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Epigenetic regulation of macrophage polarization by DNA methyltransferase 3b
- Source :
- Molecular endocrinology (Baltimore, Md.). 28(4)
- Publication Year :
- 2014
-
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.
- Subjects :
- Adipose tissue macrophages
Macrophage polarization
Peroxisome proliferator-activated receptor
Proinflammatory cytokine
Cell Line
Epigenesis, Genetic
Mice
Endocrinology
Adipocytes
Animals
Insulin
Epigenetics
DNA (Cytosine-5-)-Methyltransferases
Obesity
Promoter Regions, Genetic
Molecular Biology
Original Research
chemistry.chemical_classification
Inflammation
biology
Macrophages
Cell Polarity
General Medicine
DNA Methylation
Cell biology
Mice, Inbred C57BL
PPAR gamma
Insulin receptor
chemistry
Saturated fatty acid
DNA methylation
embryonic structures
biology.protein
Cancer research
Signal Transduction
Subjects
Details
- ISSN :
- 19449917
- Volume :
- 28
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Molecular endocrinology (Baltimore, Md.)
- Accession number :
- edsair.doi.dedup.....748d363c5288eaa9c176b06318276572