| First Author | Wang X | Year | 2016 |
| Journal | JCI Insight | Volume | 1 |
| Issue | 19 | Pages | e87748 |
| PubMed ID | 27882346 | Mgi Jnum | J:290218 |
| Mgi Id | MGI:6442023 | Doi | 10.1172/jci.insight.87748 |
| Citation | Wang X, et al. (2016) Epigenetic regulation of macrophage polarization and inflammation by DNA methylation in obesity. JCI Insight 1(19):e87748 |
| abstractText | Obesity is associated with increased classically activated M1 adipose tissue macrophages (ATMs) and decreased alternatively activated M2 ATMs, both of which contribute to obesity-induced inflammation and insulin resistance. However, the underlying mechanism remains unclear. We find that inhibiting DNA methylation pharmacologically using 5-aza-2'-deoxycytidine or genetically by DNA methyltransferase 1 (DNMT1) deletion promotes alternative activation and suppresses inflammation in macrophages. Consistently, mice with myeloid DNMT1 deficiency exhibit enhanced macrophage alternative activation, suppressed macrophage inflammation, and are protected from obesity-induced inflammation and insulin resistance. The promoter and 5'-untranslated region of peroxisome proliferator-activated receptor gamma1 (PPARgamma1) are enriched with CpGs and are epigenetically regulated. The saturated fatty acids stearate and palmitate and the inflammatory cytokine TNF-alpha significantly increase, whereas the TH2 cytokine IL-4 significantly decreases PPARgamma1 promoter DNA methylation. Accordingly, inhibiting PPARgamma1 promoter DNA methylation pharmacologically using 5-aza-2'-deoxycytidine or genetically by DNMT1 deletion promotes macrophage alternative activation. Our data therefore establish DNA hypermethylation at the PPARgamma1 promoter induced by obesity-related factors as a critical determinant of ATM proinflammatory activation and inflammation, which contributes to insulin resistance in obesity. |
