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

Katherine E Pinnick, George Nicholson, Konstantinos N Manolopoulos, 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, MolPAGE Consortium

Research output: Contribution to journalArticlepeer-review

94 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)3785-97
Number of pages13
Issue number11
Early online date19 Jun 2014
Publication statusPublished - Nov 2014


  • Abdominal Fat
  • Adipose Tissue
  • Adult
  • Cardiovascular Diseases
  • DNA Methylation
  • Female
  • Humans
  • Intra-Abdominal Fat
  • Male
  • Middle Aged
  • Obesity
  • Risk Factors
  • Subcutaneous Fat, Abdominal
  • T-Box Domain Proteins


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