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High-fat diets (HFD) are thought to contribute to the development of metabolism-related diseases. The long-term impact of HFD may be mediated by epigenetic mechanisms, and indeed, HFD has been reported to induce DNA methylation changes in white adipose tissue (WAT) near metabolism related genes. However, previous studies were limited to a single WAT depot, a single time-point and primarily examined the pre-pubertal period. To define dynamic DNA methylation patterns specific for WAT depots, we investigated DNA methylation of  Pparg2  and  Leptin  in gonadal adipose tissue (GAT) and subcutaneous adipose tissue (SAT), at baseline and after 6, 12 and 24 weeks of HFD exposure in adult mice. HFD induced hypermethylation of both the  Leptin  promoter (max. 19.6% at week 24,  P  = 2.6·10 −3 ) and the  Pparg2  promoter in GAT (max. 10.5% at week 12,  P  = 0.001). The differential methylation was independent of immune cell infiltration upon HFD exposure. In contrast, no differential methylation in the  Pparg2  and  Leptin  promoter was observed in SAT.  Leptin  and  Pparg2  DNA methylation were correlated with gene expression in GAT. Our study shows that prolonged exposure to HFD in adulthood is associated with a gradually increasing DNA methylation level at the  Leptin  and  Pparg2  promoters in a depot-specific manner.

Prolonged high-fat diet induces gradual and fat depot-specific DNA methylation changes in adult mice