mechanisms of leptin resistance would be an important subject. We and other groups have recently suggested that leptin resistance may be derived from ER stress. These results raised the possibility that attenuating ER stress would be effective treatment for the disease. In the present review article, recent understanding of the mechanisms of the development of obesity and the potential novel therapeutic approaches targeting ER stress are discussed. PMID: 22041693 [PubMed - indexed for MEDLINE] 536. Peptides. 2011 Nov;32(11):2340-7. doi: 10.1016/j.peptides.2011.10.006. Epub 2011 Oct 29. Ghrelin in neuroendocrine tumors. Vu JP(1), Wang HS, Germano PM, Pisegna JR. Author information: (1)Department of Gastroenterology and Hepatology, Veterans Administration GLAHS, Los Angeles, CA 90073, USA. Ghrelin is a 28 amino acid peptide, primarily produced by the oxyntic mucosa X/A like neuroendocrine cells in the stomach. It is also found in the small intestine, hypothalamus, pituitary gland, pancreas, heart, adipose tissue, and immune system. In gastrointestinal neuroendocrine tumors (NETs) ghrelin release has been well documented. Ghrelin is a brain-gut circuit peptide with an important role in the physiological regulation of appetite, response to hunger and starvation, metabolic and endocrine functions as energy expenditure, gastric motility and acid secretion, insulin secretion and glucose homeostasis, as well as in the potential connection to the central nervous system. Recently, there has been a significant interest in the biological effects of ghrelin in NETs. In this article, we present a comprehensive review of ghrelin's expression and a brief summary of ghrelin's physiological role in NETs patients with carcinoids, type A chronic atrophic gastritis (CAG), with or without MEN-1, and with and without liver metastases. We hope, with the research reviewed here, to offer compelling evidence of the potential significance of ghrelin in NETs, as well as to provide a useful guide to the future work in this area. Published by Elsevier Inc. PMID: 22041110 [PubMed - indexed for MEDLINE] 537. Mol Aspects Med. 2012 Feb;33(1):26-34. doi: 10.1016/j.mam.2011.10.011. Epub 2011 Oct 21. Immunity as a link between obesity and insulin resistance. Kalupahana NS(1), Moustaid-Moussa N, Claycombe KJ. Author information: (1)Obesity Research Center, The University of Tennessee, United States. Obesity is a major public health problem in the United States and worldwide. Further, obesity is causally linked to the pathogenesis of insulin resistance, metabolic syndrome and type-2 diabetes (T2D). A chronic low-grade inflammation occurring in adipose tissue is at least in part responsible for the obesity-induced insulin resistance. This adipose tissue inflammation is characterized by changes in immune cell populations giving rise to altered adipo/cytokine profiles, which in turn induces skeletal muscle and hepatic insulin resistance. Detailed molecular mechanisms of insulin resistance, adipose tissue inflammation and the implications of these findings on therapeutic strategies are discussed in this review. Published by Elsevier Ltd. PMID: 22040698 [PubMed - indexed for MEDLINE] 538. Biofactors. 2011 Nov-Dec;37(6):413-20. doi: 10.1002/biof.185. Epub 2011 Oct 28. Adipokines: biofactors from white adipose tissue. A complex hub among inflammation, metabolism, and immunity. Conde J(1), Scotece M, Gómez R, López V, Gómez-Reino JJ, Lago F, Gualillo O. Author information: (1)NEIRID Lab (NeuroEndocrine Interaction in Rheumatology and Inflammatory Diseases), SERGAS, Santiago University Clinical Hospital, Institute of Medical Research (IDIS), Building C, Level-2, Santiago de Compostela, Spain. Until the identification of leptin, the first adipokine discovered in 1994, adipose tissue was considered only as an energy storage tissue. However, it is now clear that adipose tissue is an endocrine/paracrine/autocrine organ, which plays a relevant role in physiopathology of several inflammatory diseases. Actually, it is mainly involved not only in the low-grade inflammatory status in obesity but also in other relevant inflammatory conditions and autoimmune disorders. In this review article, we discuss the main biological activities of leptin, adiponectin, lipocalin-2, resistin, and visfatin, as well as their contributions to certain inflammatory conditions. Copyright © 2011 International Union of Biochemistry and Molecular Biology, Inc. PMID: 22038756 [PubMed - indexed for MEDLINE] 539. Acta Pharmacol Sin. 2012 Feb;33(2):182-8. doi: 10.1038/aps.2011.131. Epub 2011 Oct 31. Why do anti-inflammatory therapies fail to improve insulin sensitivity? Gao ZG(1), Ye JP. Author information: (1)Antioxidant and Gene Regulation Lab, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA. Chronic inflammation occurs in obese conditions in both humans and animals. It also contributes to the pathogenesis of type 2 diabetes (T2D) through insulin resistance, a status in which the body loses its ability to respond to insulin. Inflammation impairs insulin signaling through the functional inhibition of IRS-1 and PPARγ. Insulin sensitizers (such as rosiglitazone and pioglitazone) inhibit inflammation while improving insulin sensitivity. Therefore, anti-inflammatory agents have been suggested as a treatment strategy for insulin resistance. This strategy has been tested in laboratory studies and clinical trials for more than 10 years; however, no significant progress has been made in any of the model systems. This status has led us to re-evaluate the biological significance of chronic inflammation in obesity. Recent studies have consistently asserted that obesity-associated inflammation helps to maintain insulin sensitivity. Inflammation stimulates local adipose tissue remodeling and promotes systemic energy expenditure. We propose that these beneficial activities of inflammation provide an underlying mechanism for the failure of anti-inflammatory therapy in the treatment of insulin resistance. Current literature will be reviewed in this article to present evidence that supports this viewpoint. PMCID: PMC3270211 PMID: 22036866 [PubMed - indexed for MEDLINE] 540. Cell Biosci. 2011 Oct 28;1:35. doi: 10.1186/2045-3701-1-35. Recent progress in the study of brown adipose tissue. Yao X(1), Shan S, Zhang Y, Ying H. Author information: (1)Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. yinghao@sibs.ac.cn. Brown adipose tissue in mammals plays a critical role in maintaining energy balance by thermogenesis, which means dissipating energy in the form of heat. It is held that in mammals, long-term surplus food intake results in energy storage in the form of triglyceride and may eventually lead to obesity. Stimulating energy-dissipating function of brown adipose tissue in human body may counteract fat accumulation. In order to utilize brown adipose tissue as a therapeutic target, the mechanisms underlying brown adipocyte differentiation and function should be better elucidated. Here we review the molecular mechanisms involved in brown adipose tissue development and thermogenesis, and share our thoughts on current challenges and possible future therapeutic approaches. PMCID: PMC3219668 PMID: 22035495 [PubMed] 541. Diabetol Metab Syndr. 2011 Oct 28;3(1):29. doi: 10.1186/1758-5996-3-29. The macrophage at the intersection of immunity and metabolism in obesity. Samaan MC(1). Author information: (1)Division of Pediatric Endocrinology, Department of Pediatrics, McMaster Children's Hospital, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada. samaanc@mcmaster.ca. Obesity is a worldwide pandemic representing one of the major challenges that societies face around the globe. Identifying the mechanisms involved in its development and propagation will help the development of preventative and therapeutic strategies that may help control its rising rates.Obesity is associated with chronic low-grade inflammation, and this is believed to be one of the major contributors to the development of insulin resistance, which is an early event in obesity and leads to type 2 diabetes when the pancreas fails to keep up with increased demand for insulin. In this review, we discuss the role of macrophages in mediation of inflammation in obesity in metabolic organs including adipose tissue, skeletal muscle and liver. The presence of immune cells at the interface with metabolic organs modulates both metabolic function and inflammatory responses in these organs, and may provide a potential therapeutic target to modulate metabolic function in obesity. PMCID: PMC3223491 PMID: 22035457 [PubMed] 542. Antioxid Redox Signal. 2012 Jul 1;17(1):81-94. doi: 10.1089/ars.2011.4358. Epub 2011 Dec 19. Modulation of h(2)s metabolism by statins: a new aspect of cardiovascular pharmacology. Bełtowski J(1), Jamroz-Wiśniewska A. Author information: (1)Department of Pathophysiology, Medical University, Lublin, Poland. jerzy.beltowski@umlub.pl SIGNIFICANCE: Statins (3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors) are commonly used in the treatment of cardiovascular diseases. Statins reduce plasma low-density lipoproteins, inhibit inflammatory reaction, improve endothelial function, ameliorate oxidative stress, and reduce platelet activity. Consequently, statins markedly decrease the risk of acute cardiovascular events. H(2)S is synthesized in all layers of the vascular wall, including the endothelium, smooth muscle cells, and perivascular adipose tissue (PVAT). RECENT ADVANCES: Recent studies demonstrate that PVAT-derived H(2)S decreases vascular tone by activating K(ATP) and/or KCNQ potassium channels in smooth muscle cells. Lipophilic atorvastatin, but not hydrophilic pravastatin, increases net H(2)S production in PVAT by inhibiting its mitochondrial oxidation, and augments the anticontractile effect of PVAT. Inhibition of H(2)S metabolism results from atorvastatin-induced decrease in coenzyme Q, which is a cofactor of H(2)S oxidation by sulfide:quinone oxidoreductase. In contrast to H(2)S, statins do not impair mitochondrial oxidation of organic substrates. CRITICAL ISSUES: Taking into account antiatherosclerotic and anti-inflammatory effect of H(2)S, the gas may mediate some of the beneficial effects of statins on the cardiovascular system. In addition, specific statins differ in their ability to enhance H(2)S signaling. FUTURE DIRECTIONS: Since both statins and H(2)S reduce ischemia-reperfusion injury, the possible effect of statins on H(2)S oxidation in other tissues such as the heart and the kidney needs to be examined. Inhibition of H(2)S metabolism may be a new therapeutic strategy to improve H(2)S signaling, especially in the mitochondrial compartment. PMCID: PMC3342564 PMID: 22034938 [PubMed - indexed for MEDLINE] 543. Annu Rev Med. 2012;63:329-43. doi: 10.1146/annurev-med-042010-113026. Epub 2011 Oct 27. Role of fructose-containing sugars in the epidemics of obesity and metabolic syndrome. Stanhope KL(1). Author information: (1)Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California, USA. klstanhope@ucdavis.edu There is controversy concerning the role of sugar in the epidemics of obesity and metabolic syndrome. There is less controversy concerning the effects of fructose on components of metabolic syndrome; consumption of fructose has been shown to increase visceral adipose deposition and de novo lipogenesis (DNL), produce dyslipidemia, and decrease insulin sensitivity in older, overweight/obese subjects. This review examines the potential mechanisms of these effects of fructose and considers whether these mechanisms are relevant to the effects of consuming sucrose or high-fructose corn syrup. Evidence demonstrating that the commonly consumed sugars increase visceral adipose deposition, DNL, and insulin insensitivity is limited or inconclusive. Evidence that sugar consumption promotes development of an unfavorable lipid profile is strong and suggests that the upper added sugar consumption limit of 25% of energy or less, suggested in the Report of the Dietary Guidelines Advisory Committee on the Dietary Guidelines for Americans 2010, may merit re-evaluation. PMID: 22034869 [PubMed - indexed for MEDLINE] 544. Obes Rev. 2012 Feb;13(2):136-49. doi: 10.1111/j.1467-789X.2011.00942.x. Epub 2011 Oct 31. The renin-angiotensin system: a link between obesity, inflammation and insulin resistance. Kalupahana NS(1), Moustaid-Moussa N. Author information: (1)Obesity Research Center, The University of Tennessee, Knoxville, TN 37996-4588, USA. The renin-angiotensin system (RAS) is classically known for its role in regulation of blood pressure, fluid and electrolyte balance. Recently, several local RASs in organs such as brain, heart, pancreas and adipose tissue have also been identified. Evidence from clinical trials suggests that in addition to anti-hypertensive effects, pharmacological inhibition of RAS also provides protection against the development of type-2 diabetes. Moreover, animal models with targeted inactivation of RAS genes exhibit improved insulin sensitivity and are protected from high-fat diet-induced obesity and insulin resistance. Because there is evidence for RAS overactivation in obesity, it is possible that RAS is a link between obesity and insulin resistance. This review summarizes the evidence and mechanistic insights on the associations between RAS, obesity and insulin resistance, with special emphasis on the role of adipose tissue RAS in the pathogenesis of metabolic derangements in obesity. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 22034852 [PubMed - indexed for MEDLINE] 545. Plast Reconstr Surg. 2011 Nov;128(5):411e-418e. doi: 10.1097/PRS.0b013e31822b669f. Evaluation of clinical outcomes and aesthetic results after autologous fat grafting for contour deformities of the reconstructed breast. de Blacam C(1), Momoh AO, Colakoglu S, Tobias AM, Lee BT. Author information: (1)Department of Surgery, Division of Plastic and Reconstructive Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Comment in Plast Reconstr Surg. 2012 Sep;130(3):500e-1e. BACKGROUND: Autologous fat grafting is gaining widespread acceptance for the management of soft-tissue deformities of the reconstructed breast. However, published data on long-term outcomes and aesthetic results of fat grafting to the breast are lacking. The purpose of this study was to review the authors' early experience of fat grafting in the correction of acquired contour deformities after postmastectomy breast reconstruction. METHODS: A detailed retrospective review of 49 patients who underwent fat grafting to 68 reconstructed breasts was carried out. Clinical outcomes were analyzed and aesthetic results were assessed with objective grading of preoperative and postoperative photographs by two independent, blinded plastic surgeons. RESULTS: On average, 67 cc of fat was injected into each breast per session. There were 111 fat injection procedures, as more than one injection was required in 51.5 percent of cases. Average follow-up time was 2.4 years. Complications occurred in 6.3 percent of procedures, including fat necrosis (3.6 percent), oil cysts (1.8 percent), and infection (0.9 percent). Aesthetic outcome was significantly improved across all measurements, including volume, contour, placement, and superomedial fullness (p<0.001 for all). CONCLUSION: Although further studies are required to provide surgeons with definitive guidelines for the implementation of this technique, fat injection is a safe intervention and significantly improves the aesthetic results in patients with contour deformities of the reconstructed breast. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID: 22030501 [PubMed - indexed for MEDLINE] 546. Plast Reconstr Surg. 2011 Nov;128(5):382e-394e. doi: 10.1097/PRS.0b013e31822b7a3b. The low transverse extended latissimus dorsi flap based on fat compartments of the back for breast reconstruction: anatomical study and clinical results. Bailey SH(1), Saint-Cyr M, Oni G, Wong C, Maia M, Nguyen V, Pessa JE, Colohan S, Rohrich RJ, Mojallal A. Author information: (1)Department of Plastic Surgery, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9132, USA. BACKGROUND: Despite many modifications to the extended latissimus dorsi flap, its use in autologous breast reconstruction remains limited because of insufficient volume and donor-site morbidity. Through a detailed analysis of the deposition of back fat, this study describes a low transverse extended latissimus dorsi flap harvest technique that increases flap volumes and improves donor-site aesthetics. METHODS: Eight fresh cadaver hemibacks were used to identify the anatomical location of the fat compartments. Correlation between the fat compartments and the fat folds was made using photographic analysis of 216 patients. Retrospective case note review was conducted of all patients who had a low transverse extended latissimus dorsi flap performed by the senior author (M.S.-C.). RESULTS: Cadaveric dissection and photographic analysis confirmed the presence of the four distinct fat compartments in the back. The lower compartments 3 and 4 were the most frequently identified and the largest, with mean values of 367 cm and 271 cm, respectively. The clinical series comprised eight high-body mass index patients who underwent 12 pure autologous breast reconstructions using the low transverse skin paddle harvest technique. Donor-site complications included partial dehiscence (n=2) and minor infection (n=3). There were no instances of seroma, and fat necrosis (<5 percent) occurred in one breast. CONCLUSIONS: The low transverse skin paddle extended latissimus dorsi flap is reliable and provides sufficient volume for purely autologous breast reconstruction with low donor-site morbidity and improved body contouring for a select group of patients. The authors' initial experience with high-body mass index patients shows promising results with this flap in a challenging group. PMID: 22030499 [PubMed - indexed for MEDLINE] 547. Bioessays. 2012 Jan;34(1):50-60. doi: 10.1002/bies.201100107. Epub 2011 Oct 26. PRDM proteins: important players in differentiation and disease. Fog CK(1), Galli GG, Lund AH. Author information: (1)Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Denmark. The PRDM family has recently spawned considerable interest as it has been implicated in fundamental aspects of cellular differentiation and exhibits expanding ties to human diseases. The PRDMs belong to the SET domain family of histone methyltransferases, however, enzymatic activity has been determined for only few PRDMs suggesting that they act by recruiting co-factors or, more speculatively, confer methylation of non-histone targets. Several PRDM family members are deregulated in human diseases, most prominently in hematological malignancies and solid cancers, where they can act as both tumor suppressors or drivers of oncogenic processes. The molecular mechanisms have been delineated for only few PRDMs and little is known about functional redundancy within the family. Future studies should identify target genes of PRDM proteins and the protein complexes in which PRDM proteins reside to provide a more comprehensive understanding of the biological and biochemical functions of this important protein family. Copyright © 2012 WILEY Periodicals, Inc. PMID: 22028065 [PubMed - indexed for MEDLINE] 548. Nat Rev Endocrinol. 2011 Oct 25;8(3):183-92. doi: 10.1038/nrendo.2011.158. Resistance to type 2 diabetes mellitus: a matter of hormesis? Kolb H(1), Eizirik DL. Author information: (1)Immunobiology Research Group, Institute of Molecular Medicine, University of Düsseldorf, D-40001 Düsseldorf, Germany. hubert.kolb@uni-duesseldorf.de Type 2 diabetes mellitus is characterized by subclinical systemic inflammation and impaired regulation of blood glucose levels. Interestingly, impairment of glycemic control occurs despite substantial insulin secretion early in the course of this disease. Dysfunction of several organs (including pancreatic islets, liver, skeletal muscle, adipose tissue, gut, hypothalamus and the immune system) has been implicated in the pathogenesis of type 2 diabetes mellitus. However, diabetes-promoting lifestyle factors do not inevitably cause disease in all persons exposed. Hence, defense mechanisms must exist that can keep the detrimental influence of these risk factors at bay. Hormesis describes the phenomenon that exposure to a mild stressor confers resistance to subsequent, otherwise harmful, conditions of increased stress. This Review discusses the emerging concept that the effectiveness of an adaptive (hormetic) response to detrimental lifestyle factors determines the extent of protection from progression to type 2 diabetes mellitus. Further analysis of these protective hormetic responses at the molecular level should help to identify novel targets for preventive or therapeutic intervention in patients at risk of developing type 2 diabetes mellitus or those with overt disease. PMID: 22024974 [PubMed - indexed for MEDLINE] 549. Curr Drug Targets. 2011 Dec;12(14):2103-28. Molecular players at the intersection of obesity and osteoarthritis. Bonet ML(1), Granados N, Palou A. Author information: (1)Laboratori de Biologia Molecular, Nutrició i Biotecnologia, Departament de Biologia Fonamental i Ciències de la Salut, Universitat de les Illes Balears, Crta. Valldemossa Km 7.5, Palma de Mallorca, Spain. luisabonet@uib.es Obesity and degenerative joint disease (osteoarthritis, OA) are two multifactorial pathologies that are becoming major medical issues with the aging of the world population. The relationship of OA with obesity is complex, involving both biomechanical and metabolic links. Dysregulated production of adipose tissue-derived inflammatory mediators, hyperlipidemia, and increased systemic oxidative stress are conditions frequently associated with obesity that may favor joint degeneration. In addition, it is remarkable that many regulatory factors have been implicated in the development, maintenance and function of both adipose tissues and cartilage and other articular joint tissues. Disturbances in these factors may underlie additional links between obesity and OA. In this review, molecular players at the intersection of adipose tissue and joint cell biology - including differentiation signals and transcription factors, extracellular matrix components and remodelers, joint cell- and adipose tissue cell-derived mediators (cytokines, adipokines), hypoxia inducible transcription factors, lipids, advanced glycation end products and miRNAs - are reviewed, with emphasis on their dysregulation in obesity and OA. Knowledge of these factors may illuminate a novel, adipocentric avenue for the pathogenesis and therapy of OA and other joint diseases. PMID: 22023406 [PubMed - indexed for MEDLINE] 550. Curr Drug Deliv. 2012 Jul;9(4):326-32. "Metabolic aspects" in inflammatory bowel diseases. Kaser A(1), Tilg H. Author information: (1)Department of Medicine II (Gastroenterology and Hepatology), Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria. arthur.kaser@i-med.ac.at Mesenteric fat hypertrophy is a common feature of inflammatory bowel diseases (IBD), especially Crohn's disease. Although this "creeping fat" has been observed in the early days of this disease, its biological relevance is not understood. This adipose tissue has been recognized to release large amounts of various cytokines such as TNFa and adipocytokines such as adiponectin or leptin. Whereas leptin is definitely a pro-inflammatory adipocytokine, the role of the prototypic anti-inflammatory adipocytokine, namely adiponectin, in intestinal inflammation is less clear. Some experimental studies suggest that it could exert also pro-inflammatory activities in the gut. An important role for metabolic aspects and potentially adipocytokines has also come from recent studies demonstrating that ATG16L1- deficient mice show a strikingly enhanced expression of both adiponectin and leptin in epithelial cells. Autophagy not only plays a key role in intestinal inflammation, but is also involved in the regulation of lipid metabolism. Another recently identified pathway in IBD, namely endoplasmic stress/XBP1, regulates fatty acid synthesis and facilitates adipogenesis and adipocyte differentiataion. Therefore, XBP1 could possibly link intestinal inflammation with the development of "creeping fat" in Crohn's disease. Metabolic aspects have evolved as of key importance in experimental colitis and human IBD, and certain adipocytokines, autophagy, and ER stress might reflect the central players. PMID: 22023201 [PubMed - indexed for MEDLINE] 551. Curr Vasc Pharmacol. 2012 Mar;10(2):238-46. Aldosterone, mineralocorticoid receptor and the metabolic syndrome: role of the mineralocorticoid receptor antagonists. Ronconi V(1), Turchi F, Appolloni G, di Tizio V, Boscaro M, Giacchetti G. Author information: (1)Division of Endocrinology, Ospedali Riuniti, Universita Politecnica delle Marche, Ancona, Italy. Several lines of evidence suggest a detrimental effect of aldosterone excess on the development of metabolic alterations. Glucose metabolism derangements due to aldosterone action are frequently observed not only in patients with primary aldosteronism but also in patients with obesity. A contribution to the hyperaldosteronism observed in obese subjects can be attributed, at least in part, to the action of still unidentified adipocyte-derived factor. Aldosterone, through genomic and non-genomic actions contributes to induce several abnormalities: pancreatic fibrosis, impaired beta cell function, as well as reduced skeletal muscle and adipose tissue insulin sensitivity. Oxidative stress, systemic inflammation, together with these metabolic alterations may explain the appearance of the cardiometabolic syndrome and the progression of cardiovascular and renal diseases, in the presence of inappropriate aldosterone levels. The biological actions of aldosterone are mediated by mineralocorticoid receptor (MR), although MR can be activated through an aldosterone independent fashion. Besides salt-water homeostasis, MR activation promotes inflammation, endothelial dysfunction, cardiovascular remodelling and affects adipose tissue differentiation and function. Clinical and experimental studies have shown that MR blockade is able to suppress inflammation, to improve endothelium- dependent vasorelaxation, but most interestingly, to improve pancreatic insulin release as well as insulin-mediated glucose utilization. These actions indicate MR antagonists as a useful therapeutic tool able not only to reduce cardiovascular risk and renal damage, but also to improve metabolic sequaelae. PMID: 22022770 [PubMed - indexed for MEDLINE] 552. Regen Med. 2011 Nov;6(6 Suppl):33-41. doi: 10.2217/rme.11.62. In vivo manipulation of stem cells for adipose tissue repair/reconstruction. Yoshimura K(1), Eto H, Kato H, Doi K, Aoi N. Author information: (1)Department of Plastic Surgery, University of Tokyo School of Medicine, 7-3-1, Hongo, Bunkyo-Ku, Tokyo 113-8655, Japan. kotaro-yoshimura@umin.ac.jp Many features of adipose stem/progenitor cells, including their physiological functions and localization, have been clarified in the past decade. Adipose tissue turns over very slowly, with perivascular progenitor cells differentiating into new adipocytes to replace dead adipocytes. A number of clinical trials using freshly isolated or cultured adipose-derived stromal cells containing adipose progenitor/stem cells are ongoing. Therapeutic use of adipose stem/progenitor cells has been shown to promote angiogenesis and adipose tissue regeneration. Identification of adipocyte-releasing factors upon apoptosis/necrosis would be a breakthrough and could lead to the next stage for adipose tissue regeneration. Activation of precursors in perichondrium and periosteum shows a dramatic neogenesis by simple injection and is an ideal example of in situ tissue engineering. The 'hit and catch' strategy using a mobilizer of bone-marrow stem/progenitor cells (hit) and attractants to lead the cells to proper homing into the target tissue (catch) may be the future of stem cell manipulation. Careful design of the microenvironment, cell delivery protocol to avoid unexpected behavior and induce maximal potential, and selection of target diseases, will be critical to the success of clinical applications of adipose-derived stromal cells. PMID: 21999260 [PubMed - indexed for MEDLINE] 553. Microb Cell Fact. 2011 Aug 30;10 Suppl 1:S10. doi: 10.1186/1475-2859-10-S1-S10. Epub 2011 Aug 30. Modulation of the gut microbiota by nutrients with prebiotic properties: consequences for host health in the context of obesity and metabolic syndrome. Delzenne NM(1), Neyrinck AM, Cani PD. Author information: (1)Université catholique de Louvain, Louvain Drug Research Institute, Metabolism and Nutrition Research Group, Brussels, Belgium. nathalie.delzenne@uclouvain.be The gut microbiota is increasingly considered as a symbiotic partner for the maintenance of health. The homeostasis of the gut microbiota is dependent on host characteristics (age, gender, genetic background...), environmental conditions (stress, drugs, gastrointestinal surgery, infectious and toxic agents...). Moreover, it is dependent on the day-to-day dietary changes. Experimental data in animals, but also observational studies in obese patients, suggest that the composition of the gut microbiota is a factor characterizing obese versus lean individuals, diabetic versus non diabetic patients, or patients presenting hepatic diseases such as non alcoholic steatohepatitis. Interestingly, the changes in the gut microbes can be reversed by dieting and related weight loss. The qualitative and quantitative changes in the intake of specific food components (fatty acids, carbohydrates, micronutrients, prebiotics, probiotics), have not only consequences on the gut microbiota composition, but may modulate the expression of genes in host tissues such as the liver, adipose tissue, intestine, muscle. This in turn may drive or lessen the development of fat mass and metabolic disturbances associated with the gut barrier function and the systemic immunity. The relevance of the prebiotic or probiotic approaches in the management of obesity in humans is supported by few intervention studies in humans up to now, but the experimental data obtained with those compounds help to elucidate novel potential molecular targets relating diet with gut microbes. The metagenomic and integrative metabolomic approaches could help elucidate which bacteria, among the trillions in human gut, or more specifically which activities/genes, could participate to the control of host energy metabolism, and could be relevant for future therapeutic developments. PMCID: PMC3231917 PMID: 21995448 [PubMed - indexed for MEDLINE] 554. J Korean Med Sci. 2011 Oct;26(10):1339-43. doi: 10.3346/jkms.2011.26.10.1339. Epub 2011 Oct 1. Correlation between complicated diverticulitis and visceral fat. Jeong JH(1), Lee HL, Kim JO, Tae HJ, Jung SH, Lee KN, Jun DW, Lee OY, Yoon BC, Choi HS, Hahm JS, Song SY. Author information: (1)Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea. The aim of this study was to examine the relationship of complications related to diverticulitis and visceral obesity. The study was based on a retrospective case note review conducted at the Hanyang University Hospital. Patients were diagnosed with diverticulitis based on clinical symptoms and abdominal computed tomography (CT) findings and divided into two groups: those admitted with complicated diverticulitis and those with a simple diverticulitis episode. We compared the body mass index (BMI) and degree of visceral obesity, measured by abdominal CT. The study included 140 patients, 87 (62.1%) were simple diverticulitis and 53 (37.9%) were complicated diverticulitis. In the complicated diverticulitis group, 9 (6.4%) cases were recurrent, 29 (20.7%) were perforation or abscess patients, and 28 (20%) were patients with systemic inflammatory response syndrome (SIRS). Of the SIRS patients, 13 were involved in other complication groups. When comparing in the two groups, the complicated diverticulitis group had a significantly higher visceral fat area (128.57 cm(2) vs 102.80 cm(2), P = 0.032) and a higher ratio of visceral fat area/subcutaneous fat area (0.997 vs 0.799, P = 0.014). Visceral obesity is significantly associated with complications of diverticulitis. PMCID: PMC3192347 PMID: 22022188 [PubMed - indexed for MEDLINE] 555. Proc Nutr Soc. 2012 Feb;71(1):175-80. doi: 10.1017/S0029665111003259. Epub 2011 Oct 21. Molecular mechanisms linking adipokines to obesity-related colon cancer: focus on leptin. Drew JE(1). Author information: (1)Metabolic Health, Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB21 9SB, UK. j.drew@abdn.ac.uk Obesity is linked to increased risk of colon cancer, currently the third most common cancer. Consequently rising levels of obesity worldwide are likely to significantly impact on obesity-related colon cancers in the decades to come. Understanding the molecular mechanisms whereby obesity increases colon cancer risk is thus a focus for research to inform strategies to prevent the increasing trend in obesity-related cancers. This review will consider research on deregulation of adipokine signalling, a consequence of altered adipokine hormone secretion from excess adipose tissue, with a focus on leptin, which has been studied extensively as a potential mediator of obesity-related colon cancer. Numerous investigations using colon cell lines in vitro, in vivo studies in rodents and investigations of colon cancer patients illuminate the complexity of the interactions of leptin with colon tissues via leptin receptors expressed by the colon epithelium. Although evidence indicates a role for leptin in proliferation of colon epithelial cells in vitro, this has been contradicted by studies in rodent models. However, recent studies have indicated that leptin may influence inflammatory mediators linked with colon cancer and also promote cell growth dependent on genotype and is implicated in growth promotion of colon cancer cells. Studies in human cancer patients indicate that there may be different tumour sub-types with varying levels of leptin receptor expression, indicating the potential for leptin to induce variable responses in the different tumour types. These studies have provided insights into the complex interplay of adipokines with responsive tissues prone to obesity-related colon cancer. Deregulation of adipokine signalling via adipokine receptors located in the colon appears to be a significant factor in obesity-related colon cancer. Molecular profiling of colon tumours will be a useful tool in future strategies to characterise the influence that adipokines may have on tumour development and subsequent therapeutic intervention. Study of the molecular mechanisms linking obesity with cancer also supports recommendations to maintain a normal body weight to reduce the risk of colon cancer. PMID: 22014041 [PubMed - indexed for MEDLINE] 556. Bone. 2012 Feb;50(2):430-6. doi: 10.1016/j.bone.2011.10.001. Epub 2011 Oct 11. Central and peripheral mechanisms of the NPY system in the regulation of bone and adipose tissue. Shi YC(1), Baldock PA. Author information: (1)Neuroscience Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia. Skeletal research is currently undergoing a period of marked expansion. The boundaries of "bone" research are being re-evaluated and with this, a growing recognition of a more complex and interconnected biology than previously considered. One aspect that has become the focus of particular attention is the relationship between bone and fat homeostasis. Evidence from a number of avenues indicates that bone and adipose regulation are both related and interdependent. This review examines the neuropeptide Y (NPY) system, known to exert powerful control over both bone and fat tissue. The actions of this system are characterized by signaling both within specific nuclei of the hypothalamus and also the target tissues, mediated predominantly through two G-protein coupled receptors (Y1 and Y2). In bone tissue, elevated NPY levels act consistently to repress osteoblast activity. Moreover, both central Y2 receptor and osteoblastic Y1 receptor signaling act similarly to repress bone formation. Conversely, loss of NPY expression or receptor signaling induces increased osteoblast activity and bone mass in both cortical and cancellous envelopes. In fat tissue, NPY action is more complex. Energy homeostasis is powerfully altered by elevations in hypothalamic NPY, resulting in increases in fat accretion and body-wide energy conservation, through the action of locally expressed Y1 receptors, while local Y2 receptors act to inhibit NPY-ergic tone. Loss of central NPY expression has a markedly reduced effect, consistent with a physiological drive to promote fat accretion. In fat tissue, NPY and Y1 receptors act to promote lipogenesis, consistent with their roles in the brain. Y2 receptors expressed in adipocytes also act in this manner, showing an opposing action to their role in the hypothalamus. While direct investigation of these processes has yet to be completed, these responses appear to be interrelated to some degree. The starvation-based signal of elevated central NPY inducing marked inhibition of osteoblast activity, whilst promoting fat accretion, indicating skeletal tissue is a component of the energy conservation system. Moreover, when NPY expression is reduced, consistent with high calorie intake and weight gain, bone formation is stimulated, strengthening the skeleton. In conclusion, NPY acts to regulate both bone and fat tissue in a coordinated manner, and remains a strong candidate for mediating interactions between these two tissues. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 22008645 [PubMed - indexed for MEDLINE] 557. Histopathology. 2012 Jun;60(7):1034-44. doi: 10.1111/j.1365-2559.2011.03911.x. Epub 2011 Oct 18. The connective tissue changes of Crohn's disease. Shelley-Fraser G(1), Borley NR, Warren BF, Shepherd NA. Author information: (1)Gloucestershire Cellular Pathology Laboratory Department of Colorectal Surgery, Cheltenham General Hospital, Cheltenham, Gloucestershire, UK. Although the inflammatory pathology of Crohn's disease is manifestly its most important attribute, the connective tissue changes are important in the genesis of the more chronic features of the disease, and yet these have received little attention from clinicians, pathologists, and scientists. Fat-wrapping appears to be pathognomonic of Crohn's disease, and is an important marker of disease for surgeons. There is evidence of a complex interplay between the effector inflammatory cells of Crohn's disease and adipocytes, hyperplasia of which results in fat-wrapping. Pathologically, this is exhibited in the close relationship between the transmural inflammation that is so characteristic of Crohn's disease and fat-wrapping. Fibrosis and muscularization are also important components of the chronic changes of intestinal Crohn's disease. Neuronal and vascular changes make up the remaining connective tissue changes: these constitute a distinctive feature, and are even specific for Crohn's disease. For pathologists, the combination of these connective changes will allow a diagnosis of chronic 'burnt-out' Crohn's disease, even in the absence of its highly characteristic inflammatory features. The connective tissue changes of Crohn's disease form an important part of its long-term pathology. They deserve more attention from clinicians, diagnostic pathologists and researchers alike. © 2011 Blackwell Publishing Limited. PMID: 22008086 [PubMed - indexed for MEDLINE] 558. J Pathol. 2012 Jan;226(2):185-99. doi: 10.1002/path.3031. Interstitial guidance of cancer invasion. Gritsenko PG(1), Ilina O, Friedl P. Author information: (1)Microscopical Imaging of the Cell, Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Cancer cell invasion into healthy tissues develops preferentially along pre-existing tracks of least resistance, followed by secondary tissue remodelling and destruction. The tissue scaffolds supporting or preventing guidance of invasion vary in structure and molecular composition between organs. In the brain, the guidance is provided by myelinated axons, astrocyte processes, and blood vessels which are used as invasion routes by glioma cells. In the human breast, containing interstitial collagen-rich connective tissue, disseminating breast cancer cells preferentially invade along bundled collagen fibrils and the surface of adipocytes. In both invasion types, physical guidance prompted by interfaces and space is complemented by molecular guidance. Generic mechanisms shared by most, if not all, tissues include (i) guidance by integrins towards fibrillar interstitial collagen and/or laminins and type IV collagen in basement membranes decorating vessels and adipocytes, and, likely, CD44 engaging with hyaluronan; (ii) haptotactic guidance by chemokines and growth factors; and likely (iii) physical pushing mechanisms. Tissue-specific, resticted guidance cues include ECM proteins with restricted expression (tenascins, lecticans), cell-cell interfaces, and newly secreted matrix molecules decorating ECM fibres (laminin-332, thrombospondin-1, osteopontin, periostin). We here review physical and molecular guidance mechanisms in interstitial tissue and brain parenchyma and explore shared principles and organ-specific differences, and their implications for experimental model design and therapeutic targeting of tumour cell invasion. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID: 22006671 [PubMed - indexed for MEDLINE] 559. J Sep Sci. 2011 Dec;34(24):3470-83. doi: 10.1002/jssc.201100556. Epub 2011 Oct 17. Determination of acylglycerols from biological samples with chromatography-based methods. Hellmuth C(1), Uhl O, Segura-Moreno M, Demmelmair H, Koletzko B. Author information: (1)Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, University of Munich Medical Centre, München, Germany. christian.hellmuth@med.uni-muenchen.de Lipids are the most diverse class of metabolites in mammalian physiology and dysregulation of lipid metabolism is linked to various diseases. Alterations in acylglycerols, a major class of lipids in plasma and adipose tissue, are involved in the pathogenesis of obesity and type 2 diabetes. Therefore, determination of acylglycerols is important to depict and unravel cellular mechanisms related to pathological outcomes, and specific molecular species of acylglycerols might be promising biomarker candidates. The variety of acylglycerols can be characterized in different ways. Enzymatic assays enable the determination of total tri- or diacylglycerols showing a possible relation to diseases, but they do not allow clarification of molecular mechanism. While gas chromatography can provide an overview of the fatty acid composition of total or separated lipids, a very detailed description of the individual molecular acylglycerol species is possible via liquid chromatography, particularly when combined with mass spectrometry. This review describes the determination of acylglycerols considering recent developments, with a focus on mammalian serum/plasma and tissue. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. PMID: 22002927 [PubMed - indexed for MEDLINE] 560. Curr Opin Lipidol. 2011 Dec;22(6):479-88. doi: 10.1097/MOL.0b013e32834c7cfc. Nonalcoholic steatohepatitis: the therapeutic challenge of a global epidemic. Schattenberg JM(1), Schuppan D. Author information: (1)Department of Medicine I bCenter for Molecular and Translational Medicine, University Medical Center of the Johannes Gutenberg University, Langenbeckstraße 1, Mainz, Germany. PURPOSE OF REVIEW: Nonalcoholic fatty liver (NAFL) and especially its inflammatory variant nonalcoholic steatohepatitis (NASH) have become a major challenge to healthcare systems worldwide because of the increasing prevalence of its major risk factors obesity and type 2 diabetes, which are closely linked to overeating, physical inactivity, and the metabolic syndrome. RECENT FINDINGS: Between 10 and 20% of patients with NAFL develop NASH, which can progress to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The overall mortality in these patients is significantly increased because of both cardiovascular and liver-related complications. Sustained weight loss by diet and exercise, which is the most effective therapeutic measure, is only achieved by a minority of patients, having led to a great yet unmet need for medical therapies of NASH. SUMMARY: Pharmacological therapies should target the underlying pathophysiology that involves insulin resistance, enhanced peripheral lipolysis and release of free fatty acids, oxidative stress, accumulation of toxic lipids, adipose tissue inflammation, sensitization of hepatocytes toward apoptotic cell death, and fibrogenesis. However, pharmacological therapy that is well tolerated, cost-effective, and poses an acceptable risk-to-benefit ratio has still to be identified. This review summarizes the current and promising treatment options and their implications for future research and clinical practice. PMID: 22002020 [PubMed - indexed for MEDLINE] 561. Cell Mol Life Sci. 2012 Mar;69(5):741-62. doi: 10.1007/s00018-011-0840-1. Epub 2011 Oct 15. Metabolic syndrome as a risk factor for neurological disorders. Farooqui AA(1), Farooqui T, Panza F, Frisardi V. Author information: (1)Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, OH 43221, USA. farooqui.1@osu.edu The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. At the molecular level, metabolic syndrome is accompanied not only by dysregulation in the expression of adipokines (cytokines and chemokines), but also by alterations in levels of leptin, a peptide hormone released by white adipose tissue. These changes modulate immune response and inflammation that lead to alterations in the hypothalamic 'bodyweight/appetite/satiety set point,' resulting in the initiation and development of metabolic syndrome. Metabolic syndrome is a risk factor for neurological disorders such as stroke, depression and Alzheimer's disease. The molecular mechanism underlying the mirror relationship between metabolic syndrome and neurological disorders is not fully understood. However, it is becoming increasingly evident that all cellular and biochemical alterations observed in metabolic syndrome like impairment of endothelial cell function, abnormality in essential fatty acid metabolism and alterations in lipid mediators along with abnormal insulin/leptin signaling may represent a pathological bridge between metabolic syndrome and neurological disorders such as stroke, Alzheimer's disease and depression. The purpose of this review is not only to describe the involvement of brain in the pathogenesis of metabolic syndrome, but also to link the pathogenesis of metabolic syndrome with neurochemical changes in stroke, Alzheimer's disease and depression to a wider audience of neuroscientists with the hope that this discussion will initiate more studies on the relationship between metabolic syndrome and neurological disorders. © Springer Basel AG 2011 PMID: 21997383 [PubMed - indexed for MEDLINE] 562. Expert Opin Biol Ther. 2011 Dec;11(12):1591-7. doi: 10.1517/14712598.2011.628933. Epub 2011 Oct 13. Stem cells treatment for sciatic nerve injury. Dadon-Nachum M(1), Melamed E, Offen D. Author information: (1)Felsenstein Medical Reasearch Center, Tel Aviv University, Petah Tikva, 49100, Israel. INTRODUCTION: Sciatic nerve injury is common and usually results in degeneration of the distal axons and muscle denervation. Chronic muscle atrophy and fibrosis limit the recovery of muscle function and severely compromises efforts to restore muscle function. Despite early diagnosis and modern surgical techniques there is still poor functional recovery. AREAS COVERED: Stem cell transplantation has been investigated as a promising treatment strategy for peripheral nerve injury, and has demonstrated utility in limiting neuronal damage. The focus has been on the isolation of stem cells from bone-marrow and adipose tissue in addition to embryonic and neuronal stem cells. Transplantation of these cells into transected sciatic nerve in animal models demonstrates clinical improvement, inducing vigorous nerve regeneration accompanied by myelin synthesis. Cell replacement, trophic factor production, extracellular matrix molecule synthesis, guidance, remyelination, microenvironmental stabilization and immune modulation have been postulated as possible mechanisms for stem cell implantation. EXPERT OPINION: Although further research is still needed, this therapeutic approach will probably become a routine treatment technique in the coming years, especially with bone marrow mesenchymal stem cells. We believe that the most promising results were noted for the use of stem cells of this origin in the treatment of sciatic nerve injury. PMID: 21995439 [PubMed - indexed for MEDLINE] 563. Diabet Med. 2011 Dec;28(12):1476-86. doi: 10.1111/j.1464-5491.2011.03463.x. Mechanistic insights into insulin resistance in the genetic era. Parker VE(1), Savage DB, O'Rahilly S, Semple RK. Author information: (1)University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. Sir Harold Himsworth first observed and articulated the phenomenon of insulin resistance in the late 1930s. Although a long delay followed before his observations were acknowledged and enshrined in formal diagnostic classifications of diabetes mellitus, insulin resistance-related pathology in the early 21st century poses one of the major global healthcare challenges for contemporary physicians. Whilst insulin resistance is closely related to obesity and decreased physical fitness, despite intensive investigation it has proved extremely challenging to discriminate key events in its causation from epiphenomena, many related to compensation for the primary defect. Thus, a complete account of the molecular pathogenesis of insulin resistance-related diseases remains elusive. One approach circumventing such problems is the study of patients with single gene defects causing severe insulin resistance. In such patients the primary defect is known, and thus lessons may be learned about human physiology from detailed physiological study allied to knowledge of the function of the mutated protein. This review discusses developments in understanding of monogenic severe insulin resistance since discovery of the first insulin receptor mutations in 1988 and reviews the physiological lessons learnt, including the critical role of adipose tissue in human metabolic health and the meaning and importance of 'partial' insulin resistance for major human disease. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK. PMID: 21992440 [PubMed - indexed for MEDLINE] 564. World J Gastroenterol. 2011 Sep 7;17(33):3785-94. doi: 10.3748/wjg.v17.i33.3785. JNKs, insulin resistance and inflammation: A possible link between NAFLD and coronary artery disease. Tarantino G(1), Caputi A. Author information: (1)Department of Clinical and Experimental Medicine, Federico II University Medical School of Naples, Via Sergio Pansini 580131 Naples, Italy. tarantin@unina.it The incidence of obesity has dramatically increased in recent years. Consequently, obesity and associated disorders such as nonalcoholic fatty liver disease constitute a serious problem. Therefore, the contribution of adipose tissue to metabolic homeostasis has become a focus of interest. In this review, we discuss the latest discoveries that support the role of lipids in nonalcoholic fatty liver disease. We describe the common mechanisms (c-Jun amino-terminal kinases, endoplasmic reticulum stress, unfolded protein response, ceramide, low-grade chronic inflammation) by which lipids and their derivatives impair insulin responsiveness and contribute to inflammatory liver and promote plaque instability in the arterial wall. Presenting the molecular mechanism of lipid activation of pro-inflammatory pathways, we attempt to find a link between nonalcoholic fatty liver disease, metabolic syndrome and cardiovascular diseases. Describing the common mechanisms by which lipid derivatives, through modulation of macrophage function, promote plaque instability in the arterial wall, impair insulin responsiveness and contribute to inflammatory liver and discussing the molecular mechanism of lipid activation of pro-inflammatory pathways, the key roles played by the proliferator-activated receptor and liver X receptor α, nuclear receptors-lipid sensors that link lipid metabolism and inflammation, should be emphasized. Further studies are warranted of anti-inflammatory drugs such as aspirin, anti-interleukin-6 receptors, immune-modulators (calcineurin inhibitors), substances enhancing the expression of heat shock proteins (which protect cells from endoplasmic reticulum stress-induced apoptosis), and anti- c-Jun amino-terminal kinases in well-designed trials to try to minimize the high impact of these illnesses, and the different expressions of the diseases, on the whole population. PMCID: PMC3181439 PMID: 21987620 [PubMed - indexed for MEDLINE] 565. Curr Opin Support Palliat Care. 2011 Dec;5(4):342-9. doi: 10.1097/SPC.0b013e32834c49eb. The advantages and limitations of cross-sectional body composition analysis. MacDonald AJ(1), Greig CA, Baracos V. Author information: (1)Department of Clinical and Surgical Sciences (Surgery), University of Edinburgh, Edinburgh, UK. PURPOSE OF REVIEW: Cross-sectional (C-S) imaging is now commonly used to measure body composition in clinical studies. This review highlights the advantages, limitations and suggested future directions for this technique. RECENT FINDINGS: Current understanding of C-S imaging reproducibility, tissue identification and segmentation methods, comparison between imaging techniques and estimates of whole body composition using a single image are described. SUMMARY: C-S imaging can reliably measure muscle and fat distribution and uniquely discriminate between intra-abdominal organ and muscle component of fat-free mass. It precisely tracks changes within an individual, but is less able to distinguish true differences in whole body estimates between individuals. PMID: 21986910 [PubMed - indexed for MEDLINE] 566. Int J Obes (Lond). 2012 Aug;36(8):1017-24. doi: 10.1038/ijo.2011.192. Epub 2011 Oct 11. Causes and consequences of obesity: the contribution of recent twin studies. Naukkarinen J(1), Rissanen A, Kaprio J, Pietiläinen KH. Author information: (1)Obesity Research Unit, Division of Internal Medicine and Department of Psychiatry, Helsinki University Central Hospital, Department of Medicine, Helsinki, Finland. Obesity is a genetically complex disorder that produces a myriad of health problems. Most of the recognized complications of obesity are not only strongly influenced by lifestyle factors, but also present with independent genetic predispositions that are notoriously difficult to disentangle in humans. Most studies on the causes and consequences of acquired obesity are encumbered by the incomplete ability to control for genetic influences. However, utilizing a unique experiment of nature, namely monozygotic twins (MZ) discordant for obesity as 'clonal controls' of obese and non-obese individuals has enabled the fine characterization of the effects and possible antecedents of acquired obesity while controlling for the genetic background, as well as pointed to novel obesity predisposing candidate genes. This review is a distillation of the findings from more than 10 years of research done in an exceptionally well-characterized collection of MZ and dizygotic (DZ) twins, based on the Finnish Twin Cohorts. Topics covered include the nature of development of obesity from the childhood onwards, the role of exercise in modifying the genetic susceptibility, the resulting inflammatory, prediabetic and preatherosclerotic changes in whole body and adipose tissue physiology, as well as the newest insights provided by the omics revolution. PMID: 21986704 [PubMed - indexed for MEDLINE] 567. Curr Opin Clin Nutr Metab Care. 2011 Nov;14(6):554-61. doi: 10.1097/MCO.0b013e32834ad94b. Circadian rhythms in adipose tissue: an update. Gimble JM(1), Sutton GM, Ptitsyn AA, Floyd ZE, Bunnell BA. Author information: (1)Stem Cell Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA. gimblejm@pbrc.edu PURPOSE OF REVIEW: Over the past decade, evidence has accumulated from basic science, clinical and epidemiological studies linking circadian mechanisms to adipose tissue biology and its related comorbidities, diabetes, metabolic syndrome and obesity. This review highlights recent in-vitro and in-vivo findings from murine, human and model organism studies. RECENT FINDINGS: High-fat diets attenuate circadian mechanisms in murine adipose depots and these effects appear to be due to obesity rather than hyperglycemia. Deletion of circadian regulatory genes such as AMPK1 and nocturnin alter the circadian biology of adipose tissue. Unlike the mouse, circadian gene oscillation in human adipose tissue appears to be independent of BMI and diabetes status, suggesting that circadian mechanistic variation occurs across species. Clues for future directions in this emerging field come from studies of the hibernation and torpor state in mammals and infection models involving the Drosophila metabolic organ or 'fat body'. SUMMARY: There is a growing consensus that circadian rhythms and metabolism are tightly regulated in adipose tissue and peripheral metabolic organs. Although central mechanisms are critical, autonomous clocks exist within the adipocytes themselves. Future circadian advances are likely to result from the studies of adipose tissue-specific gene deletions. PMID: 21986477 [PubMed - indexed for MEDLINE] 568. Int J Cardiol. 2013 Jan 10;162(2):77-85. doi: 10.1016/j.ijcard.2011.09.079. Epub 2011 Oct 7. Metabolism and the heart: an overview of muscle, fat, and bone metabolism in heart failure. Loncar G(1), Fülster S, von Haehling S, Popovic V. Author information: (1)Cardiology Department, Clinical Medical Center Zvezdara, Belgrade, Serbia. loncar_goran@yahoo.com PURPOSE OF REVIEW: To review original research studies and reviews that present data on changes of body compartments and its mutual cross-talk with respect to the failing heart predominantly in non-cachectic patients with chronic heart failure (HF). RECENT FINDINGS: Thanks to the integrative approach considering the whole organism, several recent studies suggested a complex network of communication between body compartments in respect to failing heart during the natural course of body wasting in non-cachectic patients with HF. Interestingly, recent studies suggest that failing heart trough secretion of natriuretic peptides acts on fat metabolism by inducing adiponectin secretion and lipolytic actions. Soluble myostatin released from the failing heart may induce skeletal muscle wasting in HF through an endocrine-like mechanism, as well. The likelihood that adipocyte-derived hormones influence bone status has been recently proven. Increased serum adiponectin was independently associated with reduced bone mass in elderly patients with non-cachectic HF. SUMMARY: The concept of body compartments cross-talk in respect to failing heart provides a very interesting paradigm of integrative physiology. Better understanding of body compartments changes and its complex biochemical interplay may provide more efficacious and forehand treatment to prevent and/or postpone disability and improve quality of life in patients with chronic HF. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 21982619 [PubMed - indexed for MEDLINE] 569. Biol Aujourdhui. 2011;205(3):147-62. doi: 10.1051/jbio/2011017. Epub 2011 Oct 11. [Laminopathies: one gene, several diseases]. [Article in French] Bertrand AT(1), Chikhaoui K, Ben Yaou R, Bonne G. Author information: (1)UPMC Université Paris VI, IFR14, 75013 Paris, France. a.bertrand@institut-myologie.org Lamins A and C, encoded by the LMNA gene, are nuclear proteins expressed in all post-mitotic cells. Together with B-type lamins, they form a meshwork of proteins beneath the inner nuclear membrane, the lamina, in connection with the cytoskeleton. Lamins A/C also interact with chromatin and numerous proteins, including transcription factors. Mutations in LMNA are responsible for more than ten different disorders, commonly called "laminopathies". These diseases affect tissues in a specific (striated muscle, adipose tissue, peripheral nerve) or in a systemic manner (premature ageing syndromes). This wide spectrum of phenotypes is associated to a wide variety of mutations. This large clinical and genetic heterogeneity, unique to the LMNA gene, makes genotype-phenotype relations particularly difficult to establish. However, correlations have been obtained in several cases. Hence, LMNA mutations identified in premature ageing syndromes lead to the accumulation of immature proteins with a toxic effect for cells. Mutations in laminopathies of the adipose tissue mainly localize in the Ig-like domain of the proteins, potentially affecting the interaction with the SREBP-1 transcription factor. In laminopathies of the striated muscles, the mutations are spread throughout the gene. These mutations are thought to induce structural modifications of the proteins, thereby affecting their polymerization into nuclear lamina. Such defect would lead to a mechanical weakness of the nuclear lamina and of the cells, particularly in striated muscles continuously stretching. The exploration of pathophysiological mechanisms of LMNA mutations largely benefits from the numerous mouse models created, which have been widely used to analyze affected molecular pathways and to test putative therapeutic treatments. Société de Biologie, 2011. PMID: 21982404 [PubMed - indexed for MEDLINE] 570. Expert Opin Ther Targets. 2011 Nov;15(11):1297-306. doi: 10.1517/14728222.2011.628315. Epub 2011 Oct 10. Generation of reactive oxygen species in adipose-derived stem cells: friend or foe? Park SG(1), Kim JH, Xia Y, Sung JH. Author information: (1)CHA University, Department of Biomedical Science, Seoul, Korea. INTRODUCTION: Reactive oxygen species (ROS) participate in cellular apoptosis and are involved in pathophysiological etiology of degenerative diseases. However, recent studies suggest that ROS at low levels may play a pivotal role as second messengers and activate normal cellular processes. Intracellular ROS increase the proliferation, migration, and regenerative potential of adipose-derived stem cells (ASCs). In contrast, manipulations that diminish intracellular ROS levels interfere with normal ASC function. ROS generation therefore acts like a double-edged sword. AREAS COVERED: This review discusses the following research questions: i) Do ROS stimulate or suppress ASCs? ii) How are ROS generated from ASCs? iii) Which function(s) is/are regulated by intracellular ROS generation? In addition, the antioxidant/antiapoptotic effect of ASCs is briefly introduced. EXPERT OPINION: Whether ROS is harmful or beneficial is primarily a question of dosage. Low or moderate ROS generation increases the proliferation, migration and regenerative potential of ASCs. Therefore, it is beneficial to expose ASCs to moderate oxidative stress during manipulation. The addition of a ROS donor in culture can reduce the cost for the expansion of ASCs and a ROS preconditioning can enhance the regenerative potential of ASCs. PMCID: PMC3371372 PMID: 21981031 [PubMed - indexed for MEDLINE] 571. Biochim Biophys Acta. 2012 May;1821(5):852-7. doi: 10.1016/j.bbalip.2011.09.010. Epub 2011 Sep 25. Fatty acid transport proteins, implications in physiology and disease. Kazantzis M(1), Stahl A. Author information: (1)Metabolic Biology, NST, UC Berkeley, Berkeley, CA 94720, USA. Uptake of long-chain fatty acids plays pivotal roles in metabolic homeostasis and human physiology. Uptake rates must be controlled in an organ-specific fashion to balance storage with metabolic needs during transitions between fasted and fed states. Many obesity-associated diseases, such as insulin resistance in skeletal muscle, cardiac lipotoxicity, and hepatic steatosis, are thought to be driven by the overflow of fatty acids from adipose stores and the subsequent ectopic accumulation of lipids resulting in apoptosis, ER stress, and inactivation of the insulin receptor signaling cascade. Thus, it is of critical importance to understand the components that regulate the flux of fatty acid between the different organ systems. Cellular uptake of fatty acids by key metabolic organs, including the intestine, adipose tissue, muscle, heart, and liver, has been shown to be protein mediated and various unique combinations of fatty acid transport proteins (FATPs/SLC27A1-6) are expressed by all of these tissues. Here we review our current understanding of how FATPs can contribute to normal physiology and how FATP mutations as well as hypo- and hypermorphic changes contribute to disorders ranging from cardiac lipotoxicity to hepatosteatosis and ichthyosis. Ultimately, our increasing knowledge of FATP biology has the potential to lead to the development of new diagnostic tools and treatment options for some of the most pervasive chronic human disorders. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease. Copyright © 2011 Elsevier B.V. All rights reserved. PMCID: PMC3274620 PMID: 21979150 [PubMed - indexed for MEDLINE] 572. Atherosclerosis. 2012 Mar;221(1):2-11. doi: 10.1016/j.atherosclerosis.2011.09.003. Epub 2011 Sep 9. The use of THP-1 cells as a model for mimicking the function and regulation of monocytes and macrophages in the vasculature. Qin Z(1). Author information: (1)Division of Vascular Surgery, Department of Surgery, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States. qinz@uthscsa.edu Since their establishment thirty years ago, THP-1 cells have become one of most widely used cell lines to investigate the function and regulation of monocytes and macrophages in the cardiovascular system. However, because this cell line was derived from the blood of a patient with acute monocytic leukemia, the extent to which THP-1 cells mimic monocytes and macrophages in the vasculature is not entirely known. This article serves as a meaningful attempt to address this question by reviewing the recent publications. The interactions between THP-1 cells and various vascular cells (such as endothelial cells, smooth muscle cells, adipocytes, and T cells) provide insight into the roles of the interconnection of monocytes-macrophages with other vascular cells during vascular inflammation, particularly atherogenesis and obesity. Transcriptome, microRNA profile, and histone modifications of THP-1 cells shed new light on the regulatory mechanism of the monocytes-macrophages in response to various inflammatory mediators, such as oxidized low density lipoprotein, lipopolysaccharide, and glucose. These studies hint that under certain defined conditions, THP-1 cells not only resemble primary monocytes-macrophages isolated from healthy donors or donors with disease, such as diabetes mellitus, but also mimic the in situ alteration of macrophages in the adipose tissue of obese subjects and in atherosclerotic lesions. A potential trajectory is to use this cell line to study the novel molecular mechanisms in monocytes and macrophages in relation to the physiology and pathophysiology of the cardiovascular system, however, the conclusion of studies employing THP-1 cells requires further verification using primary cells and/or in vivo models to be generalized to monocytes and macrophages. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 21978918 [PubMed - indexed for MEDLINE] 573. Clin Exp Pharmacol Physiol. 2012 Feb;39(2):168-78. doi: 10.1111/j.1440-1681.2011.05623.x. Leptin and the regulation of endothelial function in physiological and pathological conditions. Bełtowski J(1). Author information: (1)Department of Pathophysiology, Medical University, Lublin, Poland. jerzy.beltowski@umlub.pl Obesity and the accompanying metabolic syndrome are among the most important causes of cardiovascular pathologies associated with endothelial dysfunction, such as arterial hypertension and atherosclerosis. This detrimental effect of obesity is mediated, in part, by excessive production of the adipose tissue hormone leptin. Under physiological conditions leptin induces endothelium-dependent vasorelaxation by stimulating nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). Leptin activates endothelial NO synthase (eNOS) through a mechanism involving AMP-activated protein kinase (AMPK) and protein kinase B/Akt, which phosphorylates eNOS at Ser(1177) , increasing its activity. Under pathological conditions, such as obesity and metabolic syndrome, the NO-mediated vasodilatory effect of leptin is impaired. Resistance to the acute NO-mimetic effect of leptin is accounted for by chronic hyperleptinaemia and may result from different mechanisms, such as downregulation of leptin receptors, increased levels of circulating C-reactive protein, oxidative stress and overexpression of suppressor of cytokine signalling-3. In short-lasting obesity, impaired leptin-induced NO production is compensated by EDHF; however, in advanced metabolic syndrome, the contribution of EDHF to the haemodynamic effect of leptin becomes inefficient. Resistance to the vasodilatory effects of leptin may contribute to the development of arterial hypertension owing to unopposed stimulation of the sympathetic nervous system by this hormone. © 2011 The Author. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd. PMID: 21973116 [PubMed - indexed for MEDLINE] 574. J Diabetes Investig. 2011 Oct 7;2(5):333-40. doi: 10.1111/j.2040-1124.2011.00133.x. Adipocytes as a vehicle for ex vivo gene therapy: Novel replacement therapy for diabetes and other metabolic diseases. Kuroda M(1), Bujo H(2), Aso M(3), Saito Y(4). Author information: (1)Center for Advanced Medicine, Chiba University Hospital. (2)Department of Genome Research and Clinical Application, Graduate School of Medicine. (3)CellGenTech, Inc., Chiba, Japan. (4)Chiba University. Because of its availability and recent advances in cell biology, adipose tissue is now considered an ideal target site for the preparation of recipient cells and for the transplantation of gene-transduced cells for supplementation of therapeutic proteins. Inherited or acquired serum protein deficiencies are the ideal targets for gene therapy. However, to develop an effective ex vivo gene therapy-based protein replacement treatment, the requirements for the recipient cells are different from those for standard gene therapy that is intended to correct the function of the recipient cells themselves. To meet the requirements for such a therapeutic strategy, recent in vitro and animal model studies have developed new methods for the preparation, culture, expansion and manipulation of adipose cells using advanced gene transduction methods and transplantation scaffolds. In this short review, we introduce the progress made in novel adipose tissue-based therapeutic strategies for the treatment of protein deficiencies by our group and other investigators, and describe their future applications for diabetes and other metabolic diseases. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00133.x, 2011). PMCID: PMC4019298 PMID: 24843509 [PubMed] 575. Circ J. 2011;75(11):2522-31. Epub 2011 Oct 5. AIMing at metabolic syndrome. -Towards the development of novel therapies for metabolic diseases via apoptosis inhibitor of macrophage (AIM).-. Miyazaki T(1), Kurokawa J, Arai S. Author information: (1)Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan. tm@m.u-tokyo.ac.jp Metabolic syndrome (MetS) is a cascade of metabolic diseases, starting with obesity and progressing to atherosclerosis, and is often fatal because of serious cardiovascular problems such as heart/brain infarction and hemorrhage. Accumulating evidence has revealed a critical involvement of inflammatory responses triggered by lesional macrophages in the pathogenesis of MetS. Importantly, we found that macrophages are associated with disease progression, not only in the induction of inflammation but also in the production of apoptosis inhibitor of macrophages (AIM), which we initially identified as a soluble factor expressed by macrophages. In atherosclerotic plaques, AIM is highly expressed by foam macrophages and inhibits apoptosis of these cells, which results in the accumulation of macrophages, causing inflammatory responses within the lesion, and ultimately disease progression. In adipose tissue, macrophage-derived AIM is incorporated into adipocytes through CD36-mediated endocytosis, thereby reducing the activity of cytosolic fatty acid synthase. This unique response stimulates lipolysis, resulting in a decrease in adipocyte size, which is physiologically relevant to the prevention of obesity. The lipolytic response also stimulates inflammation of adipocytes in association with the induction of metabolic disorders subsequent to obesity. Thus, AIM is involved in the progression of MetS in both an advancing and inhibitory fashion. Regulation of AIM could therefore be therapeutically applicable for MetS. PMID: 21970839 [PubMed - indexed for MEDLINE] 576. J Mammary Gland Biol Neoplasia. 2011 Dec;16(4):305-22. doi: 10.1007/s10911-011-9232-2. Epub 2011 Oct 4. Functional adaptations of the transcriptome to mastitis-causing pathogens: the mammary gland and beyond. Loor JJ(1), Moyes KM, Bionaz M. Author information: (1)Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. jloor@illinois.edu Application of microarrays to the study of intramammary infections in recent years has provided a wealth of fundamental information on the transcriptomics adaptation of tissue/cells to the disease. Due to its heavy toll on productivity and health of the animal, in vivo and in vitro transcriptomics works involving different mastitis-causing pathogens have been conducted on the mammary gland, primarily on livestock species such as cow and sheep, with few studies in non-ruminants. However, the response to an infectious challenge originating in the mammary gland elicits systemic responses in the animal and encompasses tissues such as liver and immune cells in the circulation, with also potential effects on other tissues such as adipose. The susceptibility of the animal to develop mastitis likely is affected by factors beyond the mammary gland, e.g. negative energy balance as it occurs around parturition. Objectives of this review are to discuss the use of systems biology concepts for the holistic study of animal responses to intramammary infection; providing an update of recent work using transcriptomics to study mammary and peripheral tissue (i.e. liver) as well as neutrophils and macrophage responses to mastitis-causing pathogens; discuss the effect of negative energy balance on mastitis predisposition; and analyze the bovine and murine mammary innate-immune responses during lactation and involution using a novel functional analysis approach to uncover potential predisposing factors to mastitis throughout an animal's productive life. PMID: 21968536 [PubMed - indexed for MEDLINE] 577. Int J Biochem Cell Biol. 2011 Dec;43(12):1651-4. doi: 10.1016/j.biocel.2011.09.006. Epub 2011 Sep 28. Epicardial fat: from the biomolecular aspects to the clinical practice. Iacobellis G(1), Malavazos AE, Corsi MM. Author information: (1)Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami, Miller School of Medicine, 1400 NW 10th Ave, Dominion Tower Suite 805-807, Miami, FL 33136, USA. giacobellis@med.miami.edu Epicardial fat is the visceral fat depot of heart. It is a metabolically active organ with anatomical and functional contiguity to the myocardium. A dichotomous role has been attributed to the epicardial fat. Under physiological conditions, epicardial fat displays biochemical and thermogenic cardio-protective properties. Under pathological circumstances epicardial fat can locally affect the heart and coronary arteries through vasocrine or paracrine secretion of pro-inflammatory cytokines. Epicardial fat can be measured with imaging techniques. Epicardial fat thickness reflects intra-abdominal and myocardial fat and correlates with metabolic syndrome and coronary artery disease. Epicardial fat measurement may play a role in the stratification of the cardio-metabolic risk and serve as therapeutic target. Weight loss and anti-inflammatory drugs targeting the fat may modulate epicardial fat. Because epicardial and myocardial tissues share the same coronary arterial supply it is reasonable to hypothesize that improved local vascularisation may resume epicardial fat to its physiological role. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 21967993 [PubMed - indexed for MEDLINE] 578. Nutr Rev. 2011 Oct;69(10):599-612. doi: 10.1111/j.1753-4887.2011.00414.x. Effect of diet on adiponectin levels in blood. Silva FM(1), de Almeida JC, Feoli AM. Author information: (1)Endocrine Division, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil. Dietary management has been considered an alternative means of modulating adiponectin levels. The purpose of this review is to examine the scientific evidence regarding the effect of diet on adiponectin levels in blood. Clinical trials were selected from Medline until April 2010 using the following MeSH terms: adipokines OR adiponectin AND diet OR lifestyle. A total of 220 articles were identified in the initial search, and 52 studies utilizing three different methods of dietary management were included in the present review: low-calorie diets (n = 9 studies), modification of diet composition (n = 33), and diet plus exercise (n = 10). Daily intake of fish or omega-3 supplementation increased adiponectin levels by 14-60%. Weight loss achieved with a low-calorie diet plus exercise increased adiponectin levels in the range of 18-48%. A 60-115% increase in adiponectin levels was obtained with fiber supplementation. In conclusion, dietary management can be an effective therapeutic means of increasing adiponectin levels. Studies investigating different forms of adiponectin and changes in the types of adipose tissue are necessary in order to elucidate the mechanisms involved in the modulation of adiponectin levels. © 2011 International Life Sciences Institute. PMID: 21967160 [PubMed - indexed for MEDLINE] 579. J Anim Sci. 2012 Mar;90(3):942-9. doi: 10.2527/jas.2011-4616. Epub 2011 Sep 30. Meat Science and Muscle Biology Symposium: the influence of extracellular matrix on intramuscular and extramuscular adipogenesis. Hausman GJ(1). Author information: (1)Poultry Processing and Swine Physiology Research, ARS, Richard B. Russell Research Center, USDA, Athens, GA 30605, USA. Gary.Hausman@ars.usda.gov The extracellular matrix (ECM) and specific ECM components can have a major influence on cell growth, development, and phenotype. The influence of the ECM and ECM components on adipogenesis in vivo and in vitro will be reviewed in this paper. Engelbreth-Holm-Swarm substratum and laminin per se markedly increased attachment, spreading, and hypertrophy of preadipocytes in serum-free primary cultures of porcine adipose tissue stromal-vascular cells. Furthermore, primary cultures of stromal-vascular cells showed that preadipocytes express ECM components after preadipocyte recruitment. Staining for plant lectins, type IV collagen, and laminin in fetal pig adipose tissue demonstrates that adipocyte reactivity for laminin was strong throughout fetal development and was similar for developing adipocytes and vasculature. However, lectin binding and type IV collagen reactivity of blood vessels preceded that for adipocytes. Therefore, these studies indicated that the ECM and in particular laminin may play a critical role in morphological aspects of preadipocyte development. Specific inhibitors and modulators of collagen synthesis have been used to evaluate the role of collagens in the differentiation of bovine intramuscular preadipocytes (BIP) and other preadipocyte cell lines. Triglyceride accretion of BIP cells was inhibited by a general inhibitor of collagen biosynthesis, whereas specific inhibitors or modulators of type IV collagen inhibited 3T3-L1 cell differentiation. Further study revealed that compared with collagens types I to IV, type V and VI collagens have an important and active role in BIP adipogenesis. The growth of intramuscular bovine adipose tissue may be dependent on collagen newly synthesized and organized by the adipocytes per se. The role of extracellular or ECM proteolysis in regulating adipogenesis also will be reviewed in this paper. Many members of the matrix metalloproteinase (MMP) family are expressed by adipocytes, and specific inhibition of MMP-9 greatly reduces adipogenesis in vitro. Possibly, MMP and other proteases regulate turnover of key adipocyte ECM proteins that are involved in the regulation of preadipocyte proliferation and differentiation. PMID: 21965449 [PubMed - indexed for MEDLINE] 580. Acta Diabetol. 2011 Dec;48(4):257-73. doi: 10.1007/s00592-011-0333-6. Epub 2011 Oct 2. Gut microbiota and diabetes: from pathogenesis to therapeutic perspective. Burcelin R(1), Serino M, Chabo C, Blasco-Baque V, Amar J. Author information: (1)Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France. remy.burcelin@inserm.fr More than several hundreds of millions of people will be diabetic and obese over the next decades in front of which the actual therapeutic approaches aim at treating the consequences rather than causes of the impaired metabolism. This strategy is not efficient and new paradigms should be found. The wide analysis of the genome cannot predict or explain more than 10-20% of the disease, whereas changes in feeding and social behavior have certainly a major impact. However, the molecular mechanisms linking environmental factors and genetic susceptibility were so far not envisioned until the recent discovery of a hidden source of genomic diversity, i.e., the metagenome. More than 3 million genes from several hundreds of species constitute our intestinal microbiome. First key experiments have demonstrated that this biome can by itself transfer metabolic disease. The mechanisms are unknown but could be involved in the modulation of energy harvesting capacity by the host as well as the low-grade inflammation and the corresponding immune response on adipose tissue plasticity, hepatic steatosis, insulin resistance and even the secondary cardiovascular events. Secreted bacterial factors reach the circulating blood, and even full bacteria from intestinal microbiota can reach tissues where inflammation is triggered. The last 5 years have demonstrated that intestinal microbiota, at its molecular level, is a causal factor early in the development of the diseases. Nonetheless, much more need to be uncovered in order to identify first, new predictive biomarkers so that preventive strategies based on pre- and probiotics, and second, new therapeutic strategies against the cause rather than the consequence of hyperglycemia and body weight gain. PMCID: PMC3224226 PMID: 21964884 [PubMed - indexed for MEDLINE] 581. Intern Emerg Med. 2013 Jun;8(4):283-9. doi: 10.1007/s11739-011-0700-x. Epub 2011 Oct 2. COPD and the metabolic syndrome: an intriguing association. Clini E(1), Crisafulli E, Radaeli A, Malerba M. Author information: (1)Department of Oncology, Haematology and Pneumology, University of Modena, Modena, Italy. enrico.clini@unimore.it Chronic Obstructive Pulmonary Disease (COPD) has been recently recognized as a condition involving more than the lungs. The presence of common factors in COPD and in other chronic extra-pulmonary diseases, as well as the co-existence of these conditions in the same adult individual, supports the hypothesis of a shared pathogenetic pathway. We will here review the interplay between coexisting COPD and the metabolic syndrome (MS), based on the most updated knowledge. We will discuss this clinical condition from the definition, to the pathophysiology and to the clinical implications. Basically, MS is more likely to be present in a COPD patients, and increased levels of circulatory pro-inflammatory proteins from both the lung and adipose tissue coincide in these patients. The relative impact of the coexisting COPD and MS may depend on several factors: the presence of physical inactivity and of systemic inflammation related to a smoking habit, sedentary lifestyle, airway inflammation and obstruction, adipose tissue and inflammatory marker activation. More studies will be required to elucidate the association between COPD and MS and to formulate individualized management approaches for this specific disease phenotype. PMID: 21964838 [PubMed - indexed for MEDLINE] 582. Mol Genet Metab. 2011 Dec;104(4):666-9. doi: 10.1016/j.ymgme.2011.08.035. Epub 2011 Sep 8. Shared genetic variance between the features of the metabolic syndrome: heritability studies. Povel CM(1), Boer JM, Feskens EJ. Author information: (1)Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands. Cecile.Povel@rivm.nl Heritability estimates of MetS range from approximately 10%-30%. The genetic variation that is shared among MetS features can be calculated by genetic correlation coefficients. The objective of this paper is to identify MetS feature as well as MetS related features which have much genetic variation in common, by reviewing the literature regarding genetic correlation coefficients. Identification of features, that have much genetic variation in common, may eventually facilitate the search for pleitropic genetic variants that may explain the clustering of MetS features. A PubMed search with the search terms "(metabolic syndrome OR insulin resistance syndrome) and (heritability OR genetic correlation OR pleiotropy)" was performed. Studies published before 7th July 2011, which presented genetic correlation coefficients between the different MetS features and genetic correlation coefficients of MetS and its features with adipose tissue-, pro-inflammatory and pro-thrombotic biomarkers were included. Nine twin and 19 family studies were included in the review. Genetic correlations varied, but were strongest between waist circumference and HOMA-IR (r(2): 0.36 to 0.79, median: 0.50), HDL cholesterol and triglycerides (r(2): -0.05 to -0.59, median -0.45), adiponectin and MetS (r(2): -0.32 to -0.43; median -0.38), adiponectin and insulin (r(2): -0.10 to -0.60; median -0.30) and between adiponectin and HDL-cholesterol (r(2): -0.22 to -0.51, median -0.29). In conclusion, heritability studies suggest that genetic pleiotropy exist especially between certain MetS features, as well as between MetS and adiponectin. Further research on actual genetic variants responsible for the genetic pleiotropy of these combinations will provide more insight into the etiology of MetS. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21963081 [PubMed - indexed for MEDLINE] 583. Clin Calcium. 2011 Oct;21(10):1489-95. doi: CliCa111014891495. [Relationship between metabolic syndrome and urinary stone disease]. [Article in Japanese] Yamaguchi S(1). Author information: (1)Department of Urology, Hokkaido Social Welfare Association Furano Hospital, Japan. Epidemiologically, there are many same characteristics among patients with urolithiasis, life-style related diseases and metabolic syndrome. In a comparison with the major urological diseases, the patients with stone disease have the largest amount of visceral fat on computerized tomography. The patients who finally had a diagnosis of metabolic syndrome in urolithiasis were 43% of men and female 31%. The clinical features of the patients include increased urinary oxalate excretion, abnormal uric acid metabolism, and acidic urine. The basic studies by the animal experiments suggest that there is a close relationship between urolithiasis and metabolic syndrome. After the treatment of the urinary stone, it is very important to make a long-term follow-up by not only the prevention of recurrent stone episode but also life style management and medical treatment for metabolic syndrome. PMID: 21960234 [PubMed - indexed for MEDLINE] 584. Korean J Gastroenterol. 2011 Sep 25;58(3):125-32. doi: 10.4166/kjg.2011.58.3.125. [Stem cell properties of therapeutic potential]. [Article in Korean] Seo GS(1). Author information: (1)Department of Internal Medicine, Digestive Disease Research Institute, Wonkwang University College of Medicine, Iksan, Korea. Stem cell research is a innovative technology that focuses on using undifferentiated cells able to self-renew through the asymmetrical or symmetrical divisions. Three types of stem cells have been studied in laboratory including embryonic stem cell, adult stem cells and induced pluripotent stem cells. Embryonic stem cells are pluripotent stem cells derived from the inner cell mass and it can give rise to any fetal or adult cell type. Adult stem cells are multipotent, have the ability to differentiate into a limited number of specialized cell types, and have been obtained from the bone marrow, umbilical cord blood, placenta and adipose tissue. Stem cell therapy is the most promising therapy for several degenerative and devastating diseases including digestive tract disease such as liver failure, inflammatory bowel disease, Celiac sprue, and pancreatitis. Further understanding of biological properties of stem cells will lead to safe and successful stem cell therapies. (Korean J Gastroenterol 2011;58: 125-132). PMID: 21960099 [PubMed - indexed for MEDLINE] 585. Maturitas. 2011 Dec;70(4):322-7. doi: 10.1016/j.maturitas.2011.09.002. Epub 2011 Sep 29. Adipokines and stroke: a review of the literature. Savopoulos C(1), Michalakis K, Apostolopoulou M, Miras A, Hatzitolios A. Author information: (1)International Centre for Circulatory Health, National Heart & Lung Institute, Imperial College, London, United Kingdom. c.savopoulos@imperial.ac.uk Stroke represents one of the most important menaces to public health. A number of modifiable and non-modifiable risk factors have been identified and studied in detail; among those, obesity, the new world epidemic, seems to be one of the most important in terms of prevention. The discovery of the secretory role of the adipose tissue and of adipokines has opened new fields of research. A number of studies have been published on their relation to cardiovascular risk and the potential of using them as prevention markers. In the present review the physiology of leptin, adiponectin and resistin is described and their role in the pathogenesis of stroke is examined. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 21958940 [PubMed - indexed for MEDLINE] 586. Int J Immunopathol Pharmacol. 2011 Jan-Mar;24(1 Suppl 2):45-50. Tendinopathy and inflammation: some truths. Del Buono A(1), Battery L, Denaro V, Maccauro G, Maffulli N. Author information: (1)Department of Orthopaedic and Trauma Surgery, Campus Biomedico University of Rome, Via Alvaro del Portillo, Rome, Italy. Overuse tendinopathies are a common cause of pain and disability in athletes. According to histological findings, it is a failed healing response to overuse tendon injury. In obesity, macrophages and mast cells migrate to adipose tissue, and the resulting decreased availability of immune circulating cells should be responsible for less effective immune responses to acute tendon injury. In diabetic patients, free glucose molecules attach to collagen, alter collagen solubility, increase resistance to enzymatic degradation, and impair cross linking, contributing to the subsequent development of chronic tendinopathy secondary to a failed healing response to a tendon insult. Prolonged systemic, low-grade inflammation and impaired insulin sensitivity act as a risk factor for a failed healing response after an acute tendon insult, and predispose to the development of chronic overuse tendinopathies. Further studies may reveal novel therapeutic treatment approaches. PMID: 21669137 [PubMed - indexed for MEDLINE] 587. Nat Rev Mol Cell Biol. 2011 Sep 28;12(11):722-34. doi: 10.1038/nrm3198. Forming functional fat: a growing understanding of adipocyte differentiation. Cristancho AG(1), Lazar MA. Author information: (1)Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. Adipose tissue, which is primarily composed of adipocytes, is crucial for maintaining energy and metabolic homeostasis. Adipogenesis is thought to occur in two stages: commitment of mesenchymal stem cells to a preadipocyte fate and terminal differentiation. Cell shape and extracellular matrix remodelling have recently been found to regulate preadipocyte commitment and competency by modulating WNT and RHO-family GTPase signalling cascades. Adipogenic stimuli induce terminal differentiation in committed preadipocytes through the epigenomic activation of peroxisome proliferator-activated receptor-γ (PPARγ). The coordination of PPARγ with CCAAT/enhancer-binding protein (C/EBP) transcription factors maintains adipocyte gene expression. Improving our understanding of these mechanisms may allow us to identify therapeutic targets against metabolic diseases that are rapidly becoming epidemic globally. PMID: 21952300 [PubMed - indexed for MEDLINE] 588. Am J Reprod Immunol. 2012 Jan;67(1):1-8. doi: 10.1111/j.1600-0897.2011.01069.x. Epub 2011 Sep 23. Immunomodulatory properties of mesenchymal stem cells: cytokines and factors. Soleymaninejadian E(1), Pramanik K, Samadian E. Author information: (1)Center for Biotechnology, Institute of Science and Technology, Jawaharlal Nehru Technological University, Hyderabad, India. ehsan.soleymaninejadian@gmail.com Mesenchymal stem cells (MSCs) are defined as undifferentiated cells that are capable of self renewal and differentiation into several cell types such as chondrocyte, adipocyte, osteocyte, myocyte, hepatocyte, and neuron-like cells. MSC can be isolated from bone marrow, umbilical cord blood, adipose tissue, placenta, periosteum, trabecular bone, synovium, skeletal muscle, and deciduous teeth. Immunomodulatory of MSCs is one of the important issues nowadays, because this aspect can be clinically applied for graft-versus-host and autoimmune diseases. In this review, we tried to discuss in detail about cytokines and factors such as members of the transforming growth factor superfamily (transforming growth factor-β), hepatic growth factors (HGF), prostaglandin E2 (PGE2), IL-10, indolamine 2,3-dioxygenase (IDO), nitric oxide (NO), heme oxygenase-1 (HO-1), and human leukocyte antigen-G (HLA-G) that are involved in immunomodulatory of MSCs. © 2011 John Wiley & Sons A/S. PMID: 21951555 [PubMed - indexed for MEDLINE] 589. Obes Rev. 2012 Jan;13(1):68-91. doi: 10.1111/j.1467-789X.2011.00931.x. Epub 2011 Sep 26. A systematic review and meta-analysis of the effect of aerobic vs. resistance exercise training on visceral fat. Ismail I(1), Keating SE, Baker MK, Johnson NA. Author information: (1)Discipline of Exercise and Sport Science, University of Sydney, Sydney, New South Wales, Australia. It is increasingly recognized that the location of excess adiposity, particularly increased deposition of visceral adipose tissue (VAT), is important when determining the adverse health effects of overweight and obesity. Exercise therapy is an integral component of obesity management, but the most potent exercise prescription for VAT benefit is unclear. We aimed to evaluate the independent and synergistic effects of aerobic exercise (AEx) and progressive resistance training (PRT) and to directly compare the efficacy of AEx and PRT for beneficial VAT modulation. A systematic review and meta-analysis was performed to assess the efficacy of exercise interventions on VAT content/volume in overweight and obese adults. Relevant databases were searched to November 2010. Included studies were randomized controlled designs in which AEx or PRT in isolation or combination were employed for 4 weeks or more in adult humans, where computed tomography (CT) or magnetic resonance imaging (MRI) was used for quantification of VAT pre- and post-intervention. Of the 12196 studies from the initial search, 35 were included. After removal of outliers, there was a significant pooled effect size (ES) for the comparison between AEx therapy and control (-0.33, 95% CI: -0.52 to -0.14; P < 0.01) but not for the comparison between PRT therapy and control (0.09, 95% CI: -0.17 to -0.36; P = 0.49). Of the available nine studies which directly compared AEx with PRT, the pooled ES did not reach statistical significance (ES = 0.23, 95% CI: -0.02 to 0.50; P = 0.07 favouring AEx). The pooled ES did not reach statistical significance for interventions that combined AEx and PRT therapy vs. control (-0.28, 95% CI: -0.69 to 0.14; P = 0.19), for which only seven studies were available. These data suggest that aerobic exercise is central for exercise programmes aimed at reducing VAT, and that aerobic exercise below current recommendations for overweight/obesity management may be sufficient for beneficial VAT modification. Further investigation is needed regarding the efficacy and feasibility of multi-modal training as a means of reducing VAT. © 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 21951360 [PubMed - indexed for MEDLINE] 590. Obes Rev. 2011 Oct;12(10):866-83. doi: 10.1111/j.1467-789X.2011.00909.x. The search for compounds that stimulate thermogenesis in obesity management: from pharmaceuticals to functional food ingredients. Dulloo AG(1). Author information: (1)Department of Medicine/Physiology, University of Fribourg, Fribourg, Switzerland. abdul.dulloo@unifr.ch The concept of managing obesity through the stimulation of thermogenesis is currently a focus of considerable attention by the pharmaceutical, nutraceutical and functional food industries. This paper first reviews the landmark discoveries that have fuelled the search for thermogenic anti-obesity products that range from single-target drugs to multi-target functional foods. It subsequently analyses the thermogenic and fat-oxidizing potentials of a wide array of bioactive food ingredients which are categorized under methylxanthines, polyphenols, capsaicinoids/capsinoids, minerals, proteins/amino acids, carbohydrates/sugars and fats/fatty acids. The main outcome of this analysis is that the compounds or combination of compounds with thermogenic and fat-oxidizing potentials are those that possess both sympathomimetic stimulatory activity and acetyl-coA carboxylase inhibitory property, and are capable of targeting both skeletal muscle and brown adipose tissue. The thermogenic potentials of products so far tested in humans range from marginal to modest, i.e. 2-5% above daily energy expenditure. With an increasing number of bioactive food ingredients awaiting screening in humans, there is hope that this thermogenic potential could be safely increased to 10-15% above daily energy expenditure - which would have clinically significant impact on weight management, particularly in the prevention of obesity and in improving the long-term prognosis of post-slimming weight maintenance. © 2011 The Author. obesity reviews © 2011 International Association for the Study of Obesity. PMID: 21951333 [PubMed - indexed for MEDLINE] 591. Diabet Med. 2011 Dec;28(12):1445-54. doi: 10.1111/j.1464-5491.2011.03460.x. Current perspectives of insulin resistance and polycystic ovary syndrome. Pauli JM(1), Raja-Khan N, Wu X, Legro RS. Author information: (1)Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, PA 17033, USA. AIMS: To review the relationship between insulin resistance and polycystic ovary syndrome. METHODS: A literature review. RESULTS: Insulin resistance likely plays a central pathogenic role in polycystic ovary syndrome and may explain the pleiotropic presentation and involvement of multiple organ systems. Insulin resistance in the skeletal muscle of women with polycystic ovary syndrome involves both intrinsic and acquired defects in insulin signalling. The cellular insulin resistance in polycystic ovary syndrome has been further shown to involve a novel post-binding defect in insulin signal transduction. Treatment of insulin resistance through lifestyle therapy or with a diabetes drug has become mainstream therapy in women with polycystic ovary syndrome. However, effects with current pharmacologic treatment with metformin tend to be modest, with limited benefit as an agent to treat infertility. Insulin resistance contributes to increased risk for pregnancy complications, diabetes and cardiovascular disease risk profile in polycystic ovary syndrome, which is further exacerbated by obesity. While numerous studies demonstrate increased prevalence of cardiovascular disease risk factors in women with polycystic ovary syndrome, there are limited data showing that women with polycystic ovary syndrome are at increased risk for cardiovascular disease events. CONCLUSIONS: Insulin resistance is linked to polycystic ovary syndrome. Further study of lifestyle and pharmacologic interventions that reduce insulin resistance, such as metformin, are needed to demonstrate that they are effective in reducing the risk of diabetes, endometrial abnormalities and cardiovascular disease events in women with polycystic ovary syndrome. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK. PMID: 21950959 [PubMed - indexed for MEDLINE] 592. Diabetes. 2011 Oct;60(10):2441-9. doi: 10.2337/db11-0425. Fatty acids, obesity, and insulin resistance: time for a reevaluation. Karpe F(1), Dickmann JR, Frayn KN. Author information: (1)Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, U.K. fredrik.karpe@ocdem.ox.ac.uk PMCID: PMC3178283 PMID: 21948998 [PubMed - indexed for MEDLINE] 593. Peptides. 2011 Oct;32(10):2141-50. doi: 10.1016/j.peptides.2011.09.010. Epub 2011 Sep 16. A new look at the renin-angiotensin system--focusing on the vascular system. Nguyen Dinh Cat A(1), Touyz RM. Author information: (1)Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada. The renin-angiotensin system (RAS), critically involved in the control of blood pressure and volume homeostasis, is a dual system comprising a circulating component and a local tissue component. The rate limiting enzyme is renin, which in the circulating RAS derives from the kidney to generate Ang II, which in turn regulates cardiovascular function by binding to AT(1) and AT(2) receptors on cardiac, renal and vascular cells. The tissue RAS can operate independently of the circulating RAS and may be activated even when the circulating RAS is suppressed or normal. A functional tissue RAS has been identified in brain, kidney, heart, adipose tissue, hematopoietic tissue, gastrointestinal tract, liver, endocrine system and blood vessels. Whereas angiotensinsinogen, angiotensin converting enzyme (ACE), Ang I and Ang II are synthesized within these tissues, there is still controversy as to whether renin is produced locally or whether it is taken up from the circulation, possibly by the (pro)renin receptor. This is particularly true in the vascular wall, where expression of renin is very low. The exact function of the vascular RAS remains elusive, but may contribute to fine-tuning of vascular tone and arterial structure and may amplify vascular effects of the circulating RAS, particularly in pathological conditions, such as in hypertension, atherosclerosis and diabetes. New concepts relating to the vascular RAS have recently been elucidated including: (1) the presence of functionally active Ang-(1-7)-Mas axis in the vascular system, (2) the importance of the RAS in perivascular adipose tissue and cross talk with vessels, and (3) the contribution to vascular RAS of Ang II derived from immune and inflammatory cells within the vascular wall. The present review highlights recent progress in the RAS field, focusing on the tissue system and particularly on the vascular RAS. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21945916 [PubMed - indexed for MEDLINE] 594. Mol Cell Endocrinol. 2012 Mar 24;350(2):281-8. doi: 10.1016/j.mce.2011.09.011. Epub 2011 Sep 10. The role of the mineralocorticoid receptor in adipocyte biology and fat metabolism. Marzolla V(1), Armani A, Zennaro MC, Cinti F, Mammi C, Fabbri A, Rosano GM, Caprio M. Author information: (1)San Raffaele Sulmona, Sulmona (AQ), Italy. Aldosterone controls blood pressure by binding to the mineralocorticoid receptor (MR), a ligand-activated transcription factor which regulates critical genes controlling salt and water homeostasis in the kidney. In recent years, inappropriate MR activation has been shown to trigger deleterious responses in various tissues, including vessels, heart and brain, hence promoting vascular inflammation, cardiovascular remodeling, endothelial dysfunction, and oxidative stress. Moreover, epidemiological studies have shown a clear association between aldosterone levels and the incidence of metabolic syndrome. In particular, recent work has revealed functional MRs in adipose tissue, where they mediate the effects of aldosterone and glucocorticoids, displaying important and specific functions involving adipose differentiation, expansion and proinflammatory capacity. This recent evidence finally moved MR out of the shadow of the glucocorticoid receptor (GR), which had previously been considered the only player mediating corticosteroid action in adipose tissue. This has opened a new era of research focusing on the complexity and selectivity of MR function in adipocyte biology. The aim of this review is to summarize the latest concepts on the role of MR in white and brown adipocytes, and to discuss the potential benefits of tissue-selective MR blockade in the treatment of obesity and metabolic syndrome. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 21945603 [PubMed - indexed for MEDLINE] 595. Integr Comp Biol. 2011 Oct;51(4):505-13. doi: 10.1093/icb/icr019. Epub 2011 May 5. Leptin as a physiological mediator of energetic trade-offs in ecoimmunology: implications for disease. French SS(1), Dearing MD, Demas GE. Author information: (1)Department of Biology, Utah State University, Logan, UT 84322-5305, USA. sfrench@biology.usu.edu Organisms must distribute sufficient energy among different and often competing physiological systems. This task can become challenging, however, as resources are often limiting, resulting in energetic trade-offs. For example, energetically based trade-offs between the reproductive and immune systems are common across taxa, yet the regulatory mechanisms underlying these trade-offs remain unclear. The adipose tissue hormone leptin is an ideal candidate for the modulation of energetic trade-offs between different physiological systems as this hormone serves as a gage of fat reserves and also modulates a range of physiological activities including the reproductive and immune processes. This article presents a review of the evidence for the role of leptin as a modulator of energetic trade-offs with the immune system and suggests its importance in disease ecology. In addition, we provide a case study of the ornate tree lizard (Urosaurus ornatus), testing whether leptin is involved in mediating a well-documented influence of energy state on the trade-off between reproductive activity and immune function. Overall, the combined results suggest that leptin serves as a proximate endocrine signal of available energy to the immune system, and therefore likely to affect susceptibility to diseases. PMID: 21940777 [PubMed - indexed for MEDLINE] 596. Physiol Behav. 2012 Apr 12;106(1):22-8. doi: 10.1016/j.physbeh.2011.09.011. Epub 2011 Sep 14. Maternal obesity, metabolic disease, and allostatic load. Power ML(1), Schulkin J. Author information: (1)Department of Research, American College of Obstetricians and Gynecologists, 409 12th St SW, Washington, DC 20024, United States. mpower@acog.org Maternal obesity is a risk factor for many metabolic diseases for the mother, both during gestation and post partum, and for the child in later life. Obesity and pregnancy both result in altered physiological states, significantly different from the state of the non-obese, non-reproductive adult female. The concept of allostasis may be more appropriate for understanding the physiology of both pregnancy and obesity. In pregnancy these altered physiological states are adaptive, in both the evolutionary and physiological senses of the word. Obesity, however, represents a state outside of the adaptive evolutionary experience of our species. In both cases the altered physiological state derives at least in part from signals from an active endocrine organ. In obesity this is adipose tissue, and in pregnancy it is the placenta. The signaling molecules from adipose tissue and placenta all have multiple functions and can affect multiple organ systems. Placenta acts as a central regulator of metabolism for both the maternal and fetal compartments, in essence acting as a "third brain" during pregnancy. Both adipose tissue and placenta express many proinflammatory cytokines; obesity and pregnancy are states of low-grade inflammation. Both obesity and pregnancy are also states of insulin resistance, and maternal obesity is associated with fetal insulin resistance. We argue that obesity during pregnancy leads to sustained and inappropriate activation of normally adaptive regulatory circuits due in part to competing and conflicting signaling from adipose tissue and placenta. This results in allostatic load, leading to the eventual break down of regulatory mechanisms. The result is impaired metabolic function of the mother, and altered development of metabolic systems and potentially altered neural appetite circuits for the offspring. Copyright © 2011 Elsevier Inc. All rights reserved. PMID: 21939681 [PubMed - indexed for MEDLINE] 597. Pol Merkur Lekarski. 2011 Aug;31(182):118-21. [Metabolic obesity in normal weight individuals and cardiovascular disease]. [Article in Polish] Nowak M(1), Grzywa M. Author information: (1)Szpital Wojewódzki Nr 2 im. św. Jadwigi Królowej w Rzeszowie, Oddział Kardiologii z Pododdzialem Ostrych Zespołów Wierńcowych i z Ośrodkiem Implantacji Rozruszników Serca. nmarys@poczta.onet.pl Since thirty years there is growing interest in normal weight individuals who have metabolic disorders. These individuals are identified as metabolically obese but normal weight (MONW). Insulin resistance, elevated arterial blood pressure, abnormal lipid profile and sedentary style of live are known risk factors of atherosclerosis in general population. On the other hand, increased amount of visceral and subcutaneous abdominal adipose tissue is associated with increased risk of metabolic abnormalities. These abnormalities existing in MONW individuals exert an effect on increased risk of cardiovascular diseases and non insulin dependent diabetes mellitus. Identification of individuals at risk is difficult not only because no clear definition of MONW is established but also due to common belief that the cardiovascular risk in nonobese is low. The awareness of association of metabolic abnormalities in MONW with atherosclerosis should argue physicians into early screening and modification of cardiovascular risk factors in nonobese individuals. PMID: 21936351 [PubMed - indexed for MEDLINE] 598. Int J Obes (Lond). 2011 Sep;35 Suppl 3:S7-15. doi: 10.1038/ijo.2011.141. Bariatric surgery, adipose tissue and gut microbiota. Clément K(1). Author information: (1)Cardiometabolism Division, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France. karine.clement@psl.aphp.fr Human obesity can be viewed as a set of phenotypes that evolve over time in a sequence of stages that need to be precisely measured. Environmental, behavioral, genetic and biological factors interact to cause obesity. This presentation provides a clinical viewpoint on some biological processes that may explain some of the stages in the development of human obesity, its chronic maintenance and occurrence of complications, with a focus on brain structures, genetics, the profound alterations in adipose tissue biology and gut microbiota components. Roux-en-Y gastric bypass surgery is an increasingly effective model to study in this context because it leads to major improvements in glucose and lipid homeostasis and to the amelioration of some systemic inflammatory markers. PMID: 21912389 [PubMed - indexed for MEDLINE] 599. Horm Res Paediatr. 2011;76 Suppl 3:56-8. doi: 10.1159/000330165. Epub 2011 Sep 7. Metabolic benefits of growth hormone therapy in idiopathic short stature. Dahlgren J(1). Author information: (1)Göteborg Paediatric Growth Research Centre, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden. The US Food and Drug Administration approved use of recombinant human growth hormone (GH) for the treatment of idiopathic short stature (ISS) in children; however, few studies have evaluated metabolic outcomes. This article addresses whether children with ISS treated with GH experience the same metabolic benefits as children with GH deficiency (GHD) treated with GH. A systematic review of all published studies of GH treatment in children with ISS that included data on metabolic outcomes identified five studies. No meta-analysis has been performed.Studies show a metabolic response to GH treatment in children with ISS similar to that observed in children with GHD; effects include a transient decrease in insulin sensitivity and a dose-dependent increase in insulin-like growth factor I. However, no increase in the risk of diabetes was found. Children with ISS seem to benefit from GH treatment in terms of height gain without any severe negative metabolic outcomes. Copyright © 2011 S. Karger AG, Basel. PMID: 21912170 [PubMed - indexed for MEDLINE] 600. Curr Opin Support Palliat Care. 2011 Dec;5(4):356-60. doi: 10.1097/SPC.0b013e32834bde0e. Lipid mobilization in cachexia: mechanisms and mediators. Bing C(1). Author information: (1)Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK. bing@liverpool.ac.uk PURPOSE OF REVIEW: Extensive loss of body fat is considered as a hallmark of cancer cachexia which affects the quality of life and shortens survival. Evidence suggests that increased lipid mobilization has a central role in adipose tissue wasting. This review summarizes recent progress, with a particular focus on the mechanisms and the potential mediators of lipid mobilization in cachexia. RECENT FINDINGS: Accelerated fat loss begins at around 7 months before death and predicts survival in advance cancer patients. Adipose tissue remodelling with reduced lipid storage is evident in cancer patients with cachexia. Enhanced lipolysis regulated by adipose triglyceride lipase and hormone-sensitive lipase could be essential for triacylglycerol degradation. In addition to cytokines, other factors such as zinc-α2-glycoprotein (ZAG) are implicated in adipose atrophy. ZAG expression and release by adipose tissue is upregulated in weight-losing cancer patients, and serum ZAG has been shown as a marker for pancreatic cancer-associated cachexia, suggesting that ZAG may function locally and systemically to stimulate lipid mobilization. SUMMARY: Recent progress in clinical and mechanistic studies provides some new insights into the pathogenesis of adipose atrophy in cachexia. Further studies to unravel the mechanisms and mediators may lead to novel pharmacological targets to ameliorate cachexia syndrome. PMID: 21934502 [PubMed - indexed for MEDLINE] 601. Hellenic J Cardiol. 2011 Jul-Aug;52(4):327-36. Update on the cardiovascular risk in obesity: endocrine and paracrine role of the adipose tissue. Schäfer K(1), Konstantinides SV. Author information: (1)Department of Cardiology and Pulmonary Medicine, Georg August University, Göttingen, Germany. katrin.schaefer@med.uni-goettingen.de PMID: 21933764 [PubMed - indexed for MEDLINE] 602. Sheng Li Ke Xue Jin Zhan. 2011 Jun;42(3):169-74. [Research progress in regulation of adiponectin receptors expression]. [Article in Chinese] Cui XB(1), Han Y, Li L, Wu LL. Author information: (1)Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. Adiponectin is an adipokine mainly secreted by adipose tissue, which exerts insulin-sensitivity, anti-inflammation, anti-atherosclerosis and cardio-protective effects. These biological effects are mediated by adiponectin receptor 1 and adiponectin receptor 2. Expression levels of adiponectin receptor affect activation of downstream signaling pathway and biological effects. Research about regulation factors of adiponectin receptor expression contributes discovering the molecular mechanism and provides new ideas for the prevention and treatment of the metabolism disorder and cardiovascular diseases. PMID: 21932513 [PubMed - indexed for MEDLINE] 603. Nat Rev Endocrinol. 2011 Sep 20;8(1):11-21. doi: 10.1038/nrendo.2011.151. Management of the metabolic effects of HIV and HIV drugs. Brown TT(1), Glesby MJ. Author information: (1)Division of Endocrinology and Metabolism, Johns Hopkins University, 1830 East Monument Street, Baltimore, MD 21287, USA. tbrown27@jhmi.edu Morphologic and metabolic abnormalities, including subcutaneous adipose tissue wasting, central adipose tissue accumulation, dyslipidemia and disorders of glucose metabolism are common among HIV-infected patients receiving highly active antiretroviral therapy (HAART) and contribute to the risk of cardiovascular disease in this population. The pathogenesis of these disorders is due to complicated interactions between effects of chronic HIV infection, HAART medications and patient factors, including genetic susceptibility. HAART has transformed HIV into a chronic condition for many patients and as a result the majority of HIV-infected patients in many areas of the developed world will soon be aged ≥50 years. Given that metabolic and cardiovascular diseases increase with aging, knowledge of the optimal management of these conditions is essential for practitioners caring for HIV-infected patients, including endocrine subspecialists. This Review highlights the clinical management of these disorders, focusing on the latest evidence regarding the efficacy of treatment strategies, newly available medications and potential interactions between HAART medications and medications used to treat metabolic disorders. PMCID: PMC3371609 PMID: 21931374 [PubMed - indexed for MEDLINE] 604. Acta Pol Pharm. 2011 Sep-Oct;68(5):803-4. Insights into the antihypertensive effects of conjugated linoleic acid (CLA) in different rodent models. Khan SA(1). Author information: (1)LECOM School of Pharmacy, 1858, West Grandview Blvd., Erie, PA 16509 USA. seherkhan@lecom.edu PMID: 21928728 [PubMed - indexed for MEDLINE] 605. J Anim Sci. 2012 Jun;90(6):1835-45. doi: 10.2527/jas.2011-4516. Epub 2011 Sep 16. Ruminant Nutrition Symposium: Optimizing Performance of the Offspring: nourishing and managing the dam and postnatal calf for optimal lactation, reproduction, and immunity. Bach A(1). Author information: (1)Department of Ruminant Production, Institute for Research and Technology in Agrifood, Barcelona, Spain. alex.bach@irta.es For several mammalian species, it has been shown that fetal and early postnatal nutrition has a role in long-term lipid and glucose metabolism of the offspring, and it thus also may have consequences on milk yield in the dairy cow. For instance, high-energy diets during the last weeks of pregnancy may result in increased glycemia, which in turn, may alter fetal adipose tissue development. However, most research efforts on management and nutrition of dry cows have focused on minimizing metabolic disorders of the postpartum cow without devoting much attention to potential consequences for the offspring. Similarly, nutritional needs for proper placental development and early fetal growth have received little attention, despite the fact that alterations in placental and fetal development may alter expression of genes participating in homeorhesis of the offspring. Therefore, nutrition of the pregnant cow, both while lactating and dry, should also consider aspects of placental and fetal development that may affect health and performance of the progeny. Similarly, newborn calves and young heifers are fed to ensure a particular growth target without compromising mammary development, although data linking postnatal growth targets with future milk yield are scarce. However, milk yield not only depends on mammary development, but also on nutrient partitioning, which is regulated by the endocrine milieu. There are some periods of time during development where nutrition may have long-lasting effects on metabolic function and milk production. For instance, the first months of postnatal life seem to be critical because recent data from both ret