Distinct Developmental Profile of Lower-Body Adipose Tissue Defines Resistance Against Obesity-Associated Metabolic Complications

• DOI: 10.2337/db14-0385
• Publication Date: 2014-06-20T06:59:58Z
• Authors: Katherine E. Pinnick; George Nicholson; Konstantinos N. M...; Siobhán E. McQuaid; Philippe Valet; Keith N. Frayn; Nathan Denton; Josine L. Min; Krina T. Zondervan; Jan Fleckner; ; Mark I. McCarthy; Chris C. Holmes; Fredrik Karpe
• Keywords: Adult; Male; 0301 basic medicine; Subcutaneous Fat; Abdominal Fat; 610; Intra-Abdominal Fat; 03 medical and health sciences; Endocrinology; Risk Factors; Cardiovascular Disease; Internal Medicine; Humans; Abdominal; Obesity; 2. Zero hunger; Risk Factor; Medicine (all); T-Box Domain Protein; DNA Methylation; Middle Aged; Subcutaneous Fat, Abdominal; Diabetes and Metabolism; Adipose Tissue; Cardiovascular Diseases; Female; T-Box Domain Proteins; Human

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/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, 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.