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

Abstract

Obesity and insulin resistance are a global health problem and directly linked to macrophage-driven inflammation of the adipose tissue. Glucocorticoid (GC) therapy, widely used to treat inflammatory conditions, is associated with metabolic side effects, including adiposity and insulin resistance. It is unknown however, whether anti-inflammatory actions of glucocorticoids at physiological levels can have beneficial effects on adipose tissue inflammation. We hypothesized that GCs may limit insulin resistance by acting on immune cells. By deletion of the GC receptor (GR) in macrophages in mice, we show that GC signaling in macrophages protects against obesity-related insulin resistance, by limiting adipose tissue inflammation. Consequently, the reduction of anti-inflammatory macrophages leads to diminished maintenance of body temperature during cold exposure and endotoxin shock, linking GC action in macrophages to homeothermy. Mechanistically, Macrophages deficient for GR are unable to fully develop into an anti-inflammatory phenotype and are refractory to IL-4 signaling, due to reduced STAT6 DNA loading. Our results demonstrate that GCs play an important homeostatic role in macrophages during obesity by limiting adipose tissue inflammation and promoting insulin sensitivity. We also identify a cooperation of GC signaling with STAT6 in macrophages to promote alternative activation, in turn assisting in homeothermy.