Glucocorticoid Activation of Anti-Inflammatory Macrophages in Coordination with STAT6 Protects Against Insulin Resistance

Deletion of the GC receptor (GR) in macrophages in mice, aggravates obesity-related insulin resistance, by reducing anti-inflammatory macrophages, and enhancing adipose tissue inflammation. Consequently, the reduction of anti-inflammatory macrophages leads to exaggerated adipose tissue lipolysis and severe hepatic steatosis. Mechanistically, macrophages deficient for GR show a diminished response to IL-4 driven anti-inflammatory polarization, due to disruption of an epigenetic crosstalk between GC and IL-4 signaling involving synergistic loading of GR and STAT6. Our results demonstrate that GR plays an important role in macrophage polarization during obesity by limiting adipose tissue inflammation and lipolysis to promote insulin sensitivity Overall design: RNA-seq of F4/80 purified ATMs isolated from eWAT of obese WT and GRLysMCre mice. RNA-seq from cultured fetal liver derived macrophages from WT and GRnull mice treated with dexamethasone, interleukin 4 or a combination of both. ChIP-seq of anti-H3K27ac precipitated chromatin from cultured bone marrow liver derived macrophages from WT and GRLysMCre mice treated with dexamethasone and interleukin 4.