title: Epigenetic regulation of macrophage polarization by DNA methyltransferase 3b.
abstract: Adipose tissue macrophages (ATMs) undergo a phenotypic switch from alternatively activated antiinflammatory M2 macrophages in lean individuals to classically activated proinflammatory M1 macrophages in obese subjects. However, the molecular mechanism underlying this process remains unclear. In this study we aim to determine whether DNA methyltransferase 3b (DNMT3b) regulates macrophage polarization and inflammation. We found that the expression of DNMT3b was significantly induced in macrophages exposed to the saturated fatty acid stearate, was higher in ATMs isolated from obese mice, but was significantly lower in alternatively activated M2 vs classically activated M1 ATMs, suggesting a role for DNMT3b in regulation of macrophage polarization and inflammation in obesity. DNMT3b knockdown promoted macrophage polarization to alternatively activated M2 phenotype and suppressed macrophage inflammation, whereas overexpressing DNMT3b did the opposite. Importantly, in a macrophage-adipocyte coculture system, we found that DNMT3b knockdown significantly improved adipocyte insulin signaling. The promoter of peroxisome proliferator activated receptor (PPAR)γ1, a key transcriptional factor that regulates macrophage polarization, is enriched with CpG sites. Chromatin immunoprecipitation assays showed that DNMT3b bound to the methylation region at PPARγ1 promoter, which was further enhanced by stearate. Moreover, pyrosequencing analysis revealed that stearate increased DNA methylation at PPARγ1, which was prevented by DNMT3b deficiency. Therefore, our data demonstrate that DNMT3b plays an important role in regulating macrophage polarization through epigenetic mechanisms. In obesity, elevated saturated fatty acids enhance DNMT3b expression, leading to DNA methylation at the PPARγ1 promoter, which may contribute to deregulated adipose tissue macrophage polarization, inflammation, and insulin resistance.
authors.affiliation: Center for Infection and Immunity Research (X.Y., D.L.), School of Life Sciences, Hubei University, Wuhan, China; Department of Biology (X.Y., B.X., H.S.), Georgia State University, Atlanta, Georgia 30303; Department of Internal Medicine (X.W., B.X., H.S.), Wake Forest University School of Medicine, Winston-Salem, North Carolina 27106; and Department of Animal and Avian Sciences (L.Y.), University of Maryland, College Park, Maryland 20742.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Yang
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Wang
authors.forename: Dongxu
authors.initials: D
authors.lastname: Liu
authors.forename: Liqing
authors.initials: L
authors.lastname: Yu
authors.forename: Bingzhong
authors.initials: B
authors.lastname: Xue
authors.forename: Hang
authors.initials: H
authors.lastname: Shi
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D016764:Cell Polarity / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000201:enzymology / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D007328:Insulin; D047495:PPAR gamma; D000097584:DNA Methyltransferase 3B