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• W2885775983 abstract "Obesity increases the risks of developing cardiovascular and metabolic diseases and degrades quality of life, ultimately increasing the risk of death. However, not all forms of obesity are equally dangerous: some individuals, despite higher percentages of body fat, are at less risk for certain chronic obesity-related complications. Many open questions remain about why this occurs. Data suggest that the physical location of fat and the overall health of fat dramatically influence disease risk; for example, higher concentrations of visceral relative to subcutaneous adipose tissue are associated with greater metabolic risks. As such, understanding the determinants of the location and health of adipose tissue can provide insight about the pathological consequences of obesity and can begin to outline targets for novel therapeutic approaches to combat the obesity epidemic. Although age and sex hormones clearly play roles in fat distribution and location, much remains unknown about gene regulation at the level of adipose tissue or how genetic variants regulate fat distribution. In this review, we discuss what is known about the determinants of body fat distribution, and we highlight the important roles of sex hormones, aging, and genetic variation in the determination of body fat distribution and its contribution to obesity-related comorbidities. Obesity increases the risks of developing cardiovascular and metabolic diseases and degrades quality of life, ultimately increasing the risk of death. However, not all forms of obesity are equally dangerous: some individuals, despite higher percentages of body fat, are at less risk for certain chronic obesity-related complications. Many open questions remain about why this occurs. Data suggest that the physical location of fat and the overall health of fat dramatically influence disease risk; for example, higher concentrations of visceral relative to subcutaneous adipose tissue are associated with greater metabolic risks. As such, understanding the determinants of the location and health of adipose tissue can provide insight about the pathological consequences of obesity and can begin to outline targets for novel therapeutic approaches to combat the obesity epidemic. Although age and sex hormones clearly play roles in fat distribution and location, much remains unknown about gene regulation at the level of adipose tissue or how genetic variants regulate fat distribution. In this review, we discuss what is known about the determinants of body fat distribution, and we highlight the important roles of sex hormones, aging, and genetic variation in the determination of body fat distribution and its contribution to obesity-related comorbidities. Decades of epidemiological research have shown that body fat distribution influences disease risk independently of total body weight or body fat percentage (1Kissebah A.H. Vydelingum N. Murray R. Evans D.J. Hartz A.J. Kalkhoff R.K. Adams P.W. Relation of body fat distribution to metabolic complications of obesity.J. Clin. Endocrinol. Metab. 1982; 54: 254-260Crossref PubMed Google Scholar, 2Bonora E. Del Prato S. Bonadonna R.C. Gulli G. Solini A. Shank M.L. Ghiatas A.A. Lancaster J.L. Kilcoyne R.F. Alyassin A.M. et al.Total body fat content and fat topography are associated differently with in vivo glucose metabolism in nonobese and obese nondiabetic women.Diabetes. 1992; 41: 1151-1159Crossref PubMed Google Scholar). While early investigators regarded adipose as a rather homogenous tissue, contemporary evidence indicates that discrete fat depots function and respond to metabolic challenges (such as increased caloric intake) in different ways, with significant clinical implications (3Guglielmi V. Sbraccia P. Obesity phenotypes: depot-differences in adipose tissue and their clinical implications.Eat. Weight Disord. 2018; 23: 3-14Crossref PubMed Scopus (26) Google Scholar). For instance, adipose tissue depots differ in terms of susceptibility to vasculature inflammation, endothelial function, and activity of LPL (a critical enzyme mediating fatty acid uptake into adipocytes) (4Tahara N. Yamagishi S. Kodama N. Tahara A. Honda A. Nitta Y. Igata S. Matsui T. Takeuchi M. Kaida H. et al.Clinical and biochemical factors associated with area and metabolic activity in the visceral and subcutaneous adipose tissues by FDG-PET/CT.J. Clin. Endocrinol. Metab. 2015; 100: E739-E747Crossref PubMed Scopus (0) Google Scholar). There are also depot-specific differences in lipid turnover in obese individuals, which have been linked to obesity-related comorbidities (5Spalding K.L. Bernard S. Naslund E. Salehpour M. Possnert G. Appelsved L. Fu K.Y. Alkass K. Druid H. Thorell A. et al.Impact of fat mass and distribution on lipid turnover in human adipose tissue.Nat. Commun. 2017; 8: 15253Crossref PubMed Scopus (26) Google Scholar). Additionally, there are data to suggest that factors such as adipokines are differentially released from different adipose tissue depots and this too is with metabolic syndrome (MetS) risk (6Liu X. Li X. Li C. Gong C. Liu S. Shi Y. Study on regulation of adipokines on body fat distribution and its correlation with metabolic syndrome in type 2 diabetes mellitus.Minerva Endocrinol. 2017; (Epub ahead of print. December 4, 2017; doi:10.23736/S0391-1977.17.02773-0.)Google Scholar). Body adiposity is located mainly either beneath the skin [subcutaneous adipose tissue (SCAT)] or around internal organs [visceral adipose tissue (VAT)], although it can also be found in bone marrow (yellow bone marrow), retro-orbital and periarticular regions, and within tissues such as muscle (intermuscular) (7Gesta S. Tseng Y.H. Kahn C.R. Developmental origin of fat: tracking obesity to its source.Cell. 2007; 131: 242-256Abstract Full Text Full Text PDF PubMed Scopus (929) Google Scholar) and vital organs, often referred as ectopic fat deposition. Predominantly, adipose tissue is accumulated as SCAT (80–90%) (8Karastergiou K. Smith S.R. Greenberg A.S. Fried S.K. Sex differences in human adipose tissues - the biology of pear shape.Biol. Sex Differ. 2012; 3: 13Crossref PubMed Scopus (302) Google Scholar), and the main depots of SCAT are the abdominal, subscapular (on the upper back), gluteal, and femoral (thigh) areas (8Karastergiou K. Smith S.R. Greenberg A.S. Fried S.K. Sex differences in human adipose tissues - the biology of pear shape.Biol. Sex Differ. 2012; 3: 13Crossref PubMed Scopus (302) Google Scholar, 9Ibrahim M.M. Subcutaneous and visceral adipose tissue: structural and functional differences.Obes. Rev. 2010; 11: 11-18Crossref PubMed Scopus (831) Google Scholar). The importance of this depot distinction is that SCAT depots are located right under the skin and do not communicate with internal organs. Whole-body studies using imaging techniques have revealed that premenopausal women present with more SCAT in the abdominal and gluteofemoral areas than men, especially superficial SCAT, which would be the adipose tissue that is most proximal to the skin (8Karastergiou K. Smith S.R. Greenberg A.S. Fried S.K. Sex differences in human adipose tissues - the biology of pear shape.Biol. Sex Differ. 2012; 3: 13Crossref PubMed Scopus (302) Google Scholar). Alternatively, VAT is mainly located inside the intraabdominal cavity in close proximity to major organs, including the liver and intestines. One important distinction with this depot is that it drains its constituents (fatty free acids and adipokines) into the portal circulation (10Shen W. Wang Z. Punyanita M. Lei J. Sinav A. Kral J.G. Imielinska C. Ross R. Heymsfield S.B. Adipose tissue quantification by imaging methods: a proposed classification.Obes. Res. 2003; 11: 5-16Crossref PubMed Google Scholar), where they can exert their actions to affect metabolism (7Gesta S. Tseng Y.H. Kahn C.R. Developmental origin of fat: tracking obesity to its source.Cell. 2007; 131: 242-256Abstract Full Text Full Text PDF PubMed Scopus (929) Google Scholar). It is thought that VAT accounts for 6–20% of total body fat, with higher amounts in males than in females (8Karastergiou K. Smith S.R. Greenberg A.S. Fried S.K. Sex differences in human adipose tissues - the biology of pear shape.Biol. Sex Differ. 2012; 3: 13Crossref PubMed Scopus (302) Google Scholar). Additionally, there is a small amount of VAT around the heart, known as epicardial fat. Several studies have reported positive associations of abdominal VAT accumulation, also known as “android” fat distribution, with mortality, CVD, and the MetS risk (11Pischon T. Boeing H. Hoffmann K. Bergmann M. Schulze M.B. Overvad K. van der Schouw Y.T. Spencer E. Moons K.G. Tjonneland A. et al.General and abdominal adiposity and risk of death in Europe.N. Engl. J. Med. 2008; 359: 2105-2120Crossref PubMed Scopus (1359) Google Scholar, 12Zong G. Zhang Z. Yang Q. Wu H. Hu F.B. Sun Q. Total and regional adiposity measured by dual-energy X-ray absorptiometry and mortality in NHANES 1999–2006.Obesity (Silver Spring). 2016; 24: 2414-2421Crossref PubMed Scopus (20) Google Scholar, 13Dong B. Peng Y. Wang Z. Adegbija O. Hu J. Ma J. Ma Y.H. Joint association between body fat and its distribution with all-cause mortality: a data linkage cohort study based on NHANES (1988–2011).PLoS One. 2018; 13: e0193368Crossref PubMed Scopus (0) Google Scholar, 14Czernichow S. Kengne A.P. Stamatakis E. Hamer M. Batty G.D. Body mass index, waist circumference and waist-hip ratio: which is the better discriminator of cardiovascular disease mortality risk?: evidence from an individual-participant meta-analysis of 82 864 participants from nine cohort studies.Obes. Rev. 2011; 12: 680-687PubMed Google Scholar, 15Barreira T.V. Staiano A.E. Harrington D.M. Heymsfield S.B. Smith S.R. Bouchard C. Katzmarzyk P.T. Anthropo­metric correlates of total body fat, abdominal adiposity, and cardiovascular disease risk factors in a biracial sample of men and women.Mayo Clin. Proc. 2012; 87: 452-460Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 16Kouli G.M. Panagiotakos D.B. Kyrou I. Georgousopoulou E.N. Chrysohoou C. Tsigos C. Tousoulis D. Pitsavos C. Visceral adiposity index and 10-year cardiovascular disease incidence: The ATTICA study.Nutr. Metab. Cardiovasc. Dis. 2017; 27: 881-889Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). Risks associated with CVD have been particularly well-demonstrated; for example, waist circumference (WC) and waist to hip ratio (WHR), which are commonly used to measure abdominal fat accumulation, were associated with poor cardiac mechanics, including worse global longitudinal and diastolic strain rate (17Selvaraj S. Martinez E.E. Aguilar F.G. Kim K.Y. Peng J. Sha J. Irvin M.R. Lewis C.E. Hunt S.C. Arnett D.K. et al.Association of central adiposity with adverse cardiac mechanics: findings from the Hypertension Genetic Epidemiology Network Study.Circ. Cardiovasc. Imaging. 2016; 9: e004396Crossref PubMed Scopus (36) Google Scholar) as well as left ventricular remodeling and reduced function (18Wilner B. Garg S. Ayers C.R. Maroules C.D. McColl R. Matulevicius S.A. de Lemos J.A. Drazner M.H. Peshock R. Neeland I.J. Dynamic relation of changes in weight and indices of fat distribution with cardiac structure and function: the Dallas Heart Study.J. Am. Heart Assoc. 2017; 6: e005897Crossref PubMed Scopus (10) Google Scholar). Abdominal VAT accumulation has also been linked with systemic oxidative stress, another mechanism that may increase CVD risk (19Kelli H.M. Corrigan III, F.E. Heinl R.E. Dhindsa D.S. Hammadah M. Samman-Tahhan A. Sandesara P. O'Neal W.T. Al Mheid I. Ko Y.A. et al.Relation of changes in body fat distribution to oxidative stress.Am. J. Cardiol. 2017; 120: 2289-2293Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). Even in the nonobese, abdominal fat accumulation is linked with hypertension (20Owolabi E.O. Ter Goon D. Adeniyi O.V. Central obesity and normal-weight central obesity among adults attending healthcare facilities in Buffalo City Metropolitan Municipality, South Africa: a cross-sectional study.J. Health Popul. Nutr. 2017; 36: 54Crossref PubMed Scopus (29) Google Scholar) and predisposes individuals to diseases associated with MetS (21Goluch-Koniuszy Z.S. Kuchlewska M. Body composition in 13-year-old adolescents with abdominal obesity, depending on the BMI value.Adv. Clin. Exp. Med. 2017; 26: 973-979Crossref PubMed Scopus (3) Google Scholar, 22Oliveira R.G. Guedes D.P. Performance of anthropometric indicators as predictors of metabolic syndrome in Brazilian adolescents.BMC Pediatr. 2018; 18: 33Crossref PubMed Scopus (11) Google Scholar). WC, WHR, and dual-energy X-ray absorptiometry imaging methods measure the combined volumes of abdominal VAT and SCAT; thus, these measures cannot speak to the relative contributions of abdominal VAT versus SCAT to disease risk. However, the metabolic activity of abdominal SCAT has been associated with a worsening of plasma lipids, insulin, and C-reactive protein, while abdominal VAT is associated with dysregulated glucose homeostasis and fatty liver (23Kwon H.W. Lee S.M. Lee J.W. Oh J.E. Lee S.W. Kim S.Y. Association between volume and glucose metabolism of abdominal adipose tissue in healthy population.Obes. Res. Clin. Pract. 2017; 11: 133-143Crossref PubMed Scopus (10) Google Scholar). In the Jackson Heart Study, while both abdominal VAT and SCAT volumes were positively correlated with fasting plasma glucose and triglyceride levels, VAT deposition in the abdomen was most strongly associated with hypertension, type 2 diabetes mellitus (T2DM), and MetS risk (24Liu J. Fox C.S. Hickson D.A. May W.D. Hairston K.G. Carr J.J. Taylor H.A. Impact of abdominal visceral and subcutaneous adipose tissue on cardiometabolic risk factors: the Jackson Heart Study.J. Clin. Endocrinol. Metab. 2010; 95: 5419-5426Crossref PubMed Scopus (268) Google Scholar). These data imply that depot-specific mechanisms contribute to different aspects of cardiometabolic risk. In contrast to abdominal VAT, accumulation of fat in the gluteofemoral SCAT depot produces a “gynoid” body fat pattern, and it has long been believed that deposition of excess adipose tissue in this depot is not associated with MetS risk (25Björntorp P. The regulation of adipose tissue distribution in humans.Int. J. Obes. Relat. Metab. Disord. 1996; 20: 291-302PubMed Google Scholar, 26Donahue R.P. Abbott R.D. Central obesity and coronary heart disease in men.Lancet. 1987; 2: 1215Abstract PubMed Google Scholar, 27Lapidus L. Bengtsson C. Larsson B. Pennert K. Rybo E. Sjostrom L. Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of participants in the population study of women in Gothenburg, Sweden.Br. Med. J. (Clin. Res. 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Hence, many obesity-associated pathologies are correlated with abdominal VAT versus gluteofemoral SCAT deposition. Body fat distribution in humans is sexually dimorphic, with men and women having differential distribution of adipose tissue. On average, premenopausal women accumulate more SCAT fat in the gluteofemoral depot (32Dua A. Hennes M.I. Hoffmann R.G. Maas D.L. Krakower G.R. Sonnenberg G.E. Kissebah A.H. Leptin: a significant indicator of total body fat but not of visceral fat and insulin insensitivity in African-American women.Diabetes. 1996; 45: 1635-1637Crossref PubMed Google Scholar, 33Havel P.J. Kasim-Karakas S. Mueller W. Johnson P.R. Gingerich R.L. Stern J.S. Relationship of plasma leptin to plasma insulin and adiposity in normal weight and overweight women: effects of dietary fat content and sustained weight loss.J. Clin. Endocrinol. Metab. 1996; 81: 4406-4413Crossref PubMed Scopus (343) Google Scholar, 34Legato M.J. Gender-specific aspects of obesity.Int. J. Fertil. 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The prevalence of metabolic diseases associated with abdominal obesity, such as insulin resistance and CVD, also increase in postmenopausal women (38Després J.P. The insulin resistance-dyslipidemic syndrome of visceral obesity: effect on patients' risk.Obes. Res. 1998; 6: 8S-17SCrossref PubMed Google Scholar, 39Lamarche B. Abdominal obesity and its metabolic complications: implications for the risk of ischaemic heart disease.Coron. Artery Dis. 1998; 9: 473-481Crossref PubMed Google Scholar). Thus, there is evidence to suggest that sex and sex hormones are key determinants of body fat distribution. In the following sections, we will describe how the sex hormones, estrogen and testosterone, are implicated in body fat distribution. In an effort to begin to understand how sex hormones influence body fat distribution, data have been accumulated in both human and rodent studies. In both cases, human and rodent studies demonstrate that estrogens drive fat accumulation in the gluteofemoral SCAT depot rather than in the abdominal VAT depot (40Kangas R. Morsiani C. Pizza G. Lanzarini C. Aukee P. Kaprio J. Sipila S. Franceschi C. Kovanen V. Laakkonen E.K. et al.Menopause and adipose tissue: miR-19a-3p is sensitive to hormonal replacement.Oncotarget. 2017; 9: 2279-2294Crossref PubMed Scopus (7) Google Scholar, 41Marchand G.B. Carreau A.M. Weisnagel S.J. Bergeron J. Labrie F. Lemieux S. Tchernof A. Increased body fat mass explains the positive association between circulating estradiol and insulin resistance in postmenopausal women.Am. J. Physiol. Endocrinol. Metab. 2018; 314: E448-E456Crossref PubMed Scopus (9) Google Scholar, 42Tao Z. Zheng L.D. Smith C. Luo J. Robinson A. Almeida F.A. Wang Z. Olumi A.F. Liu D. Cheng Z. Estradiol signaling mediates gender difference in visceral adiposity via autophagy.Cell Death Dis. 2018; 9: 309Crossref PubMed Scopus (4) Google Scholar), implicating estrogens as determinants of body fat distribution (37Puder J.J. Monaco S.E. Sen Gupta S. Wang J. Ferin M. Warren M.P. Estrogen and exercise may be related to body fat distribution and leptin in young women.Fertil. Steril. 2006; 86: 694-699Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 43Garaulet M. Perex-Llamas F. Fuente T. Zamora S. Tebar F.J. Anthropometric, computed tomography and fat cell data in an obese population: relationship with insulin, leptin, tumor necrosis factor-alpha, sex hormone-binding globulin and sex hormones.Eur. J. Endocrinol. 2000; 143: 657-666Crossref PubMed Google Scholar, 44Leenen R. van der Kooy K. Seidell J.C. Deurenberg P. Koppeschaar H.P. Visceral fat accumulation in relation to sex hormones in obese men and women undergoing weight loss therapy.J. Clin. Endocrinol. Metab. 1994; 78: 1515-1520Crossref PubMed Scopus (0) Google Scholar). In girls, increases in circulating estrogens occur during puberty onset and coincide with a marked increase in gluteofemoral SCAT fat deposition (45Wells J.C. Sexual dimorphism of body composition.Best Pract. Res. Clin. Endocrinol. Metab. 2007; 21: 415-430Crossref PubMed Scopus (441) Google Scholar). The resulting “gynoid” fat distribution is typical of reproductive-aged women; however, as ovarian production of estrogens declines after menopause, abdominal VAT mass increases. Estrogen replacement therapy in postmenopausal women decreases abdominal VAT mass (46Papadakis G.E. Hans D. Rodriguez E.G. Vollenweider P. Waeber G. Marques-Vidal P. Lamy O. Menopausal hormone therapy is associated with reduced total and visceral adiposity, the OsteoLaus cohort.J. Clin. Endocrinol. Metab. 2018; 103: 1948-1957Crossref PubMed Scopus (0) Google Scholar). Moreover, the ability of estrogens to affect body fat distribution is not confined to women. Evidence of the benefit of estrogens in men and male mice is demonstrated by studies showing that loss of estrogen signaling in males promotes obesity and impairs glucose metabolism (47Carani C. Qin K. Simoni M. Faustini-Fustini M. Serpente S. Boyd J. Korach K.S. Simpson E.R. Effect of testosterone and estradiol in a man with aromatase deficiency.N. Engl. J. Med. 1997; 337: 91-95Crossref PubMed Scopus (909) Google Scholar, 48Maffei L. Rochira V. Zirilli L. Antunez P. Aranda C. Fabre B. Simone M.L. Pignatti E. Simpson E.R. Houssami S. et al.A novel compound heterozygous mutation of the aromatase gene in an adult man: reinforced evidence on the relationship between congenital oestrogen deficiency, adiposity and the metabolic syndrome.Clin. Endocrinol. (Oxf.). 2007; 67: 218-224Crossref PubMed Scopus (0) Google Scholar, 49Morishima A. Grumbach M.M. Simpson E.R. Fisher C. Qin K. 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Wulczyn K.E. Thomas B.J. et al.Gonadal steroids and body composition, strength, and sexual function in men.N. Engl. J. Med. 2013; 369: 1011-1022Crossref PubMed Scopus (365) Google Scholar, 53Chao J. Rubinow K.B. Kratz M. Amory J.K. Matsumoto A.M. Page S.T. Short-term estrogen withdrawal increases adiposity in healthy men.J. Clin. Endocrinol. Metab. 2016; 101: 3724-3731Crossref PubMed Scopus (0) Google Scholar). Taken together, these data support that estrogens per se mediate preferential fat accumulation in the SCAT, but the mechanisms remain unclear. Estrogens are mainly produced by the ovaries in premenopausal women and by the testes in men, but there is also local production of estrogens in adipose tissue mediated by aromatase; thus, estrogens can have a local effect in adipose tissue as well (54Nelson L.R. Bulun S.E. Estrogen production and action.J. Am. Acad. Dermatol. 2001; 45: S116-S124Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 55Siiteri P.K. Adipose tissue as a source of hormones.Am. J. Clin. Nutr. 1987; 45: 277-282Crossref PubMed Scopus (421) Google Scholar). In general, estrogens act through binding of estrogen receptors in a wide variety of organs, including adipose tissue (56Morselli E. Santos R.S. Criollo A. Nelson M.D. Palmer B.F. Clegg D.J. The effects of oestrogens and their receptors on cardiometabolic health.Nat. Rev. Endocrinol. 2017; 13: 352-364Crossref PubMed Scopus (47) Google Scholar, 57Morselli E. de Souza Santos R. Gao S. Avalos Y. Criollo A. Palmer B.F. Clegg D.J. Impact of estrogens and estrogen receptor-α in brain lipid metabolism.Am. J. Physiol. Endocrinol. Metab. 2018; 315: E7-E14Crossref PubMed Scopus (9) Google Scholar). Estrogen receptor α (ERα) has been shown to impact whole-body energy expenditure, body fat accumulation, and glucose homeostasis both in humans and mice (58Frank A.P. Palmer B.F. Clegg D.J. Do estrogens enhance activation of brown and beiging of adipose tissues?.Physiol. Behav. 2018; 187: 24-31Crossref PubMed Scopus (0) Google Scholar). Specifically, both male and female mice with total body deletion of ERα (ERαKO mice) are obese, insulin resistant, and dyslipidemic (59Heine P.A. Taylor J.A. Iwamoto G.A. Lubahn D.B. Cooke P.S. Increased adipose tissue in male and female estrogen receptor-alpha knockout mice.Proc. Natl. Acad. Sci. USA. 2000; 97: 12729-12734Crossref PubMed Scopus (918) Google Scholar); similarly, knockout of ERα selectively in the adipose tissue of mice increased adipocyte size, adipose tissue inflammation, and fibrosis, and altered fat distribution in both males and females (60Davis K.E. Neinast M.D. Sun K. Skiles W.M. Bills J.D. Zehr J.A. Zeve D. Hahner L.D. Cox D.W. Gent L.M. et al.The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis.Mol. Metab. 2013; 2: 227-242Crossref PubMed Scopus (137) Google Scholar, 61Martínez de Morentin P.B. 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During a “healthy” adipose tissue expansion, when adipose tissue reaches the diffusional limit of oxygen, a stress signal is induced to promote angiogenesis, and remodeling of the extracellular matrix occurs to facilitate further expansion and minimize hypoxia, or lack of oxygen, within the adipose tissue. At the same time, cells from the stromal vascular fraction of adipose tissue, which includes preadipocytes, endothelial cells, immune cells, and fibroblasts, among others (63Bora P. Majumdar A.S. Adipose tissue-derived stromal vascular fraction in regenerative medicine: a brief review on biology and translation.Stem Cell Res. Ther. 2017; 8: 145Crossref PubMed Scopus (114) Google Scholar), also face functional changes in response to alteration in the energy status/stress, and this contributes to adipose tissue expansion and remodeling (64Choe S.S. Huh J.Y. Hwang I.J. Kim J.I. Kim J.B. Adipose tissue remodeling: its role in energy metabolism and metabolic disorders.Front. Endocrinol. (Lausanne). 2016; 7: 30Crossref PubMed Scopus (355) Google Scholar). During chronic overnutrition, however, adipose tissue expands beyond the tissue's ability for adequate angiogenesis and remodeling, which results in hypoxia, fibrosis, and adipocyte death, which are major contributors to metabolic disturbances, as seen in obesity and diseases such as T2DM (65Crewe C. An Y.A. Scherer P.E. The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis.J. Clin. Invest. 2017; 127: 74-82Crossref PubMed Scopus (184) Google Scholar). On the other hand, in situations where metabolic fuels are not sufficient to meet energy needs, a lipolytic cascade is initiated and results in the breakdown of triglycerides into free fatty acids and glycerol. Thus, adipose tissue is expanded and remodeled in response to alterations in the energy status/stress (64Choe S.S. Huh J.Y. Hwang I.J. K" @default.
• W2885775983 created "2018-08-22" @default.
• W2885775983 creator A5017181603 @default.
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• W2885775983 date "2019-10-01" @default.
• W2885775983 modified "2023-10-15" @default.
• W2885775983 title "Determinants of body fat distribution in humans may provide insight about obesity-related health risks" @default.
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