Abstract
Sirtuin 1 (SIRT1) is a metabolic sensor regulating energy homeostasis in mammals. Previous results demonstrate that overexpression of human SIRT1 selectively in adipose tissue of mice (Adipo-SIRT1) enhances insulin sensitivity and prevents metabolic ageing. The present study revealed that Adipo-SIRT1 were protected from metabolic abnormalities caused by high-fat diet (HFD) feeding. In adipose tissue of Adipo-SIRT1, the expression of clusterin was significantly upregulated and located at the mitochondria–ER contacts (MERCs). In mice lacking the expression of clusterin (CKO), HFD-induced metabolic abnormalities and ER stress were significantly enhanced and could not be prevented by overexpression of SIRT1 in adipose tissue. Clusterin was involved in the regulation of both the protein and lipid compositions of MERCs in adipose tissue of Adipo-SIRT1, in turn preventing the excessive activation of ER stress and facilitating the delivery of omega-3 polyunsaturated fatty acids (ω-3 PUFA) via high density lipoprotein (HDL) particles. In conclusion, adiposeSIRT1 protected mice from dietary obesity-induced metabolic dysfunction at least partly by facilitating the dynamic ER-mitochondria interactions via clusterin.
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