Distinct Developmental Profile of Lower-Body Adipose Tissue Defines Resistance Against Obesity-Associated Metabolic Complications
- Katherine E. Pinnick1,*,
- George Nicholson2,3,*,
- Konstantinos N. Manolopoulos4,
- Siobhán E. McQuaid1,
- Philippe Valet5,
- Keith N. Frayn1,
- Nathan Denton1,
- Josine L. Min6,
- Krina T. Zondervan6,
- Jan Fleckner7,
- The MolPAGE consortium8,
- Mark I. McCarthy1,6,9,
- Chris C. Holmes2 and
- Fredrik Karpe1,9
- 1Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
- 2Department of Statistics, University of Oxford, Oxford, UK
- 3MRC Harwell, Harwell Science and Innovation Campus, Harwell, UK
- 4Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK
- 5Institut des Maladies Metaboliques et Cardiovasculaires, Inserm-Universite Paul Sabatier, Toulouse, France
- 6Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
- 7Novo Nordisk A/S, Novo Nordisk Park, Gentofte, Denmark
- 8The members of the MolPAGE consortium are listed in the Acknowledgments
- 9NIHR Oxford Biomedical Research Centre, OUH Trust, Oxford
- Address correspondence to: Dr Katherine Pinnick ( ) or Prof. Fredrik Karpe ( )
Upper- and lower-body fat depots exhibit opposing associations with obesity-related metabolic disease. We defined the relationship between DXA-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 (GSAT) and abdominal subcutaneous adipose tissue (ASAT) was performed across the BMI spectrum (n=49; 21.4-45.5kg/m2). 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, arterio-venous release of the pro-inflammatory 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. shRNA-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 function. The less inflammatory nature of lower-body adipose tissue offers insight into the opposing metabolic disease risk associations between upper- and lower-body obesity.
* These authors contributed equally to this work
- Received March 7, 2014.
- Accepted June 8, 2014.
- © 2014 by the American Diabetes Association.
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