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Diabetes. 2014 Nov;63(11):3785-97. doi: 10.2337/db14-0385. Epub 2014 Jun 19.

Distinct developmental profile of lower-body adipose tissue defines resistance against obesity-associated metabolic complications.

Author information

  • 1Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K. katherine.pinnick@ocdem.ox.ac.uk fredrik.karpe@ocdem.ox.ac.uk.
  • 2Department of Statistics, University of Oxford, Oxford, U.K. Medical Research Council Harwell, Harwell Science and Innovation Campus, Harwell, U.K.
  • 3Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, U.K.
  • 4Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.
  • 5Institut des Maladies Metaboliques et Cardiovasculaires, INSERM-Université Paul Sabatier, Toulouse, France.
  • 6Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
  • 7Novo Nordisk A/S, Novo Nordisk Park, Gentofte, Denmark.
  • 8Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K. National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, U.K.
  • 9Department of Statistics, University of Oxford, Oxford, U.K.
  • 10Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K. National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, U.K.

Abstract

Upper- and lower-body fat depots exhibit opposing associations with obesity-related metabolic disease. We defined the relationship between DEXA-quantified fat depots and diabetes/cardiovascular risk factors in a healthy population-based cohort (n = 3,399). Gynoid fat mass correlated negatively with insulin resistance after total fat mass adjustment, whereas the opposite was seen for abdominal fat. Paired transcriptomic analysis of gluteal subcutaneous adipose tissue (GSAT) and abdominal subcutaneous adipose tissue (ASAT) was performed across the BMI spectrum (n = 49; 21.4-45.5 kg/m(2)). In both depots, energy-generating metabolic genes were negatively associated and inflammatory genes were positively associated with obesity. However, associations were significantly weaker in GSAT. At the systemic level, arteriovenous release of the proinflammatory cytokine interleukin-6 (n = 34) was lower from GSAT than ASAT. Isolated preadipocytes retained a depot-specific transcriptional "memory" of embryonic developmental genes and exhibited differential promoter DNA methylation of selected genes (HOTAIR, TBX5) between GSAT and ASAT. Short hairpin RNA-mediated silencing identified TBX5 as a regulator of preadipocyte proliferation and adipogenic differentiation in ASAT. In conclusion, intrinsic differences in the expression of developmental genes in regional adipocytes provide a mechanistic basis for diversity in adipose tissue (AT) function. The less inflammatory nature of lower-body AT offers insight into the opposing metabolic disease risk associations between upper- and lower-body obesity.

© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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