Epigenetic Programming of Estrogen Receptor in Adipose Tissue by High Fat Diet Regulates Obesity-Induced Inflammation

Adipose inflammation plays a key role in obesity-induced metabolic abnormalities. Epigenetic regulation, including DNA methylation, is a molecular link between environmental factors and complex diseases. Here we showed that DNA methylation, controlled by DNA methyltransferase 1 particularly, is a key determinant of adipose chemotaxis and inflammation. Whole genome DNA methylation profiling with reduced representative bisulfide sequencing (RRBS) analysis revealed that high fat diet (HFD) feeding induced a dynamic change of DNA methylome in white adipose tissue (WAT) of mice. Among these changes there was a significant increase in DNA methylation at the promoter of estrogen receptor α (Esr1), corresponding to the down-regulation of Esr1 expression during HFD. HFD feeding increased the expression of DNA methyltransferase 1 (Dnmt1) and Dnmt3a as well as the binding of DNMT1 and 3a to the Esr1 promoter in WAT of mice. Mice with DNMT1 deficiency in adipocytes (AD1KO) displayed increased Esr1 expression, decreased adipose inflammation and improved insulin sensitivity upon HFD challenge, while D3aKO mice showed a mild metabolic phenotype. The promoter activity of Esr1 promoter enriched with CpG sites was regulated by DNA methylation. Using a modified CRISPR/RNA-guided system to specifically target DNA methylation at the Esr1 promoter in WAT, we found that reducing DNA methylation at the Esr1 promoter increased Esr1 expression, decreased adipose inflammation and improved insulin sensitivity in mice fed HFD. Our study demonstrates that DNA methylation at the Esr1 promoter plays an important role in regulation of adipose inflammation, which may contribute to obesity-induced insulin resistance.