摘要：SummarySIRT1 is a metabolic sensor regulating energy homeostasis. The present study revealed that mice with selective overexpression of human SIRT1 in adipose tissue (Adipo-SIRT1) were protected from high-fat diet (HFD)-induced metabolic abnormalities. Adipose SIRT1 was enriched at mitochondria-ER contacts (MERCs) to trigger mitohormesis and unfolded protein response (UPRmt), in turn preventing ER stress. As a downstream target of UPRmt, clusterin was significantly upregulated and acted together with SIRT1 to regulate the protein and lipid compositions at MERCs of adipose tissue. In mice lacking clusterin, HFD-induced metabolic abnormalities were significantly enhanced and could not be prevented by overexpression of SIRT1 in adipose tissue. Treatment with ER stress inhibitors restored adipose SIRT1-mediated beneficial effects on systemic energy metabolism. In summary, adipose SIRT1 facilitated the dynamic interactions and communications between mitochondria and ER, via MERCs, in turn triggering a mild mitochondrial stress to instigate the defense responses against dietary obesity-induced metabolic dysfunctions.Graphical abstractDisplay OmittedHighlights•Adipose SIRT1 triggers mitohormesis and UPRmt, in turn upregulating clusterin•Adipose SIRT1 and clusterin regulate the protein and lipid compositions at MERCs•Adipose SIRT1 and clusterin reinforce UPRmt-mediated anti-ER stress signaling•Adipose SIRT1 dysfunction causes obesity and associated metabolic abnormalitiesBiological sciences; Molecular physiology; Cell biology
