An analysis of DNA methylation in human adipose tissue reveals differential modification of obesity genes before and after gastric bypass and weight loss

TLDR

Environmental factors influence obesity through epigenetic mechanisms, with adipose tissue central to obesity‑related metabolic dysfunction. The study investigates DNA methylation changes in adipose tissue of obese women before and after gastric bypass and weight loss. The authors profiled 485,577 CpG sites in matched subcutaneous and omental adipose tissue samples taken before and after weight loss. Differential methylation was observed in both omental and subcutaneous adipose tissue, with a higher proportion of hypermethylated CpGs before weight loss, enrichment in 3′UTRs and gene bodies, and changes in obesity‑related genes such as CETP, FOXP2, HDAC4, and HOX clusters that correlated with clinical traits and mRNA expression, marking the first global methylation profiling of adipose tissue pre‑ and post‑gastric bypass.

Abstract

Environmental factors can influence obesity by epigenetic mechanisms. Adipose tissue plays a key role in obesity-related metabolic dysfunction, and gastric bypass provides a model to investigate obesity and weight loss in humans.Here, we investigate DNA methylation in adipose tissue from obese women before and after gastric bypass and significant weight loss. In total, 485,577 CpG sites were profiled in matched, before and after weight loss, subcutaneous and omental adipose tissue. A paired analysis revealed significant differential methylation in omental and subcutaneous adipose tissue. A greater proportion of CpGs are hypermethylated before weight loss and increased methylation is observed in the 3' untranslated region and gene bodies relative to promoter regions. Differential methylation is found within genes associated with obesity, epigenetic regulation and development, such as CETP, FOXP2, HDAC4, DNMT3B, KCNQ1 and HOX clusters. We identify robust correlations between changes in methylation and clinical trait, including associations between fasting glucose and HDAC4, SLC37A3 and DENND1C in subcutaneous adipose. Genes investigated with differential promoter methylation all show significantly different levels of mRNA before and after gastric bypass.This is the first study reporting global DNA methylation profiling of adipose tissue before and after gastric bypass and associated weight loss. It provides a strong basis for future work and offers additional evidence for the role of DNA methylation of adipose tissue in obesity.