A Metabolomics-Based Investigation of the Effects of a Short-Term Body Weight Reduction Program in a Cohort of Adolescents with Obesity: A Prospective Interventional Clinical Study
[en] Metabolomics applied to assess the response to a body weight reduction program (BWRP) may generate valuable information concerning the biochemical mechanisms/pathways underlying the BWRP-induced cardiometabolic benefits. The aim of the present study was to establish the BWRP-induced changes in the metabolomic profile that characterizes the obese condition. In particular, a validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) targeted metabolomic approach was used to determine a total of 188 endogenous metabolites in the plasma samples of a cohort of 42 adolescents with obesity (female/male = 32/10; age = 15.94 ± 1.33 year; body mass index standard deviation score (BMI SDS) = 2.96 ± 0.46) who underwent a 3-week BWRP, including hypocaloric diet, physical exercise, nutritional education, and psychological support. The BWRP was capable of significantly improving body composition (e.g., BMI SDS, p < 0.0001), glucometabolic homeostasis (e.g., glucose, p < 0.0001), and cardiovascular function (e.g., diastolic blood pressure, p = 0.016). A total of 64 metabolites were significantly reduced after the intervention (at least p < 0.05), including 53 glycerophospholipids (23 PCs ae, 21 PCs aa, and 9 lysoPCs), 7 amino acids (tyrosine, phenylalanine, arginine, citrulline, tryptophan, glutamic acid, and leucine), the biogenic amine kynurenine, 2 sphingomyelins, and (free) carnitine (C0). On the contrary, three metabolites were significantly increased after the intervention (at least p < 0.05)—in particular, glutamine, trans-4-hydroxyproline, and the octadecenoyl-carnitine (C18:1). In conclusion, when administered to adolescents with obesity, a short-term BWRP is capable of changing the metabolomic profile in the plasma.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Rigamonti, Antonello E. ✱; University of Milan > Department of Clinical Sciences and Community Health
Frigerio, Gianfranco ✱; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Environmental Cheminformatics
Caroli, Diana; Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) > Experimental Laboratory for Auxo-Endocrinological Research
De Col, Alessandra; Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) > Experimental Laboratory for Auxo-Endocrinological Research
Cella, Silvano G.; University of Milan > Department of Clinical Sciences and Community Health
Sartorio, Alessandro; Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) > Experimental Laboratory for Auxo-Endocrinological Research
Fustinoni, Silvia; University of Milan > Department of Clinical Sciences and Community Health
✱ These authors have contributed equally to this work.
External co-authors :
yes
Language :
English
Title :
A Metabolomics-Based Investigation of the Effects of a Short-Term Body Weight Reduction Program in a Cohort of Adolescents with Obesity: A Prospective Interventional Clinical Study
Publication date :
19 January 2023
Journal title :
Nutrients
ISSN :
2072-6643
Publisher :
Multidisciplinary Digital Publishing Institute (MDPI), Basel, Switzerland
The research was funded by the Italian Ministry of Health. The two metabolomics kits used were purchased in the frame of the grant “Call Piattaforme 2018” by Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico. G.F. is currently supported by the Luxembourg National Research Fund (FNR) (project: A18/BM/12341006).
Di Cesare M. Sorić M. Bovet P. Miranda J.J. Bhutta Z. Stevens G.A. Laxmaiah A. Kengne A.P. Bentham J. The epidemiological burden of obesity in childhood: A worldwide epidemic requiring urgent action BMC Med. 2019 17 212 10.1186/s12916-019-1449-8 31760948
Jebeile H. Kelly A.S. O’Malley G. Baur L.A. Obesity in children and adolescents: Epidemiology, causes, assessment, and management Lancet Diabetes Endocrinol. 2022 10 351 365 10.1016/S2213-8587(22)00047-X 35248172
Rigamonti A.E. Bondesan A. Rondinelli E. Cella S.G. Sartorio A. The Role of Aspartate Transaminase to Platelet Ratio Index (APRI) for the Prediction of Non-Alcoholic Fatty Liver Disease (NAFLD) in Severely Obese Children and Adolescents Metabolites 2022 12 155 10.3390/metabo12020155 35208229
Rigamonti A.E. Caroli D. Grugni G. Cella S.G. Sartorio A. Frequent Medical Supervision Increases the Effectiveness of a Longitudinal Multidisciplinary Body Weight Reduction Program: A Real-World Experience in a Population of Children and Adolescents with Obesity Nutrients 2021 13 3362 10.3390/nu13103362 34684362
Rigamonti A.E. Tringali G. Micheli R. De Col A. Tamini S. Saezza A. Cella S.G. Sartorio A. Impact of a Three-Week in-Hospital Multidisciplinary Body Weight Reduction Program on Body Composition, Muscle Performance and Fatigue in a Pediatric Obese Population with or without Metabolic Syndrome Nutrients 2020 12 208 10.3390/nu12010208
Rigamonti A.E. Bollati V. Favero C. Albetti B. Caroli D. Abbruzzese L. Cella S.G. Sartorio A. Effect of a 3-Week Multidisciplinary Body Weight Reduction Program on the Epigenetic Age Acceleration in Obese Adults J. Clin. Med. 2022 11 4677 10.3390/jcm11164677 36012914
Lin X. Li H. Obesity: Epidemiology, Pathophysiology, and Therapeutics Front. Endocrinol. 2021 12 706978 10.3389/fendo.2021.706978
Hurtado A.M.D. Acosta A. Precision Medicine and Obesity Gastroenterol. Clin. N. Am. 2021 50 127 139 10.1016/j.gtc.2020.10.005
Rangel-Huerta O.D. Pastor-Villaescusa B. Gil A. Are we close to defining a metabolomic signature of human obesity? A systematic review of metabolomics studies Metabolomics 2019 15 93 10.1007/s11306-019-1553-y
Wu Y. Perng W. Peterson K.E. Precision Nutrition and Childhood Obesity: A Scoping Review Metabolites 2020 10 235 10.3390/metabo10060235
Handakas E. Lau C.H. Alfano R. Chatzi V.L. Plusquin M. Vineis P. Robinson O. A systematic review of metabolomic studies of childhood obesity: State of the evidence for metabolic determinants and consequences Obes. Rev. 2022 23 (Suppl. S1) e13384 10.1111/obr.13384 34797026
Leal-Witt M.J. Ramon-Krauel M. Samino S. Llobet M. Cuadras D. Jimenez-Chillaron J.C. Yanes O. Lerin C. Untargeted metabolomics identifies a plasma sphingolipid-related signature associated with lifestyle intervention in prepubertal children with obesity Int. J. Obes. 2018 42 72 78 10.1038/ijo.2017.201 28947825
Leal-Witt M.J. Llobet M. Samino S. Castellano P. Cuadras D. Jimenez-Chillaron J.C. Yanes O. Ramon-Krauel M. Lerin C. Lifestyle Intervention decreases urine trimethylamine N-oxide levels in prepubertal children with obesity Obesity 2018 26 1603 1610 10.1002/oby.22271
Pathmasiri W. Pratt K.J. Collier D.N. Lutes L.D. McRitchie S. Sumner S.C.J. Integrating metabolomic signatures and psychosocial parameters in responsivity to an immersion treatment model for adolescent obesity Metabolomics 2012 8 1037 1051 10.1007/s11306-012-0404-x
Wahl S. Holzapfel C. Yu Z.H. Breier M. Kondofersky I. Fuchs C. Singmann P. Prehn C. Adamski J. Grallert H. et al. Metabolomics reveals determinants of weight loss during lifestyle intervention in obese children Metabolomics 2013 9 1157 1167 10.1007/s11306-013-0550-9
Reinehr T. Wolters B. Knop C. Lass N. Hellmuth C. Harder U. Peissner W. Wahl S. Grallert H. Adamski J. et al. Changes in the serum metabolite profile in obese children with weight loss Eur. J. Nutr. 2014 54 173 181 10.1007/s00394-014-0698-8
Reinehr T. Kulle A. Rothermel J. Knop-Schmenn C. Lass N. Bosse C. Holterhus P.M. Longitudinal analyses of the steroid metabolome in obese PCOS girls with weight loss Endocr. Connect. 2017 6 213 224 10.1530/EC-17-0051 28373267
Short K.R. Chadwick J.Q. Teague A.M. Tullier M.A. Wolbert L. Coleman C. Copeland K.C. Effect of obesity and exercise training on plasma amino acids and amino metabolites in American Indian adolescents J. Clin. Endocrinol. Metab. 2019 104 3249 3261 10.1210/jc.2018-02698
Sohn M.J. Chae W. Ko J.S. Cho J.Y. Kim J.E. Choi J.Y. Jang H.B. Lee H.J. Park S.I. Park K.H. et al. Metabolomic Signatures for the Effects of Weight Loss Interventions on Severe Obesity in Children and Adolescents Metabolites 2021 12 27 10.3390/metabo12010027
Cacciari E. Milani S. Balsamo A. Spada E. Bona G. Cavallo L. Cerutti F. Gargantini L. Greggio N. Tonini G. et al. Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr) J. Endocrinol. Investig. 2006 29 581 593 10.1007/BF03344156
Ramos Salas X. Alberga A.S. Cameron E. Estey L. Forhan M. Kirk S.F.L. Russell-Mayhew S. Sharma A.M. Addressing weight bias and discrimination: Moving beyond raising awareness to creating change Obes. Rev. 2017 18 1323 1335 10.1111/obr.12592 28994243
Rubino F. Puhl R.M. Cummings D.E. Eckel R.H. Ryan D.H. Mechanick J.I. Nadglowski J. Ramos Salas X. Schauer P.R. Twenefour D. et al. Joint international consensus statement for ending stigma of obesity Nat. Med. 2020 26 485 497 10.1038/s41591-020-0803-x 32127716
Wallace T.M. Levy J.C. Matthews D.R. Use and abuse of HOMA modeling Diabetes Care 2004 27 1487 1495 10.2337/diacare.27.6.1487
Zimmet P. Alberti K.G. Kaufman F. Tajima N. Silink M. Arslanian S. Wong G. Bennett P. Shaw J. Caprio S. et al. The metabolic syndrome in children and adolescents—An IDF consensus report Pediatr. Diabetes 2007 8 299 306 10.1111/j.1399-5448.2007.00271.x 17850473
McCharty H.D. Jarret K.V. Crawley H.F. The development of waist circumference percentiles in British children aged 5.0–16.9 y Eur. J. Clin. Nutr. 2001 55 902 907 10.1038/sj.ejcn.1601240 11593353
Biocrates-Life-Sciences-AG AbsoluteIDQ® p180 Kit Available online: https://biocrates.com/absoluteidq-p180-kit/ (accessed on 31 January 2022)
Frigerio G. Favero C. Savino D. Mercadante R. Albetti B. Dioni L. Vigna L. Bollati V. Pesatori A.C. Fustinoni S. Plasma Metabolomic Profiling in 1391 Subjects with Overweight and Obesity from the SPHERE Study Metabolites 2021 11 194 10.3390/metabo11040194
Benjamini Y. Hochberg Y. Controlling the false discovery rate: A practical and powerful approach to multiple testing J. R. Stat. Soc. B 1995 57 289 300 10.1111/j.2517-6161.1995.tb02031.x
R Core Team R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria 2021 Available online: https://www.R-project.org/ (accessed on 31 January 2022)
Wickham H. Averick M. Bryan J. Chang W. McGowan L.D. François R. Grolemund G. Hayes A. Henry L. Hester J. et al. Welcome to the Tidyverse J. Open Source Softw. 2019 4 1686 10.21105/joss.01686
Kuznetsova A. Brockhoff P.B. Christensen R.H.B. lmerTest Package: Tests in Linear Mixed Effects Models J. Stat. Softw. 2017 82 1 26 10.18637/jss.v082.i13
Pang Z. Zhou G. Ewald J. Chang L. Hacariz O. Basu N. Xia J. Using MetaboAnalyst 5.0 for LC-HRMS spectra processing, multi-omics integration and covariate adjustment of global metabolomics data Nat. Protoc. 2022 17 1735 1761 10.1038/s41596-022-00710-w
Jeppesen J. Kiens B. Regulation and limitations to fatty acid oxidation during exercise J. Physiol. 2012 590 1059 1068 10.1113/jphysiol.2011.225011 22271865
Hodge A.M. Simpson J.A. Gibson R.A. Sinclair A.J. Makrides M. O’Dea K. English D.R. Giles G.G. Plasma phospholipid fatty acid composition as a biomarker of habitual dietary fat intake in an ethnically diverse cohort Nutr. Metab. Cardiovasc. Dis. 2007 17 415 426 10.1016/j.numecd.2006.04.005 16962297
Sakka S. Siahanidou T. Voyatzis C. Pervanidou P. Kaminioti C. Lazopoulou N. Kanaka-Gantenbein C. Chrousos G.P. Papassotiriou I. Elevated circulating levels of lipoprotein-associated phospholipase A2 in obese children Clin. Chem. Lab. Med. 2015 53 1119 1125 10.1515/cclm-2014-1081 25581763
Murugesan G. Lysophosphatidylcholine regulates human microvascular endothelial cell expression of chemokines J. Mol. Cell. Cardiol. 2003 35 1375 1384 10.1016/j.yjmcc.2003.08.004
Wahl S. Yu Z. Kleber M. Singmann P. Holzapfel C. He Y. Mittelstrass K. Polonikov A. Prehn C. Römisch-Margl W. et al. Childhood obesity is associated with changes in the serum metabolite profile Obes. Facts 2012 5 660 670 10.1159/000343204 23108202
Polidori N. Grasso E.A. Chiarelli F. Giannini C. Amino Acid-Related Metabolic Signature in Obese Children and Adolescents Nutrients 2022 14 1454 10.3390/nu14071454
Palmer N.D. Stevens R.D. Antinozzi P.A. Anderson A. Bergman R.N. Wagenknecht L.E. Newgard C.B. Bowden D.W. Metabolomic profile associated with insulin resistance and conversion to diabetes in the Insulin Resistance Atherosclerosis Study J. Clin. Endocrinol. Metab. 2015 100 E463 E468 10.1210/jc.2014-2357
Perng W. Gillman M.W. Fleisch A.F. Michalek R.D. Watkins S.M. Isganaitis E. Patti M.E. Oken E. Metabolomic profiles and childhood Obesuty 2014 22 2570 2578 10.1002/oby.20901
Huffman K.M. Shah S.H. Stevens R.D. Bain J.R. Muehlbauer M. Slentz C.A. Tanner C.J. Kuchibhatla M. Houmard J.A. Newgard C.B. et al. Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women Diabetes Care 2009 32 1678 1683 10.2337/dc08-2075
Krebs M. Krssak M. Bernroider E. Anderwald C. Brehm A. Meyerspeer M. Nowotny P. Roth E. Waldhäusl W. Roden M. Mechanism of amino acid-induced skeletal muscle insulin resistance in humans Diabetes 2002 51 599 605 10.2337/diabetes.51.3.599
Tai E.S. Tan M.L. Stevens R.D. Low Y.L. Muehlbauer M.J. Goh D.L. Ilkayeva O.R. Wenner B.R. Bain J.R. Lee J.J.M. et al. Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men Diabetologia 2010 53 757 767 10.1007/s00125-009-1637-8
Newgard C.B. An J. Bain J.R. Muehlbauer M.J. Stevens R.D. Lien L.F. Haqq A.M. Shah S.H. Arlotto M. Slentz C.A. et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance Cell Metab. 2009 9 311 326 10.1016/j.cmet.2009.02.002
Vanweert F. Schrauwen P. Phielix E. Role of branched-chain amino acid metabolism in the pathogenesis of obesity and type 2 diabetes-related metabolic disturbances BCAA metabolism in type 2 diabetes Nutr. Diabetes 2022 12 35 10.1038/s41387-022-00213-3
Holecek M. Branched-chain amino acids in health and disease: Metabolism, alterations in blood plasma, and as supplements Nutr. Metab. 2018 15 33 10.1186/s12986-018-0271-1 29755574
Neinast M.D. Jang C. Hui S. Murashige D.S. Chu Q. Morscher R.J. Li X. Zhan L. White E. Anthony T.G. et al. Quantitative analysis of the whole-body metabolic fate of branched-chain amino acids Cell Metab. 2019 29 417 429.e4 10.1016/j.cmet.2018.10.013 30449684
Holecek M. Branched-chain amino acids and branched-chain keto acids in hyperammonemic states: Metabolism and as supplements Metabolites 2020 10 324 10.3390/metabo10080324 32784821
She P. Van Horn C. Reid T. Hutson S.M. Cooney R.N. Lynch C.J. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism Am. J. Physiol. Endocrinol. Metab. 2007 293 E1552 E1563 10.1152/ajpendo.00134.2007
Suryawan A. Hawes J.W. Harris R.A. Shimomura Y. Jenkins A.E. Hutson S.M. A molecular model of human branched-chain amino acid metabolism Am. J. Clin. Nutr. 1998 68 72 81 10.1093/ajcn/68.1.72
Wynn R.M. Kato M. Machius M. Chuang J.L. Li J. Tomchick D.R. Chuang D.T. Molecular mechanism for regulation of the human mitochondrial branched-chain alphaketoacid dehydrogenase complex by phosphorylation Structure 2004 12 2185 2196 10.1016/j.str.2004.09.013
Doisaki M. Katano Y. Nakano I. Hirooka Y. Itoh A. Ishigami M. Hayashi K. Goto H. Fujita Y. Kadota Y. et al. Regulation of hepatic branched-chain alpha-keto acid dehydrogenase kinase in a rat model for type 2 diabetes mellitus at different stages of the disease Biochem. Biophys. Res. Commun. 2010 393 303 307 10.1016/j.bbrc.2010.02.004 20138840
Adams S.H. Emerging perspectives on essential amino acid metabolism in obesity and the insulin-resistant state Adv. Nutr. 2011 2 445 456 10.3945/an.111.000737 22332087
Zhou M. Shao J. Wu C.Y. Shu L. Dong W. Liu Y. Chen M. Wynn R.M. Wang J. Wang J. et al. Targeting BCAA catabolism to treat obesity-associated insulin resistance Diabetes 2019 68 1730 1746 10.2337/db18-0927
She P. Reid T.M. Bronson S.K. Vary T.C. Hajnal A. Lynch C.J. Hutsonet S.M. Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle Cell Metab. 2007 6 181 194 10.1016/j.cmet.2007.08.003
White P.J. McGarrah R.W. Grimsrud P.A. Tso S.C. Yang W.H. Haldeman J.M. Grenier-Larouche T. Lapworth A.L. Astapova I. Hannou S.A. et al. The BCKDH kinase and phosphatase integrate BCAA and lipid metabolism via regulation of ATP-citrate lyase Cell Metab. 2018 27 1281 10.1016/j.cmet.2018.04.015
Lian K. Du C. Liu Y. Zhu D. Yan W. Zhang H. Hong Z. Liu P. Zhang L. Pei H. et al. Impaired adiponectin signaling contributes to disturbed catabolism of branched-chain amino acids in diabetic mice Diabetes 2015 64 49 59 10.2337/db14-0312
Zhou M. Lu G. Gao C. Wang Y. Sun H. Tissue-specific and nutrient regulation of the branched-chain alpha-keto acid dehydrogenase phosphatase, protein phosphatase 2Cm (PP2Cm) J. Biol. Chem. 2012 287 23397 23406 10.1074/jbc.M112.351031
Lu G. Sun H. She P. Youn J.Y. Warburton S. Ping P. Vondriska T.M. Cai H. Lynch C.J. Wang Y. Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells J. Clin. Investig. 2009 119 1678 1687 10.1172/JCI38151
Sun H. Olson K.C. Gao C. Prosdocimo D.A. Zhou M. Wang Z. Jeyaraj D. Youn J. Ren S. Liu Y. et al. Catabolic defect of branched-chain amino acids promotes heart failure Circulation 2016 133 2038 2049 10.1161/CIRCULATIONAHA.115.020226
Lake A.D. Novak P. Shipkova P. Aranibar N. Robertson D.G. Reily M.D. Lehman-McKeeman L.D. Vaillancourt R.R. Cherrington N.J. Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease Amino Acids 2015 47 603 615 10.1007/s00726-014-1894-9
Joshi M. Jeoung N.H. Popov K.M. Harris R.A. Identification of a novel PP2C-type mitochondrial phosphatase Biochem. Biophys. Res. Commun. 2007 356 38 44 10.1016/j.bbrc.2007.02.108
Biswas D. Duffley L. Pulinilkunnil T. Role of branched-chain amino acidcatabolizing enzymes in intertissue signaling, metabolic remodeling, and energy homeostasis FASEB J. 2019 33 8711 8731 10.1096/fj.201802842RR
Fisch S. Gray S. Heymans S. Haldar S.M. Wang B. Pfister O. Cui L. Kumar A. Lin Z. Sen-Banerjee S. et al. Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy Proc. Natl. Acad. Sci. USA 2007 104 7074 7079 10.1073/pnas.0701981104
Hirata Y. Nomura K. Senga Y. Okada Y. Kobayashi K. Okamoto S. Minokoshi Y. Imamura M. Takeda S. Hosooka T. et al. Hyperglycemia induces skeletal muscle atrophy via a WWP1/KLF15 axis JCI Insight 2019 4 e124952 10.1172/jci.insight.124952
Greco D. Kotronen A. Westerbacka J. Puig O. Arkkila P. Kiviluoto T. Laitinen S. Kolak M. Fisher R.M. Hamsten A. et al. Gene expression in human NAFLD Am. J. Physiol.-Gastrointest. Liver Physiol. 2008 294 G1281 G1287 10.1152/ajpgi.00074.2008
Sperringer J.E. Addington A. Hutson S.M. Branched-chain amino acids and brain metabolism Neurochem. Res. 2017 42 1697 1709 10.1007/s11064-017-2261-5
Hernandez-Alvarez M.I. Diaz-Ramos A. Berdasco M. Cobb J. Planet E. Cooper D. Pazderska A. Wanic K. O’Hanlon D. Gomez A. et al. Early-onset and classical forms of type 2 diabetes show impaired expression of genes involved in muscle branched-chain amino acids metabolism Sci. Rep. 2017 7 13850
Salinas-Rubio D. Tovar A.R. Torre-Villalvazo I. Granados-Portillo O. Torres N. Pedraza-Chaverri J. Noriega L.G. Interaction between leucine and palmitate catabolism in 3T3-L1 adipocytes and primary adipocytes from control and obese rats J. Nutr. Biochem. 2018 59 29 36 10.1016/j.jnutbio.2018.05.011
Takeuchi Y. Yahagi N. Aita Y. Murayama Y. Sawada Y. Piao X. Toya N. Oya Y. Shikama A. Takarada A. et al. KLF15 enables rapid switching between lipogenesis and gluconeogenesis during fasting Cell Rep. 2016 16 2373 2386 10.1016/j.celrep.2016.07.069
Hsiao G. Chapman J. Ofrecio J.M. Wilkes J. Resnik J.L. Thapar D. Subramaniam S. Searset D.D. Multi-tissue, selective PPARgamma modulation of insulin sensitivity and metabolic pathways in obese rats Am. J. Physiol. Endocrinol. Metab. 2011 300 E164 E174 10.1152/ajpendo.00219.2010 20959535
0Neinast M. Murashige D. Arany Z. Branched chain amino acids Annu. Rev. Physiol. 2019 81 139 164 10.1146/annurev-physiol-020518-114455 30485760
Altman N.S. An introduction to kernel and nearest-neighbor nonparametric regression Am. Stat. 1992 46 175 185
Lerin C. Goldfine A.B. Boes T. Liu M. Kasif S. Dreyfuss J.M. De Sousa-Coelho A.L. Daher G. Manoli I. Sysol J.R. et al. Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism Mol. Metab. 2016 5 926 936 10.1016/j.molmet.2016.08.001 27689005
Lefort N. Glancy B. Bowen B. Willis W.T. Bailowitz Z. De Filippis E.A. Brophy C. Meyer C. Højlund K. Yi Z. et al. Increased reactive oxygen species production and lower abundance of complex I subunits and carnitine palmitoyltransferase 1B protein despite normal mitochondrial respiration in insulin-resistant human skeletal muscle Diabetes 2010 59 2444 2452 10.2337/db10-0174 20682693
Lotta L.A. Scott R.A. Sharp S.J. Burgess S. Luan J. Tillin T. Schmidt A.F. Imamura F. Stewart I.D. Perry J.R.B. et al. Genetic predisposition to an impaired metabolism of the branched-chain amino acids and risk of type 2 diabetes: A Mendelian randomisation analysis PLoS Med. 2016 13 e1002179 10.1371/journal.pmed.1002179
Mann G. Mora S. Madu G. Adegoke O.A.J. Branched-chain Amino Acids: Catabolism in Skeletal Muscle and Implications for Muscle and Whole-body Metabolism Front. Physiol. 2021 12 702826 10.3389/fphys.2021.702826
Shah S.H. Crosslin D.R. Haynes C.S. Nelson S. Turer C.B. Stevens R.D. Muehlbauer M.J. Wenner B.R. Bain J.R. Laferrère B. et al. Branched- chain amino acid levels are associated with improvement in insulin resistance with weight loss Diabetologia 2012 55 321 330 10.1007/s00125-011-2356-5
Newgard C.B. Interplay between lipids and branched-chain amino acids in development of insulin resistance Cell Metab. 2012 15 606 614 10.1016/j.cmet.2012.01.024
She P. Olson K.C. Kadota Y. Inukai A. Shimomura Y. Hoppel C.L. Adams S.H. Kawamata Y. Matsumoto H. Sakai R. et al. Leucine and protein metabolism in obese Zucker rats PLoS ONE 2013 8 e59443 10.1371/journal.pone.0059443
Magkos F. Bradley D. Schweitzer G.G. Finck B.N. Eagon J.C. Ilkayeva O. Newgard C.B. Effect of Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding on branched-chain amino acid metabolism Diabetes 2013 62 2757 2761 10.2337/db13-0185
Fiehn O. Garvey W.T. Newman J.W. Lok K.H. Hoppel C.L. Adams S.H. Plasma metabolomic profiles reflective of glucose homeostasis in non-diabetic and type 2 diabetic obese African-American women PLoS ONE 2010 5 e15234 10.1371/journal.pone.0015234
Adams S.H. Hoppel C.L. Lok K.H. Zhao L. Wong S.W. Minkler P.E. Hwang D.H. Newman J.W. Garvey W.T. Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women J. Nutr. 2009 139 1073 1081 10.3945/jn.108.103754
Um S.H. D’Alessio D. Thomas G. Nutrient overload, insulin resistance, and ribo- somal protein S6 kinase 1, S6K1 Cell Metab. 2006 3 393 402 10.1016/j.cmet.2006.05.003
Um S.H. Frigerio F. Watanabe M. Picard F. Joaquin M. Sticker M. Fumagalli S. Allegrini P.R. Kozma S.C. Auwerx J. et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity Nature 2004 431 200 205 10.1038/nature02866
Krebs M. Brunmair B. Brehm A. Artwohl M. Szendroedi J. Nowotny P. Roth E. Fürnsinn C. Promintzer M. Anderwald C. et al. The Mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man Diabetes 2007 56 1600 1607 10.2337/db06-1016
Tremblay F. Brule S. Hee Um S. Li Y. Masuda K. Roden M. Sun X.J. Krebs M. Polakiewicz R.D. Thomas G. et al. Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance Proc. Natl. Acad. Sci. USA 2007 104 14056 14061 10.1073/pnas.0706517104
Gleason C.E. Lu D. Witters L.A. Newgard C.B. Birnbaum M.J. The role of AMPK and mTOR in nutrient sensing in pancreatic beta-cells J. Biol. Chem. 2007 282 10341 11051 10.1074/jbc.M610631200
Nagao H. Nishizawa H. Bamba T. Nakayama Y. Isozumi N. Nagamori S. Kanai Y. Tanaka Y. Kita S. Fukuda S. et al. Increased dynamics of tricarboxylic acid cycle and glutamate synthesis in obese adipose tissue: In vivo metabolic turnover analysis J. Biol. Chem. 2017 292 4469 4483 10.1074/jbc.M116.770172
Maltais-Payette I. Boulet M.M. Prehn C. Adamski J. Tchernof A. Circulating glutamate concentration as a biomarker of visceral obesity and associated metabolic alterations Nutr. Metab. 2018 15 78 10.1186/s12986-018-0316-5
Yoo H.C. Yu Y.C. Sung Y. Han J.M. Glutamine reliance in cell metabolism Exp. Mol. Med. 2020 52 1496 1516 10.1038/s12276-020-00504-8
Petrus P. Lecoutre S. Dollet L. Wiel C. Sulen A. Gao H. Tavira B. Laurencikiene J. Rooyackers O. Checa A. et al. Glutamine Links Obesity to Inflammation in Human White Adipose Tissue Cell Metab. 2020 31 375 390.e11 10.1016/j.cmet.2019.11.019
Lewis B.A. Hanover J.A. O-GlcNAc and the epigenetic regulation of gene expression J. Biol. Chem. 2014 289 34440 34448 10.1074/jbc.R114.595439
Kenđel Jovanović G. Mrakovcic-Sutic I. Pavičić Žeželj S. Šuša B. Rahelić D. Klobučar Majanović S. The Efficacy of an Energy-Restricted Anti-Inflammatory Diet for the Management of Obesity in Younger Adults Nutrients 2020 12 3583 10.3390/nu12113583
Khanna D. Khanna S. Khanna P. Kahar P. Patel B.M. Obesity: A Chronic Low-Grade Inflammation and Its Markers Cureus 2022 14 e22711 10.7759/cureus.22711
Butte N.F. Liu Y. Zakeri I.F. Mohney R.P. Mehta N. Voruganti V.S. Göring H. Cole S.A. Comuzzie A.G. Global metabolomic profiling targeting child- hood obesity in the Hispanic population Am. J. Clin. Nutr. 2015 102 256 267 10.3945/ajcn.115.111872
Kim J.Y. Park J.Y. Kim O.Y. Ham B.M. Kim H.J. Kwon D.Y. Jang Y. Lee J. Metabolic profiling of plasma in overweight/obese and lean men using ultra performance liquid chromatography and Q-TOF mass spectrometry (UPLC-Q-TOF MS) J. Proteome Res. 2010 9 4368 4375 10.1021/pr100101p
Fattuoni C. Mandò C. Palmas F. Anelli G.M. Novielli C. Parejo Laudicina E. Savasi V.M. Barberini L. Dessì A. Pintus R. et al. Preliminary metabolomics analysis of placenta in maternal obesity Placenta 2018 61 89 95 10.1016/j.placenta.2017.11.014
Wang S.M. Yang R.Y. Wang M. Ji F.S. Li H.X. Tang Y.M. Chen W.X. Dong J. Identification of serum metabolites associated with obesity and traditional risk factors for metabolic disease in Chinese adults Nutr. Metab. Cardiovasc. Dis. 2018 28 112 118 10.1016/j.numecd.2017.09.009
Houttu N. Mokkala K. Laitinen K. Overweight and obe- sity status in pregnant women are related to intestinal microbiota and serum metabolic and inflammatory profiles Clin. Nutr. 2018 37 1955 1966 10.1016/j.clnu.2017.12.013
Yu H.T. Fu X.Y. Xu B. Zuo L.L. Ma H.B. Wang S.R. Untargeted metabolomics approach (UPLC-Q-TOF-MS) explores the biomarkers of serum and urine in overweight/obese young men Asia Pac. J. Clin. Nutr. 2018 27 1067 1076 30272855
Hellmuth C. Kirchberg F.F. Lass N. Harder U. Peissner W. Koletzko B. Reinehr T. Tyrosine is associated with insulin resistance in longitudinal metabolomic profiling of obese children J. Diabetes Res. 2016 2016 1 10 10.1155/2016/2108909 26881241
Fernstrom J.D. Branched-chain amino acids and brain function J. Nutr. 2005 135 1539S 1546S 10.1093/jn/135.6.1539S 15930466
Libert D.M. Nowacki A.S. Natowicz M.R. Metabolomic analysis of obesity, metabolic syndrome, and type 2 diabetes: Amino acid and acylcarnitine levels change along a spectrum of metabolic wellness PeerJ 2018 6 e5410 10.7717/peerj.5410
Buckley W.T. Milligan L.P. Participation of cysteine and cystine in inactivation of tyrosine aminotransferase in rat liver homogenates Biochem. J. 1978 176 449 454 10.1042/bj1760449
Pastore A. Noce A. Di Giovamberardino G. De Stefano A. Callà C. Zenobi R. Dessì M. Di Daniele N. Homocysteine, cysteine, folate and vitamin B12 status in type 2 diabetic patients with chronic kidney disease J. Nephrol. 2015 28 571 576 10.1007/s40620-014-0126-4
Ramzan I. Taylor M. Phillips B. Wilkinson D. Smith K. Hession K. Idris I. Atherton P. A Novel Dietary Intervention Reduces Circulatory Branched-Chain Amino Acids by 50%: A Pilot Study of Relevance for Obesity and Diabetes Nutrients 2020 13 95 10.3390/nu13010095
Tam C.S. Clément K. Baur L.A. Tordjman J. Obesity and low-grade inflammation: A paediatric perspective Obes. Rev. 2010 11 118 126 10.1111/j.1467-789X.2009.00674.x
Campbell B.M. Charych E. Lee A.W. Möller T. Kynurenines in CNS disease: Regulation by inflammatory cytokines Front. Neurosci. 2014 8 12 10.3389/fnins.2014.00012
Ball H.J. Sanchez-Perez A. Weiser S. Austin C.J.D. Astelbauer F. Miu J. McQuillan J.A. Stocker R. Jermiin L.S. Huntet N.H. Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice Gene 2007 396 203 213 10.1016/j.gene.2007.04.010 17499941
Palego L. Betti L. Rossi A. Giannaccini G. Tryptophan Biochemistry: Structural, Nutritional, Metabolic, and Medical Aspects in Humans J. Amino Acids 2016 2016 8952520 10.1155/2016/8952520 26881063
Wolowczuk I. Hennart B. Leloire A. Bessede A. Soichot M. Taront S. Caiazzo R. Raverdy V. Pigeyre M. ABOS Consortium et al. Tryptophan metabolism activation by indoleamine 2,3-dioxygenase in adipose tissue of obese women: An attempt to maintain immune homeostasis and vascular tone AJP Regul. Integr. Comp. Physiol. 2012 303 R135 R143 10.1152/ajpregu.00373.2011 22592557
Mangge H. Summers K.L. Meinitzer A. Zelzer S. Almer G. Prassl R. Schnedl W.J. Reininghaus E. Paulmichl K. Weghuber D. et al. Obesity-related dysregulation of the tryptophan-kynurenine metabolism: Role of age and parameters of the metabolic syndrome Obesity 2014 22 195 201 10.1002/oby.20491
Oxenkrug G. Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways Mol. Neurobiol. 2013 48 294 301 10.1007/s12035-013-8497-4
Rosen D.A. Maengwyn-Davies G.D. Becker B. Stone H.H. Friedenwald J.S. Xanthurenic acid excretion studies in diabetics with and without retinopathy Proc. Soc. Exp. Biol. Med. 1955 88 321 323 10.3181/00379727-88-21576
Meyramov G. Korchin V. Kocheryzkina N. Diabetogenic activity of xanturenic acid determined by its chelating properties? Transplant. Proc. 1998 30 2682 2684 10.1016/S0041-1345(98)00788-X
Wurtman J. Wurtman R. The Trajectory from Mood to Obesity Curr. Obes. Rep. 2018 7 1 5 10.1007/s13679-017-0291-6
Carraça E.V. Encantado J. Battista F. Beaulieu K. Blundell J.E. Busetto L. van Baak M. Dicker D. Ermolao A. Farpour-Lambert N. et al. Effect of exercise training on psychological outcomes in adults with overweight or obesity: A systematic review and meta-analysis Obes. Rev. 2021 22 (Suppl. S4) e13261 10.1111/obr.13261
Lin T.W. Kuo Y.M. Exercise benefits brain function: The monoamine connection Brain Sci. 2013 3 39 53 10.3390/brainsci3010039
Xie Y. Bowe B. Li T. Xian H. Yan Y. Al-Aly Z. Higher blood urea nitrogen is associated with increased risk of incident diabetes mellitus Kidney Int. 2018 93 741 752 10.1016/j.kint.2017.08.033 29241622
Koppe L. Nyam E. Vivot K. Manning Fox J.E. Dai X.Q. Nguyen B.N. Trudel D. Attané C. Moullé V.S. MacDonald P.E. et al. Urea impairs beta cell glycolysis and insulin secretion in chronic kidney disease J. Clin. Investig. 2016 126 3598 3612 10.1172/JCI86181 27525435
Wu G. Morris S.M. Jr. Arginine metabolism: Nitric oxide and beyond Biochem. J. 1998 336 1 17 10.1042/bj3360001 9806879
Kashyap S.R. Roman L.J. Lamont J. Masters B.S. Bajaj M. Suraamornkul S. Belfort R. Berria R. Kellogg D.L. Jr. Liu Y. et al. Insulin resistance is associated with impaired nitric oxide synthase activity in skeletal muscle of type 2 diabetic subjects J. Clin. Endocrinol. Metab. 2005 90 1100 1105 10.1210/jc.2004-0745
Carracedo J. Merino A. Briceno C. Soriano S. Buendia P. Calleros L. Rodrigue M. Martín-Malo A. Aljama P. Ramírez R. Carbamylated low-density lipoprotein induces oxidative stress and accelerated senescence in human endothelial progenitor cells FASEB J. 2011 25 1314 1322 10.1096/fj.10-173377
Pietzner M. Kaul A. Henning A.K. Kastenmuller G. Artati A. Lerch M.M. Adamski J. Nauck M. Friedrich N. Comprehensive metabolic profiling of chronic low-grade inflammation among generally healthy individuals BMC Med. 2017 15 210 10.1186/s12916-017-0974-6
Cao Y.F. Li J. Zhang Z. Liu J. Sun X.Y. Feng X.F. Luo H.H. Yang W. Li S.N. Yang X. et al. Plasma Levels of Amino Acids Related to Urea Cycle and Risk of Type 2 Diabetes Mellitus in Chinese Adults Front. Endocrinol. 2019 10 50 10.3389/fendo.2019.00050
Eriksen P.L. Vilstrup H. Rigbolt K. Suppli M.P. Sørensen M. Heebøll S. Veidal S.S. Knop F.K. Thomsen K.L. Non-alcoholic fatty liver disease alters expression of genes governing hepatic nitrogen conversion Liver Int. 2019 39 2094 2101 10.1111/liv.14205
Koutoukidis D.A. Astbury N.M. Tudor K.E. Morris E. Henry J.A. Noreik M. Jebb S.A. Aveyard P. Association of Weight Loss Interventions with Changes in Biomarkers of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis JAMA Intern. Med. 2019 179 1262 1271 10.1001/jamainternmed.2019.2248
Sailer M. Dahlhoff C. Giesbertz P. Eidens M.K. de Wit N. Rubio-Aliaga I. Boekschoten M.V. Müller M. Daniel H. Increased plasma citrulline in mice marks diet-induced obesity and may predict the development of the metabolic syndrome PLoS ONE 2013 8 e63950 10.1371/journal.pone.0063950 23691124
Karna E. Szoka L. Huynh T.Y.L. Palka J.A. Proline-dependent regulation of collagen metabolism Cell Mol. Life Sci. 2020 77 1911 1918 10.1007/s00018-019-03363-3
Brown H. Milner A. Kennedy J. Delena S. Hydroxyproline excretion during starvation of obese subjects Metabolism 1968 17 345 351 10.1016/0026-0495(68)90103-0
Tofas T. Jamurtas A.Z. Fatouros I. Nikolaidis M.G. Koutedakis Y. Sinouris E.A. Papageorgakopoulou N. Theocharis D.A. Plyometric exercise increases serum indices of muscle damage and collagen breakdown J. Strength Cond. Res. 2008 22 490 496 10.1519/JSC.0b013e31816605a0
Dolan E. Dumas A. Keane K.M. Bestetti G. Freitas L.H.M. Gualano B. Kohrt W.M. Kelley G.A. Pereira R.M.R. Sale C. et al. The Bone Biomarker Response to an Acute Bout of Exercise: A Systematic Review with Meta-Analysis Sports Med. 2022 52 2889 2908 10.1007/s40279-022-01718-8
