Chchd10: A Novel Metabolic Sensor Modulating Adipose Tissue Homeostasis

Abstract Dysregulation of adipose tissue (AT) homeostasis in obesity contributes to metabolic stress and disorders. Here, we identified that Coiled‐coil‐helix‐coiled‐coil‐helix domain containing 10 (Chchd10) is a novel regulator of AT remodeling upon excess energy intake. Chchd10 is significantly reduced in the white adipose tissue (WAT) of mice in response to high‐fat diet (HFD) feeding. AT‐Chchd10 deficiency accelerates adipogenesis predominantly in subcutaneous AT of mice to store excess energy in response to short‐term HFD feeding while upregulates glutathione S‐transferase A4 (GSTA4) to facilitate 4‐HNE clearance mainly in visceral AT to prevent protein carbonylation‐induced cell dysfunction after long‐term HFD feeding. Hence, Chchd10 deficiency attenuates diet‐induced obesity and related metabolic disorders in mice. Mechanistically, Chchd10 deficiency enhances adipogenesis and GSTA4 expression by activating TDP43/Raptor/p62/Keap1/NRF2 axis. Notably, the beneficial effect of Chchd10 deficiency is eliminated in hypertrophic adipocytes, where p62 is strikingly reduced. Collectively, Chchd10 is a metabolic sensor maintaining AT homeostasis, and the loss of p62 in adipose tissue under obese conditions impairs Chchd10‐mediated AT remodeling.