Myeloid cell TRAF3 promotes metabolic inflammation, insulin resistance, and hepatic steatosis in obesity

Myeloid cells, particularly macrophages, mediate metabolic inflammation, thus promoting insulin resistance and metabolic disease progression in obesity. Numerous cytokines, toxic metabolites, damage-associated molecular patterns, and pathogen-associated molecular patterns are involved in activating macrophages via their cognate receptors in obesity. TRAF3 (TNF receptor-associated factor 3) is a common signaling molecule for these ligands/receptors and negatively regulates the proinflammatory NF-κB and MAPK pathways, but its metabolic activity is unknown. We here show that myeloid cell TRAF3 is required for metabolic inflammation and metabolic disease progression in obesity. Myeloid cell-specific deletion of TRAF3 significantly attenuated insulin resistance, hyperglycemia, hyperinsulinemia, glucose intolerance, and hepatic steatosis in mice with either genetic (ob/ob) or high-fat diet (HFD)-induced obesity. Myeloid cell-specific deletion of TRAF3 had the opposite effects on metabolic inflammation between o...