COMMD10-deficiency in adipose tissue macrophages attenuates obesity and insulin resistance by boosting mitochondrial and antioxidant functions
During obesity, adipose tissue macrophages (ATM) colonize the white adipose tissue (WAT), where they adapt inflammatory and 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 were fed with high-fat-diet (HFD) for 12 weeks. They gained less weight despite similar food intake, and showed improved systemic metabolic indices, sustained adipose tissue insulin sensitivity, increased lipolysis and reduced adipocyte hypertrophy and liver steatosis. COMMD10-deficient ATM directly improved insulin sensitivity and increase lipolysis in co-cultured adipocytes. COMMD10-deficient ATM exhibited increased oxidative respiration and mitochondrial membrane potential after short term (five weeks) and chronic (12 weeks) HFD. Their oxidative respiration was fueled by both glucose and lipids. They better adapted to mitochondrial activation by upregulating NRF2-dependent antioxidant transcriptional module. their increase in mitochondrial activity was furthered supported by COMMD10 modulation of cellular copper-iron balance and interaction with various oxidative phosphorylation related proteins. Our study illuminates COMMD10 as a pivotal regulator of mitochondrial energy production in ATM during constant energy surplus. Overall design: To investigate the regulatory role of COMMD10 in metabolically activated macrophage, we established a mouse model with COMMD10 depletion in macrophage by crossing conditional Commd10fl/fl  mice with Cx3cr1cre/+ mice (Cx3cr1?Commd10). Cx3cr1?Commd10 mice and their littermate control Commd10fl/fll mice were placed on HFD for 12 weeks. Subsequently, metabolically activated ATM (CD9+) were sorted from epiWAT. Comparative gene expression profiling analysis was performed by  RNA-seq of  5 control samples and 3 COMMD10 depleted ATM samples