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

Xianfeng Wang¹, Qiang Cao^1,2,3, Liqing Yu⁴

¹Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

|November 25, 2016

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.

Insights

Obesity drives inflammation and insulin resistance by increasing M1 adipose tissue macrophages (ATMs). Inhibiting DNA methylation promotes M2 ATMs, reducing inflammation and protecting against obesity-related insulin resistance.

Area of Science:

Immunology
Epigenetics
Metabolic Disease

Background:

Obesity is linked to altered adipose tissue macrophage (ATM) polarization, favoring pro-inflammatory M1 ATMs over anti-inflammatory M2 ATMs.
This shift contributes to obesity-induced inflammation and insulin resistance, but the underlying epigenetic mechanisms are not fully understood.

Purpose of the Study:

To investigate the role of DNA methylation in regulating ATM polarization and its contribution to obesity-related metabolic dysfunction.
To identify specific epigenetic targets involved in controlling macrophage activation in obesity.

Main Methods:

Pharmacological inhibition of DNA methylation using 5-aza-2'-deoxycytidine.
Genetic deletion of DNA methyltransferase 1 (DNMT1) in myeloid cells.
Analysis of macrophage polarization markers and inflammatory responses.
Assessment of insulin resistance in mouse models of obesity.

Main Results:

Inhibition of DNA methylation, either pharmacologically or genetically, promoted M2 ATM activation and suppressed inflammation.
Myeloid DNMT1-deficient mice showed improved ATM polarization, reduced inflammation, and protection from obesity-induced insulin resistance.
Obesity-related factors (fatty acids, TNF-α) decreased DNA methylation at the peroxisome proliferator-activated receptor γ1 (PPARγ1) promoter, enhancing M2 activation.

Conclusions:

Obesity-induced DNA hypermethylation at the PPARγ1 promoter is a critical driver of pro-inflammatory ATM activation.
Epigenetic regulation of PPARγ1 by DNA methylation influences ATM polarization and contributes to insulin resistance in obesity.

Read full analysis

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