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Epigenetic regulation of macrophage polarization and inflammation by DNA methylation in obesity.


ABSTRACT: 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 ?1 (PPAR?1) are enriched with CpGs and are epigenetically regulated. The saturated fatty acids stearate and palmitate and the inflammatory cytokine TNF-? significantly increase, whereas the TH2 cytokine IL-4 significantly decreases PPAR?1 promoter DNA methylation. Accordingly, inhibiting PPAR?1 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 PPAR?1 promoter induced by obesity-related factors as a critical determinant of ATM proinflammatory activation and inflammation, which contributes to insulin resistance in obesity.

SUBMITTER: Wang X 

PROVIDER: S-EPMC5111504 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Epigenetic regulation of macrophage polarization and inflammation by DNA methylation in obesity.

Wang Xianfeng X   Cao Qiang Q   Yu Liqing L   Shi Huidong H   Xue Bingzhong B   Shi Hang H  

JCI insight 20161117 19


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. Con  ...[more]

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