COMMD10-deficiency in adipose tissue macrophages attenuates obesity and insulin resistance by boosting mitochondrial and antioxidant functions

Abstract During obesity, adipose tissue macrophages (ATM) colonize the white adipose tissue (WAT), where they acquire metabolically activated phenotypes. Here, we demonstrate that COMMD10 is a key regulator of macrophage oxidative capacity in response to chronic caloric excess. Mice with COMMD10-deficiency targeted to macrophages fed high-fat-diet (HFD) gained less weight, showed improved serum metabolic indices, enhanced systemic and WAT insulin sensitivity, and reduced adipocyte hypertrophy and liver steatosis. COMMD10-deficient ATM exhibited increased oxidative respiration and mitochondrial membrane potential after short and long term HFD. These findings were recapitulated in COMMD10-deficient BM-derived macrophages and human THP1 monocyte-derived macrophages. Intracellular copper was elevated in COMMD10-deficient macrophages, and its chelation normalized their increased mitochondrial respiration. Both glucose and lipids fueled the increased oxidative respiration in COMMD10-deficient ATM, and they better adapted to oxidative stress by upregulating NRF2-dependent antioxidant transcriptional modules. Overall, COMMD10-deficiency in ATM safely augments mitochondrial energy production and improves obesity-associated metabolic derangements.