Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All...
  • Videos
  • Collections
    • Recently published
    • Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Transfers
  • Current issue
  • Past issues
  • By specialty
  • Contact
  • Recently published
  • Technical Advances
  • Clinical Medicine
  • Editorials
  • Top read articles
Epigenetic regulation of macrophage polarization and inflammation by DNA methylation in obesity
Xianfeng Wang, … , Bingzhong Xue, Hang Shi
Xianfeng Wang, … , Bingzhong Xue, Hang Shi
Published November 17, 2016
Citation Information: JCI Insight. 2016;1(19):e87748. https://doi.org/10.1172/jci.insight.87748.
View: Text | PDF
Categories: Research Article Inflammation

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

  • Text
  • PDF
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

Xianfeng Wang, Qiang Cao, Liqing Yu, Huidong Shi, Bingzhong Xue, Hang Shi

×

Figure 1

DNA methyltransferase 1 (DNMT1) expression is lower in M2 than in M1 adipose tissue macrophages (ATMs) and is upregulated in isolated ATMs from ob/ob mice.

Options: View larger image (or click on image) Download as PowerPoint
DNA methyltransferase 1 (DNMT1) expression is lower in M2 than in M1 adi...
(A–G) Expression of M1 and M2 markers, including CD11c (A), iNOS (B), TNF-α (C), IL-1β (D), CD206 (E), ARG1 (F), and IL-10 (G), in M1, M2, double+ and double– ATMs isolated from adipose tissue of 8- to 10-week-old male C57BL/6J mice. Cells from 3 to 4 mice were pooled for RNA isolation and gene expression measurements. M1, F4/80+CD11c+CD206–; M2, F4/80+CD11c–CD206+; double+, F4/80+CD11c+CD206+; double–, F4/80+CD11c–CD206–. (H) DNMT1 expression in M1 and M2 ATMs. (I–K) M1 (I) and M2 (J) markers and DNMT1 (K) expression in ATMs isolated from 14-week-old lean and ob/ob mice. Cells from 3 to 4 lean mice were pooled, whereas cells from individual ob/ob mice were used for RNA isolation and gene expression measurements. Data are expressed as the mean ± SEM. n = 3–7. Groups labeled with different letters are statistically different from each other. *P < 0.05. Differences between groups were analyzed for statistical significance by Student’s t test or ANOVA with Fischer’s probable least-squares difference post hoc test.
Follow JCI Insight:
Copyright © 2019 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts