“Here we show that adipocytes are a source of Th2 cytokines, including IL-13 and to a lesser extent IL-4, which induce macrophage PPARδ/β (Ppard/b) expression through a STAT6 binding site on its promoter to activate alternative activation. Co-culture studies indicate that Ppard ablation renders macrophages incapable of transition to the M2 phenotype, which in turns causes inflammation and metabolic derangement in adipocytes. Remarkably, a similar regulatory mechanism by hepatocyte-derived Th2 cytokines and macrophage PPARδ is found to control hepatic lipid metabolism. The physiological relevance of this paracrine pathway is demonstrated in myeloid-specific PPARδ−/− mice, which develop insulin resistance and show increased adipocyte lipolysis and severe hepatosteatosis. These findings provide a molecular basis to modulate tissue-resident macrophage activation and insulin sensitivity,” the researchers wrote.

The study, Adipocyte-Derived Th2 Cytokines and Myeloid PPARd Regulate Macrophage Polarization and Insulin Sensitivity, was supported by NIH grants, the American Heart Association and the American Diabetes Association.