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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