title: 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 γ1 (PPARγ1) are enriched with CpGs and are epigenetically regulated. The saturated fatty acids stearate and palmitate and the inflammatory cytokine TNF-α significantly increase, whereas the TH2 cytokine IL-4 significantly decreases PPARγ1 promoter DNA methylation. Accordingly, inhibiting PPARγ1 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 PPARγ1 promoter induced by obesity-related factors as a critical determinant of ATM proinflammatory activation and inflammation, which contributes to insulin resistance in obesity.
authors.affiliation: Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.|Department of Biology.|Center for Obesity Reversal, Georgia State University, Atlanta, Georgia, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of Animal and Avian Science, University of Maryland, College Park, Maryland, USA.
authors.forename: Liqing
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Huidong
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.|Department of Biology.|Center for Obesity Reversal, Georgia State University, Atlanta, Georgia, USA.
authors.forename: Bingzhong
authors.initials: B
authors.lastname: Xue
authors.affiliation: Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.|Department of Biology.|Center for Obesity Reversal, Georgia State University, Atlanta, Georgia, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Shi
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000172:deficiency / Q000235:genetics; D019175:DNA Methylation; D000077209:Decitabine; D044127:Epigenesis, Genetic; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D007333:Insulin Resistance; D008264:Macrophages / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics* / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism; D011401:Promoter Regions, Genetic
chemical_list: D016207:Cytokines; D047495:PPAR gamma; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619381:Dnmt1 protein, mouse; D001374:Azacitidine