The methylomes of subcutaneous and visceral adipocytes in lean and obese humans reflect differential gene expression and cell origin

ST Bradford1,2, AL Statham2, S Nair2, S Van Dijk1, TJ Peters2, RV Lord3, K Samaras2,3, PL Molloy1 and SJ Clark2

  1. CSIRO, Health and Biosecurity, Sydney, Australia
  2. The Garvan Institute of Medical Research, Sydney, Australia
  3. St Vincents Hospital, Sydney, Australia

Adipose tissue is a key driver of metabolism, energy homoeostasis and inflammation and perturbations in the amount and distribution of adipose tissue have serious adverse health consequences. Excess visceral adipose tissue (VAT) promotes development of a range of diseases including type 2 diabetes mellitus, atherosclerosis and cancer, whilst subcutaneous adipose tissue (SAT) appears more benign. Mechanisms controlling differential gene expression between VAT and SAT are poorly understood. To characterize these two depots, we analysed the transcriptomes and methylomes of adipocytes isolated from SAT (SA) and VAT (VA) of normal weight subjects. We found that methylation profiles of each sample type were highly consistent between subjects and clearly segregated cell types. Regions of large differential methylation between SA and VA were often proximal to transcriptional start sites and positively correlated with gene expression. These regions showed enrichment for a proximity to developmental genes, such as HOXs and TBXs. Regions with smaller levels of differential methylation were associated with genes important in adipocyte biology. We further generated data from the VA of age and sex matched obese individuals, and identified differentially methylated regions associated with obesity. These DMRs were also enriched for developmental genes and a large proportion overlapped those DMRs identified in SA VA comparisons. This suggests that these epigenetically modified regions may mark different adipocyte subtypes and that the ratio of these subtypes can change dependent on metabolic condition, either through selective growth or differentiation, or ectopic recruitment.