{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T00:08:40Z","timestamp":1793318920821,"version":"4.5.0"},"reference-count":127,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T00:00:00Z","timestamp":1733788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Consuming a \u201cmodern\u201d Western diet and overnutrition may increase insulin secretion. Additionally, nutrition-mediated hyperinsulinemia is a major driver of ectopic fat deposition. The global prevalence of metabolic syndrome is high and growing. Within this context, people with congenital lipodystrophy often experience a severe form of metabolic syndrome. Evidence is increasingly supporting that subtle partial lipodystrophy plays an important role in the development of metabolic syndrome in the general population. In individuals in the general population with subtle partial lipodystrophy, as well as in those with congenital lipodystrophy, the subcutaneous adipose tissues are unable to accommodate surplus energy intake. In both conditions, (excess) fat is directed toward the liver, pancreas, and muscles, where it is deposited as ectopic fat, as this fat can no longer be stored in the \u201csafe\u201d subcutaneous fat depots. Ectopic fat depositions cause insulin resistance in the liver and muscles, as well as \u03b2-cell dysfunction in the pancreas. Support of a direct pathological role of ectopic fat deposition in this condition is further provided by the rapid normalization of hepatic insulin sensitivity and improvement in pancreatic \u03b2-cell function after marked reductions in ectopic fat depositions. Thus, ectopic fat deposition in the liver, pancreas, and muscles may play a causal role in the pathogenesis of metabolic syndrome even in the general population. As such, the prevention of ectopic fat deposition may reduce the risk of metabolic syndrome and mitigate its effects.<\/jats:p>","DOI":"10.3390\/ijms252413238","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T04:15:03Z","timestamp":1733804103000},"page":"13238","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["The Causal Role of Ectopic Fat Deposition in the Pathogenesis of Metabolic Syndrome"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9363-6408","authenticated-orcid":false,"given":"Joseph A. M. J. L.","family":"Janssen","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Erasmus Medical Center (Erasmus MC), Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,10]]},"reference":[{"key":"ref_1","first-page":"339","article-title":"La diff\u00e9renciation sexuelle; facteur d\u00e9terminant des formes de l\u2019ob\u00e9sit\u00e9 [Sexual differentiation; Factor determining forms of obesity]","volume":"55","author":"Vague","year":"1947","journal-title":"Presse Med."},{"key":"ref_2","first-page":"179","article-title":"Significance of obesity in medical practice","volume":"90","author":"Vague","year":"1953","journal-title":"Mars Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1172\/JCI81507","article-title":"Abdominal obesity: A marker of ectopic fat accumulation","volume":"125","author":"Smith","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1172\/JCI200422028","article-title":"The case of visceral fat: Argument for the defense","volume":"113","author":"Klein","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"633","DOI":"10.2337\/diab.45.5.633","article-title":"Abdominal fat and insulin resistance in normal and overweight women: Direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM","volume":"45","author":"Carey","year":"1996","journal-title":"Diabetes"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.2337\/diab.37.12.1595","article-title":"Banting lecture 1988. Role of insulin resistance in human disease","volume":"37","author":"Reaven","year":"1988","journal-title":"Diabetes"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1161\/CIRCULATIONAHA.109.192644","article-title":"Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity","volume":"120","author":"Alberti","year":"2009","journal-title":"Circulation"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s11906-018-0812-z","article-title":"The Global Epidemic of the Metabolic Syndrome","volume":"20","author":"Saklayen","year":"2018","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"109924","DOI":"10.1016\/j.diabres.2022.109924","article-title":"Geographic distribution of metabolic syndrome and its components in the general adult population: A meta-analysis of global data from 28 million individuals","volume":"188","author":"Noubiap","year":"2022","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Li, W., Qiu, X., Ma, H., and Geng, Q. (2022). Incidence and long-term specific mortality trends of metabolic syndrome in the United States. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1029736"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ecl.2013.09.009","article-title":"Metabolic syndrome","volume":"43","author":"Samson","year":"2014","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.2337\/diacare.28.9.2289","article-title":"The metabolic syndrome: Time for a critical appraisal: Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes","volume":"28","author":"Kahn","year":"2005","journal-title":"Diabetes Care"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e837","DOI":"10.1161\/CIRCULATIONAHA.111.077602","article-title":"Ectopic fat depots and cardiovascular disease","volume":"124","author":"Britton","year":"2011","journal-title":"Circulation"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1080\/14779072.2016.1256773","article-title":"Ectopic fat: A target for cardiometabolic risk management","volume":"14","author":"Gastaldelli","year":"2016","journal-title":"Expert. Rev. Cardiovasc. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1056\/NEJMra1011035","article-title":"Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease","volume":"371","author":"Shulman","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Vaidya, R.A., Desai, S., Moitra, P., Salis, S., Agashe, S., Battalwar, R., Mehta, A., Madan, J., Kalita, S., and Udipi, S.A. (2023). Hyperinsulinemia: An early biomarker of metabolic dysfunction. Front. Clin. Diabetes Healthc., 4.","DOI":"10.3389\/fcdhc.2023.1159664"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1111\/eci.12519","article-title":"Adipose tissue and metabolic syndrome: Too much, too little or neither","volume":"45","author":"Grundy","year":"2015","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1210\/js.2019-00065","article-title":"Hyperinsulinemia: An Early Indicator of Metabolic Dysfunction","volume":"3","author":"Thomas","year":"2019","journal-title":"J. Endocr. Soc."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Janssen, J. (2024). Overnutrition, Hyperinsulinemia and Ectopic Fat: It Is Time for A Paradigm Shift in the Management of Type 2 Diabetes. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25105488"},{"key":"ref_20","first-page":"E214","article-title":"Glucose clamp technique: A method for quantifying insulin secretion and resistance","volume":"237","author":"DeFronzo","year":"1979","journal-title":"Am. J. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1210\/rp.59.1.207","article-title":"Obesity, insulin resistance, and cardiovascular disease","volume":"59","author":"Reaven","year":"2004","journal-title":"Recent. Prog. Horm. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1056\/NEJM198805123181901","article-title":"Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians","volume":"318","author":"Lillioja","year":"1988","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"909","DOI":"10.7326\/0003-4819-113-12-909","article-title":"Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents","volume":"113","author":"Warram","year":"1990","journal-title":"Ann. Intern. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1210\/en.2015-1564","article-title":"A Mathematical Model of the Pathogenesis, Prevention, and Reversal of Type 2 Diabetes","volume":"157","author":"Ha","year":"2016","journal-title":"Endocrinology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/S0095-4543(05)70130-5","article-title":"The natural history of type 2 diabetes. Implications for clinical practice","volume":"26","author":"Edelman","year":"1999","journal-title":"Prim. Care"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1002\/dmrr.2322","article-title":"Basal state hyperinsulinemia in healthy normoglycemic adults heralds dysglycemia after more than two decades of follow up","volume":"28","author":"Dankner","year":"2012","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"86","DOI":"10.2337\/diacare.22.1.86","article-title":"Hyperinsulinemia cluster predicts the development of type 2 diabetes independently of family history of diabetes","volume":"22","author":"Kekalainen","year":"1999","journal-title":"Diabetes Care"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1016\/S0026-0495(99)90195-6","article-title":"Hyperinsulinemia in a normal population as a predictor of non-insulin-dependent diabetes mellitus, hypertension, and coronary heart disease: The Barilla factory revisited","volume":"48","author":"Zavaroni","year":"1999","journal-title":"Metabolism"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e124912","DOI":"10.1172\/jci.insight.124912","article-title":"Identification, pathophysiology, and clinical implications of primary insulin hypersecretion in nondiabetic adults and adolescents","volume":"3","author":"Trico","year":"2018","journal-title":"JCI Insight"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"179","DOI":"10.2337\/diab.36.2.179","article-title":"Plasma insulin response among Nauruans. Prediction of deterioration in glucose tolerance over 6 yr","volume":"36","author":"Sicree","year":"1987","journal-title":"Diabetes"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.2337\/diabetes.49.12.2094","article-title":"A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: Evidence for a pathogenic role of relative hyperinsulinemia","volume":"49","author":"Weyer","year":"2000","journal-title":"Diabetes"},{"key":"ref_32","first-page":"R612","article-title":"Beta-cell hyperresponsiveness: Earliest event in development of diabetes in monkeys","volume":"259","author":"Hansen","year":"1990","journal-title":"Am. J. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.jpeds.2008.01.021","article-title":"Which comes first? The obesity or the insulin? The behavior or the biochemistry?","volume":"152","author":"Lustig","year":"2008","journal-title":"J. Pediatr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1007\/s13679-017-0261-z","article-title":"Hyperinsulinemia: A Cause of Obesity?","volume":"6","author":"Erion","year":"2017","journal-title":"Curr. Obes. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s11886-016-0755-4","article-title":"Genetics of Insulin Resistance and the Metabolic Syndrome","volume":"18","author":"Brown","year":"2016","journal-title":"Curr. Cardiol. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Janssen, J. (2021). Hyperinsulinemia and Its Pivotal Role in Aging, Obesity, Type 2 Diabetes, Cardiovascular Disease and Cancer. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22157797"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S262","DOI":"10.2337\/dc08-s264","article-title":"Insulin resistance and hyperinsulinemia: Is. hyperinsulinemia the cart or the horse?","volume":"31","author":"Shanik","year":"2008","journal-title":"Diabetes Care"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2438","DOI":"10.2337\/dc12-0684","article-title":"Diabetes: Have we got it all wrong? Hyperinsulinism as the culprit: Surgery provides the evidence","volume":"35","author":"Pories","year":"2012","journal-title":"Diabetes Care"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1177\/1479164119827611","article-title":"Insulin resistance and insulin hypersecretion in the metabolic syndrome and type 2 diabetes: Time for a conceptual framework shift","volume":"16","author":"Nolan","year":"2019","journal-title":"Diab Vasc. Dis. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2174","DOI":"10.2337\/dbi21-0009","article-title":"What Regulates Basal Insulin Secretion and Causes Hyperinsulinemia?","volume":"70","author":"Corkey","year":"2021","journal-title":"Diabetes"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"941","DOI":"10.2337\/db23-0450","article-title":"Alterations in Adipose Tissue Distribution, Cell Morphology, and Function Mark Primary Insulin Hypersecretion in Youth With Obesity","volume":"73","author":"Trico","year":"2024","journal-title":"Diabetes"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"673","DOI":"10.2337\/db14-0694","article-title":"Insulin resistance as a physiological defense against metabolic stress: Implications for the management of subsets of type 2 diabetes","volume":"64","author":"Nolan","year":"2015","journal-title":"Diabetes"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"H1693","DOI":"10.1152\/ajpheart.00854.2012","article-title":"Insulin resistance protects the heart from fuel overload in dysregulated metabolic states","volume":"305","author":"Taegtmeyer","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.2337\/db19-0098","article-title":"Hypothesis: Role of Reduced Hepatic Insulin Clearance in the Pathogenesis of Type 2 Diabetes","volume":"68","author":"Bergman","year":"2019","journal-title":"Diabetes"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1507\/endocrj.EJ18-0435","article-title":"Ectopic fat, insulin resistance and metabolic disease in non-obese Asians: Investigating metabolic gradation","volume":"66","author":"Tamura","year":"2019","journal-title":"Endocr. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.cell.2021.12.016","article-title":"Adipose-tissue plasticity in health and disease","volume":"185","author":"Sakers","year":"2022","journal-title":"Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1194\/jlr.R700005-JLR200","article-title":"Thematic review series: Adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation","volume":"48","author":"Sethi","year":"2007","journal-title":"J. Lipid Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1097\/MED.0b013e3283514e13","article-title":"What causes the insulin resistance underlying obesity?","volume":"19","author":"Hardy","year":"2012","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"ref_49","unstructured":"Feingold, K.R., Anawalt, B., Blackman, M.R., Boyce, A., Chrousos, G., Corpas, E., de Herder, W.W., Dhatariya, K., Dungan, K., and Hofland, J. (2000). Adipose Tissue: Physiology to Metabolic Dysfunction. Endotext, MDText.com, Inc."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Cignarelli, A., Genchi, V.A., Perrini, S., Natalicchio, A., Laviola, L., and Giorgino, F. (2019). Insulin and Insulin Receptors in Adipose Tissue Development. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030759"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1016\/j.acra.2010.03.019","article-title":"Metabolic syndrome and ectopic fat deposition: What can CT and MR provide?","volume":"17","author":"Meng","year":"2010","journal-title":"Acad. Radiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1128\/MCB.01321-14","article-title":"Lipid-overloaded enlarged adipocytes provoke insulin resistance independent of inflammation","volume":"35","author":"Kim","year":"2015","journal-title":"Mol. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1038\/s41591-021-01501-8","article-title":"Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce","volume":"27","author":"Li","year":"2021","journal-title":"Nat. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1301\/nr.2007.jun.S7-S12","article-title":"Adipose tissue expandability in the maintenance of metabolic homeostasis","volume":"65","author":"Gray","year":"2007","journal-title":"Nutr. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Longo, M., Zatterale, F., Naderi, J., Parrillo, L., Formisano, P., Raciti, G.A., Beguinot, F., and Miele, C. (2019). Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092358"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1038\/oby.2010.56","article-title":"Sex- and depot-dependent differences in adipogenesis in normal-weight humans","volume":"18","author":"Tchoukalova","year":"2010","journal-title":"Obesity (Silver Spring)"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s00125-019-05040-3","article-title":"Sex differences in metabolic regulation and diabetes susceptibility","volume":"63","author":"Tramunt","year":"2020","journal-title":"Diabetologia"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4369","DOI":"10.2337\/db14-0318","article-title":"Genetic evidence for a normal-weight \u201cmetabolically obese\u201d phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes","volume":"63","author":"Yaghootkar","year":"2014","journal-title":"Diabetes"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1136\/jim-2016-000155","article-title":"Overnutrition, ectopic lipid and the metabolic syndrome","volume":"64","author":"Grundy","year":"2016","journal-title":"J. Investig. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.2337\/dc05-2565","article-title":"Effect of calorie restriction with or without exercise on insulin sensitivity, beta-cell function, fat cell size, and ectopic lipid in overweight subjects","volume":"29","author":"Heilbronn","year":"2006","journal-title":"Diabetes Care"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3023","DOI":"10.1210\/jcem.87.7.8638","article-title":"Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men","volume":"87","author":"Vehkavaara","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1111\/jdi.12665","article-title":"Impact of non-alcoholic fatty pancreas disease on glucose metabolism","volume":"8","author":"Yu","year":"2017","journal-title":"J. Diabetes Investig."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e2918","DOI":"10.1002\/dmrr.2918","article-title":"Ectopic fat accumulation in the pancreas and its biomarkers: A systematic review and meta-analysis","volume":"33","author":"Singh","year":"2017","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"623","DOI":"10.2147\/DMSO.S194690","article-title":"MRI assessment of ectopic fat accumulation in pancreas, liver and skeletal muscle in patients with obesity, overweight and normal BMI in correlation with the presence of central obesity and metabolic syndrome","volume":"12","author":"Pienkowska","year":"2019","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1463-1326.2006.00590.x","article-title":"Ectopic fat accumulation and metabolic syndrome","volume":"9","author":"Rasouli","year":"2007","journal-title":"Diabetes Obes. Metab."},{"key":"ref_66","first-page":"2","article-title":"Ectopic fat deposition and the metabolic syndrome in obese children and adolescents","volume":"71","author":"Cali","year":"2009","journal-title":"Horm. Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/nrendo.2010.199","article-title":"Lipodystrophy: Pathophysiology and advances in treatment","volume":"7","author":"Fiorenza","year":"2011","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_68","first-page":"39","article-title":"Ectopic fat accumulation: An important cause of insulin resistance in humans","volume":"95","year":"2002","journal-title":"J. R. Soc. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1016\/j.cell.2012.02.017","article-title":"Mechanisms for insulin resistance: Common threads and missing links","volume":"148","author":"Samuel","year":"2012","journal-title":"Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0002-9343(99)00414-3","article-title":"Lipodystrophies","volume":"108","author":"Garg","year":"2000","journal-title":"Am. J. Med."},{"key":"ref_71","first-page":"F1000 Faculty Rev-1756","article-title":"Recent advances in understanding lipodystrophy: A focus on lipodystrophy-associated cardiovascular disease and potential effects of leptin therapy on cardiovascular function","volume":"8","author":"Kress","year":"2019","journal-title":"F1000Res"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"4009","DOI":"10.1172\/JCI129190","article-title":"What lipodystrophies teach us about the metabolic syndrome","volume":"129","author":"Mann","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"S12","DOI":"10.1038\/sj.ijo.0802853","article-title":"Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus","volume":"28","author":"Heilbronn","year":"2004","journal-title":"Int. J. Obes. Relat. Metab. Disord."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1242\/dmm.002907","article-title":"Mouse models of inherited lipodystrophy","volume":"2","author":"Savage","year":"2009","journal-title":"Dis. Model. Mech."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"S11","DOI":"10.1038\/sj.ijo.0801493","article-title":"A-ZIP\/F-1 mice lacking white fat: A model for understanding lipoatrophic diabetes","volume":"24","author":"Reitman","year":"2000","journal-title":"Int. J. Obes. Relat. Metab. Disord."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1172\/JCI7901","article-title":"Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice","volume":"105","author":"Gavrilova","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.cell.2008.09.036","article-title":"Identification of white adipocyte progenitor cells in vivo","volume":"135","author":"Rodeheffer","year":"2008","journal-title":"Cell"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"367","DOI":"10.2337\/db07-0932","article-title":"High visceral and low abdominal subcutaneous fat stores in the obese adolescent: A determinant of an adverse metabolic phenotype","volume":"57","author":"Taksali","year":"2008","journal-title":"Diabetes"},{"key":"ref_79","first-page":"907","article-title":"Lipodistrophy: A paradigm for understanding the consequences of \u201coverloading\u201d adipose tissue","volume":"101","author":"Lim","year":"2021","journal-title":"Physiol. Rev."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4378","DOI":"10.2337\/db14-0319","article-title":"Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity","volume":"63","author":"Scott","year":"2014","journal-title":"Diabetes"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/ng.3714","article-title":"Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance","volume":"49","author":"Lotta","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2553","DOI":"10.1001\/jama.2018.19329","article-title":"Association of Genetic Variants Related to Gluteofemoral vs Abdominal Fat Distribution With Type 2 Diabetes, Coronary Disease, and Cardiovascular Risk Factors","volume":"320","author":"Lotta","year":"2018","journal-title":"JAMA"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.2337\/db23-0575","article-title":"Relationship of Fat Mass Ratio, a Biomarker for Lipodystrophy, With Cardiometabolic Traits","volume":"73","author":"Agrawal","year":"2024","journal-title":"Diabetes"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.2337\/dbi24-0018","article-title":"Lipodystrophy Prevalence, \u201cLipodystrophy-Like Phenotypes,\u201d and Diagnostic Challenges","volume":"73","author":"Akinci","year":"2024","journal-title":"Diabetes"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1042\/CS20140553","article-title":"Normal weight individuals who develop type 2 diabetes: The personal fat threshold","volume":"128","author":"Taylor","year":"2015","journal-title":"Clin. Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1042\/CS20230586","article-title":"Aetiology of Type 2 diabetes in people with a \u2018normal\u2019 body mass index: Testing the personal fat threshold hypothesis","volume":"137","author":"Taylor","year":"2023","journal-title":"Clin. Sci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1172\/JCI0215001","article-title":"Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy","volume":"109","author":"Petersen","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1016\/j.amjmed.2006.01.009","article-title":"Etiology of insulin resistance","volume":"119","author":"Petersen","year":"2006","journal-title":"Am. J. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"15430","DOI":"10.1073\/pnas.0904944106","article-title":"Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity","volume":"106","author":"Fabbrini","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1053\/j.gastro.2010.04.056","article-title":"Surgical removal of omental fat does not improve insulin sensitivity and cardiovascular risk factors in obese adults","volume":"139","author":"Fabbrini","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.2337\/db06-0783","article-title":"Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients","volume":"56","author":"Befroy","year":"2007","journal-title":"Diabetes"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"4361","DOI":"10.1172\/JCI86013","article-title":"Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance","volume":"126","author":"Petersen","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.cmet.2020.08.001","article-title":"A Membrane-Bound Diacylglycerol Species Induces PKC\u03f5-Mediated Hepatic Insulin Resistance","volume":"32","author":"Lyu","year":"2020","journal-title":"Cell Metab."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"8456","DOI":"10.1074\/jbc.275.12.8456","article-title":"Mechanism of insulin resistance in A-ZIP\/F-1 fatless mice","volume":"275","author":"Kim","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.2337\/diab.40.11.1397","article-title":"Development of muscle insulin resistance after liver insulin resistance in high-fat-fed rats","volume":"40","author":"Kraegen","year":"1991","journal-title":"Diabetes"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"32345","DOI":"10.1074\/jbc.M313478200","article-title":"Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease","volume":"279","author":"Samuel","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1007\/s00125-008-1116-7","article-title":"Pathogenesis of type 2 diabetes: Tracing the reverse route from cure to cause","volume":"51","author":"Taylor","year":"2008","journal-title":"Diabetologia"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/dme.12039","article-title":"Banting Memorial lecture 2012: Reversing the twin cycles of type 2 diabetes","volume":"30","author":"Taylor","year":"2013","journal-title":"Diabet. Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1097\/XCE.0000000000000201","article-title":"Pathogenesis and remission of type 2 diabetes: What has the twin cycle hypothesis taught us?","volume":"9","year":"2020","journal-title":"Cardiovasc. Endocrinol. Metab."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.cmet.2019.11.018","article-title":"Hepatic Lipoprotein Export and Remission of Human Type 2 Diabetes after Weight Loss","volume":"31","author":"Zhyzhneuskaya","year":"2020","journal-title":"Cell Metab."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"10878","DOI":"10.1073\/pnas.91.23.10878","article-title":"Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: Impairment in adipocyte-beta-cell relationships","volume":"91","author":"Lee","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.ecl.2008.09.002","article-title":"Intracellular lipid accumulation in liver and muscle and the insulin resistance syndrome","volume":"37","author":"Garvey","year":"2008","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.2337\/diabetes.50.10.2337","article-title":"Intramyocellular lipid is associated with resistance to in vivo insulin actions on glucose uptake, antilipolysis, and early insulin signaling pathways in human skeletal muscle","volume":"50","author":"Virkamaki","year":"2001","journal-title":"Diabetes"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nm0410-400","article-title":"Diacylglycerol-mediated insulin resistance","volume":"16","author":"Erion","year":"2010","journal-title":"Nat. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1001\/archinte.168.22.2449","article-title":"Effect of a Mediterranean diet supplemented with nuts on metabolic syndrome status: One-year results of the PREDIMED randomized trial","volume":"168","author":"Ros","year":"2008","journal-title":"Arch. Intern. Med."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1001\/jama.292.12.1440","article-title":"Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: A randomized trial","volume":"292","author":"Esposito","year":"2004","journal-title":"JAMA"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1017\/S000711451200298X","article-title":"Olive oil intake and CHD in the European Prospective Investigation into Cancer and Nutrition Spanish cohort","volume":"108","author":"Buckland","year":"2012","journal-title":"Br. J. Nutr."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.jhep.2019.04.013","article-title":"The beneficial effects of Mediterranean diet over low-fat diet may be mediated by decreasing hepatic fat content","volume":"71","author":"Gepner","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"777","DOI":"10.2337\/dc18-0836","article-title":"Effect of a Lifestyle Intervention Program With Energy-Restricted Mediterranean Diet and Exercise on Weight Loss and Cardiovascular Risk Factors: One-Year Results of the PREDIMED-Plus Trial","volume":"42","author":"Basora","year":"2019","journal-title":"Diabetes Care"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"3218","DOI":"10.1080\/10408398.2015.1107021","article-title":"A comprehensive meta-analysis on evidence of Mediterranean diet and cardiovascular disease: Are individual components equal?","volume":"57","author":"Grosso","year":"2017","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1093\/jn\/nxz147","article-title":"A Mediterranean Diet Rich in Extra-Virgin Olive Oil Is Associated with a Reduced Prevalence of Nonalcoholic Fatty Liver Disease in Older Individuals at High Cardiovascular Risk","volume":"149","author":"Pinto","year":"2019","journal-title":"J. Nutr."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1123\/jpah.2015-0560","article-title":"The Effect of Lifestyle Interventions on Excess Ectopic Fat Deposition Measured by Noninvasive Techniques in Overweight and Obese Adults: A Systematic Review and Meta-Analysis","volume":"13","author":"Hens","year":"2016","journal-title":"J. Phys. Act. Health"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1007\/s00125-018-4627-x","article-title":"Exercise training decreases pancreatic fat content and improves beta cell function regardless of baseline glucose tolerance: A randomised controlled trial","volume":"61","author":"Heiskanen","year":"2018","journal-title":"Diabetologia"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"E632","DOI":"10.1152\/ajpendo.2001.280.4.E632","article-title":"Elevated intramyocellular lipid concentration in obese subjects is not reduced after diet and exercise training","volume":"280","author":"Malenfant","year":"2001","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.cmet.2018.07.003","article-title":"Remission of Human Type 2 Diabetes Requires Decrease in Liver and Pancreas Fat Content but Is Dependent upon Capacity for beta Cell Recovery","volume":"28","author":"Taylor","year":"2018","journal-title":"Cell Metab."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.2337\/diacare.46.10.1579","article-title":"Subcutaneous abdominal fat and thigh muscle composition predict insulin sensitivity independently of visceral fat","volume":"46","author":"Goodpaster","year":"1997","journal-title":"Diabetes"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"144","DOI":"10.2337\/diabetes.51.1.144","article-title":"Insulin resistance in morbid obesity: Reversal with intramyocellular fat depletion","volume":"51","author":"Greco","year":"2002","journal-title":"Diabetes"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Ragavan, S., Elhelw, O., Majeed, W., Alkhaffaf, B., Senapati, S., Ammori, B.J., Mudaliar, R.N., and Syed, A.A. (2024). Weight Loss Following Bariatric Surgery in People with or without Metabolic Syndrome: A 5-Year Observational Comparative Study. J. Clin. Med., 13.","DOI":"10.3390\/jcm13010256"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"e1090","DOI":"10.1002\/hsr2.1090","article-title":"The effect of bariatric surgery on metabolic syndrome: A retrospective cohort study in Colombia","volume":"6","author":"Ramirez","year":"2023","journal-title":"Health Sci. Rep."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"364","DOI":"10.4997\/jrcpe.2017.414","article-title":"Bariatric surgery as a treatment for metabolic syndrome","volume":"47","author":"Cordero","year":"2017","journal-title":"J. R. Coll. Physicians Edinb."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"e084356","DOI":"10.1136\/bmjopen-2024-084356","article-title":"Assessing economic investment required to scale up bariatric surgery capacity in England: A health economic modelling analysis","volume":"14","author":"Pournaras","year":"2024","journal-title":"BMJ Open"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/S2213-8587(21)00179-0","article-title":"Effects of liraglutide on visceral and ectopic fat in adults with overweight and obesity at high cardiovascular risk: A randomised, double-blind, placebo-controlled, clinical trial","volume":"9","author":"Neeland","year":"2021","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.clnesp.2023.12.005","article-title":"Effects of liraglutide on intrapancreatic fat deposition in patients with type 2 diabetes","volume":"59","author":"Kuriyama","year":"2024","journal-title":"Clin. Nutr. ESPEN"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/S2213-8587(22)00070-5","article-title":"Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): A substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial","volume":"10","author":"Gastaldelli","year":"2022","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Jastreboff, A.M., le Roux, C.W., Stefanski, A., Aronne, L.J., Halpern, B., Wharton, S., Wilding, J.P.H., Perreault, L., Zhang, S., and Battula, R. Tirzepatide for Obesity Treatment and Diabetes Prevention. N. Engl. J. Med., 2024.","DOI":"10.1056\/NEJMoa2410819"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1210\/jc.2015-3213","article-title":"Biomarkers of Ectopic Fat Deposition: The Next Frontier in Serum Lipidomics","volume":"101","author":"Perreault","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.1038\/s41366-021-00854-x","article-title":"Untargeted metabolomics reveals plasma metabolites predictive of ectopic fat in pancreas and liver as assessed by magnetic resonance imaging: The TOFI_Asia study","volume":"45","author":"Wu","year":"2021","journal-title":"Int. J. Obes."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/24\/13238\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:51:07Z","timestamp":1760115067000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/24\/13238"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,10]]},"references-count":127,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ijms252413238"],"URL":"https:\/\/doi.org\/10.3390\/ijms252413238","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,10]]}}}