Boosting the immunometabolic activity of adipose tissue macrophages to attenuate obesity and its associated ailments

During obesity, adipose tissue macrophages (ATM) colonize the white adipose tissue (WAT), where they acquire a metabolically activated phenotype characterized by increased glycolysis and mitochondrial respiration. Here, we demonstrate that COMMD10 is a key regulator of macrophage cellular respiration in response to chronic caloric excess. Mice with COMMD10-deficiency targeted to macrophages fed an obesogenic diet gained less weight despite similar food intake, showed increased energy expenditure that was correlated with reduced body fat, improved serum metabolic indices, enhanced systemic and WAT insulin sensitivity, and reduced adipocyte hypertrophy and liver steatosis. Interestingly, mice with COMMD10-deficiency targeted to Kupffer liver macrophages fed an obesogenic diet showed metabolic indices resembling their littermate controls, strengthening the specific role of ATM in the improved metabolic features. Indeed, co-culturing of COMMD10-deficient ATM with 3T3L1 differentiated adipocytes preserved adipocyte insulin sensitivity. COMMD10-deficient ATM exhibited increased oxidative respiration and glycolysis. Their augmented metabolic activity was supported by several layers of regulation, including transcriptional upregulation of mitochondrial respiratory complex genes and of NRF2-dependent antioxidant genes, and enhanced utilization of glucose and lipids as fuel. Finally, impairment in COMMD10-governed regulation of CCC complex stability impeded the recycling of membrane copper transporter ATP7A, leading to an increase in intracellular copper availability for powering mitochondrial activity in macrophages.