A low visceral fat proportion, independent of total body fat mass, protects obese adolescent girls against fatty liver and glucose dysregulation: a longitudinal study



The relative proportion of visceral fat (VAT) to subcutaneous fat (SAT) has been described as a major determinant of insulin resistance (IR). Our study sought to evaluate the effect of body fat distribution on glucose metabolism and intrahepatic fat content over time in a multiethnic cohort of obese adolescents.


We examined markers of glucose metabolism by oral glucose tolerance test, and body fat distribution by abdominal MRI at baseline and after 19.2 ± 11.4 months in a cohort of 151 obese adolescents (88 girls, 63 boys; mean age 13.3 ± 3.4 years; mean BMI z-score 2.15 ± 0.70). Hepatic fat content was assessed by fast-gradient MRI in a subset of 93 subjects. We used the median value of VAT/(VAT + SAT) ratio within each gender at baseline to stratify our sample into high and low ratio groups (median value 0.0972 in girls and 0.118 in boys).


Female subjects tended to remain in their VAT/(VAT + SAT) category over time (change over follow-up P = 0.14 among girls, and P = 0.04 among boys). Baseline VAT/(VAT + SAT) strongly predicted the hepatic fat content, fasting insulin, 2-h glucose, and whole-body insulin sensitivity index at follow-up among girls, but not in boys.


The VAT/(VAT + SAT) ratio is a major determinant of impaired glucose metabolism and hepatic fat accumulation over time, and its effects are more pronounced in girls than in boys.

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  1. 1.

    de Onis M, Blossner M, Borghi E. Global prevalence and trends of overweight and obesity among preschool children. Am J Clin Nutr. 2010;92:1257–64.

  2. 2.

    Twig G, Yaniv G, Levine H, Leiba A, Goldberger N, Derazne E, et al. Body-mass index in 2.3 million adolescents and cardiovascular death in adulthood. N Engl J Med. 2016;374:2430–40.

  3. 3.

    D’Adamo E, Santoro N, Caprio S. Metabolic syndrome in pediatrics: old concepts revised, new concepts discussed. Pediatr Clin North Am. 2011;58:1241–55.

  4. 4.

    Lee MJ, Wu Y, Fried SK. Adipose tissue heterogeneity: implication of depot differences in adipose tissue for obesity complications. Mol Asp Med. 2013;34:1–11.

  5. 5.

    Weiss R, Dufour S, Taksali SE, Tamborlane WV, Petersen KF, Bonadonna RC, et al. Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning. Lancet. 2003;362:951–7.

  6. 6.

    Ravussin ESS. Increased fat intake, impaired fat oxidation, and failure of fat cell proliferation result in ectopic fat storage, insulin resistance, and type 2 diabetes mellitus. Ann N Y Acad Sci. 2002;967:363–78.

  7. 7.

    Taksali SE, Caprio S, Dziura J, Dufour S, Cali AM, Goodman TR, et al. High visceral and low abdominal subcutaneous fat stores in the obese adolescent: a determinant of an adverse metabolic phenotype. Diabetes. 2008;57:367–71.

  8. 8.

    Kursawe R, Eszlinger M, Narayan D, Liu T, Bazuine M, Cali AM, et al. Cellularity and adipogenic profile of the abdominal subcutaneous adipose tissue from obese adolescents: association with insulin resistance and hepatic steatosis. Diabetes. 2010;59:2288–96.

  9. 9.

    Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444:881–7.

  10. 10.

    Kaess BM, Pedley A, Massaro JM, Murabito J, Hoffmann U, Fox CS. The ratio of visceral to subcutaneous fat, a metric of body fat distribution, is a unique correlate of cardiometabolic risk. Diabetologia. 2012;55:2622–30.

  11. 11.

    Gastaldelli A, Sironi AM, Ciociaro D, Positano V, Buzzigoli E, Giannessi D, et al. Visceral fat and beta cell function in non-diabetic humans. Diabetologia. 2005;48:2090–6.

  12. 12.

    Miyazaki Y, DeFronzo RA. Visceral fat dominant distribution in male type 2 diabetic patients is closely related to hepatic insulin resistance, irrespective of body type. Cardiovasc Diabetol. 2009;8:44.

  13. 13.

    Kelly AS, Dengel DR, Hodges J, Zhang L, Moran A, Chow L, et al. The relative contributions of the abdominal visceral and subcutaneous fat depots to cardiometabolic risk in youth. Clin Obes. 2014;4:101–7.

  14. 14.

    Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child. 1976;51:170–9.

  15. 15.

    Yamashita A, Watanabe M, Sato K, Miyashita T, Nagatsuka T, Kondo H, et al. Reverse reaction of lysophosphatidylinositol acyltransferase. Functional reconstitution of coenzyme A-dependent transacylation system. J Biol Chem. 2003;278:30382–93.

  16. 16.

    Burgert TS, Taksali SE, Dziura J, Goodman TR, Yeckel CW, Papademetris X, et al. Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat. J Clin Endocrinol Metab. 2006;91:4287–94.

  17. 17.

    Kim H, Taksali SE, Dufour S, Befroy D, Goodman TR, Petersen KF, et al. Comparative MR study of hepatic fat quantification using single-voxel proton spectroscopy, two-point dixon and three-point IDEAL. Magn Reson Med. 2008;59:521–7.

  18. 18.

    Yeckel CW, Weiss R, Dziura J, Taksali SE, Dufour S, Burgert TS, et al. Validation of insulin sensitivity indices from oral glucose tolerance test parameters in obese children and adolescents. J Clin Endocrinol Metab. 2004;89:1096–101.

  19. 19.

    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9.

  20. 20.

    Yeckel CW, Taksali SE, Dziura J, Weiss R, Burgert TS, Sherwin RS, et al. The normal glucose tolerance continuum in obese youth: evidence for impairment in beta-cell function independent of insulin resistance. J Clin Endocrinol Metab. 2005;90:747–54.

  21. 21.

    Cohen J. Statistical power analysis for the behavioral-sciences. Perceptual and motor skills. Hillsdale, N.J. - L. Erlbaum Associates. 1988;67:1007.

  22. 22.

    Cali AM, De Oliveira AM, Kim H, Chen S, Reyes-Mugica M, Escalera S, et al. Glucose dysregulation and hepatic steatosis in obese adolescents: is there a link? Hepatology. 2009;49:1896–903.

  23. 23.

    Hevener AL, Clegg DJ, Mauvais-Jarvis F. Impaired estrogen receptor action in the pathogenesis of the metabolic syndrome. Mol Cell Endocrinol. 2015;418(Pt 3):306–21.

  24. 24.

    Palmer BF, Clegg DJ. The sexual dimorphism of obesity. Mol Cell Endocrinol. 2015;402:113–9.

  25. 25.

    Fried SK, Lee MJ, Karastergiou K. Shaping fat distribution: new insights into the molecular determinants of depot- and sex-dependent adipose biology. Obesity (Silver Spring). 2015;23:1345–52.

  26. 26.

    Meseguer APC, Cabero A. Sex steroid biosynthesis in white adipose tissue. Horm Metab Res. 2002;34:731–6.

  27. 27.

    Corbould AM, JJ, Rodgers RJ. Expression of types 1, 2, and 3 17b-hydroxysteroid dehydrogenase in subcutaneous abdominal and intra-abdominal adipose tissue of women. J Clin Endocrinol Metab. 1998;83:187–94.

  28. 28.

    Corbould AMB, LavranosTC, Rodgers RJ, Judd SJ. The effect of obesity on the ratio of type 3 17bhydroxysteroid dehydrogenase mRNA to cytochrome P450 aromatase mRNA in subcutaneous abdominal and intra-abdominal adipose tissue of women. Int J Obes. 2002;26:165–75.

  29. 29.

    Heid IM, Jackson AU, Randall JC, Winkler TW, Qi L, Steinthorsdottir V, et al. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet. 2010;42:949–60.

  30. 30.

    Shungin D, Winkler TW, Croteau-Chonka DC, Ferreira T, Locke AE, Magi R, et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature. 2015;518:187–96.

  31. 31.

    Lindgren CM, Heid IM, Randall JC, Lamina C, Steinthorsdottir V, et al. Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution. PLoS Genet. 2009;5:e1000508.

  32. 32.

    Chu AY, Deng X, Fisher VA, Drong A, Zhang Y, Feitosa MF, et al. Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation. Nat Genet. 2017;49:125–30.

  33. 33.

    Fox CS, Liu Y, White CC, Feitosa M, Smith AV, Heard-Costa N, et al. Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women. PLoS Genet. 2012;8:e1002695.

  34. 34.

    Maligie M, Crume T, Scherzinger A, Stamm E, Dabelea D. Adiposity, fat patterning, and the metabolic syndrome among diverse youth: the EPOCH study. J Pediatr. 2012;161:875–80.

  35. 35.

    Jukarainen S, Holst R, Dalgard C, Piirila P, Lundbom J, Hakkarainen A, et al. Cardiorespiratory fitness and adiposity as determinants of metabolic health-pooled analysis of two twin cohorts. J Clin Endocrinol Metab. 2017;102:1520–8.

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This work has been made possible by R01-DK111038 and R01-HD028016 to SC. NS is funded by the American Heart Association (AHA) through the 13SDG14640038 and the 16IRG27390002. AG was supported by the Robert Leet Patterson and Clara Guthrie Patterson Trust Mentored Research Award and the European Medical Information Framework (EMIF 115372). VS is funded by CTSA Grant Number UL1 RR024139 from the National Center for Research Resources (NCRR) and the National Center for Advancing Translational Science (NCATS), components of the National Institutes of Health (NIH), and NIH roadmap for Medical Research. This work was also made possible by DK045735 to the Yale Diabetes Research Center and Clinical and Translational Science Awards Grant UL1-RR- 024139 from the National Center for Advancing Translational Sciences, a component of the NIH, and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.

Author contributions

SC initiated the concept of the study and designed it together with AG. BP, JN, and MM were responsible for collecting the data. VS, DT, and GRU performed the statistical analyses. GRU, SC, and NS wrote the manuscript. SC is the guarantor of this work.

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Correspondence to Sonia Caprio.

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The authors declare that they have no conflict of interest.

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