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