SIRT1 and stress signaling in adipose tissue

Abstract

Adipose tissue is an important organ controlling energy homeostasis in mammals. During obesity, dysfunction of adipose tissue leads to systemic insulin resistance and metabolic diseases. SIRT1 (sirtuin 1) is an energy sensor and longevity regulator eliciting pleiotropic effects by catalyzing NAD+-dependent removal of acetyl groups from protein substrates. Previous studies demonstrate that adipose SIRT1 possesses the anti-metabolic ageing effects. The present study investigated mechanisms underlying the protective effects of adipose SIRT1 on metabolic dysfunction. Mice including those with adipose overexpression of human SIRT1 (Adipo-SIRT1) or their wild type (WT) littermates, and those lacking clusterin expression without (CKO) or with adipose overexpression of human SIRT1 (CKO Adipo-SIRT1) were fed with a high fat diet (HFD) for 12-weeks, starting from the age of five-weeks. Body weight and fat mass, circulating glucose, lipid and insulin levels, systemic insulin sensitivity and energy expenditure were monitored on a regular basis. At the end of treatment, serum samples were collected for analyzing the lipid contents, fatty acid composition and lipoprotein particles. Liver and adipose tissues were subjected to histological staining, biochemical and molecular analyses. Mitochondria and mitochondria-endoplasmic reticulum contacting sites (MERCs) were isolated from adipose tissue for structural and functional comparisons. Overexpression of human SIRT1 in adipose tissue prevented HFD-induced obesity, insulin resistance, hyperglycemia, dyslipidemia and metabolic dysfunction-associated fatty liver disease (MAFLD). Clusterin, a molecular chaperon, was upregulated by SIRT1 in adipose tissue. In the absence of clusterin, however, overexpression of adipose SIRT1 failed to elicit the anti-obesity, insulin sensitizing and hepatoprotective functions in mice challenged with HFD. In adipose tissue, SIRT1 triggered a mild mitochondrial stress and unfolded protein responses (UPRmt) but inhibited dietary obesity-induced ER stress. Clusterin deficiency increased HFD-induced ER stress, activation of which caused a significant reduction of SIRT1 expression in adipose tissue. However, treatment with ER stress inhibitors restored adipose SIRT1-mediated beneficial effects on systemic energy metabolism. SIRT1 and clusterin were located at the MERCs and acted to modulate the protein and lipid compositions. Clusterin increased esterification of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in adipose tissue. Treatment with ω-3 PUFAs facilitated the recruitment of SIRT1 to and the formation of MERCs. SIRT1 and clusterin coordinated the crosstalk between ER and mitochondria in adipose tissue. The increased biogenesis of high density lipoprotein (HDL) enriched with ω-3 PUFAs from adipose tissue contributed to the enhanced energy homeostasis in mice with adipose overexpression of SIRT1. Collectively, the present study demonstrated that adipose SIRT1 prevented metabolic dysfunctions associated with dietary obesity by regulating the stress signaling in adipose tissue. Further studies are warranted to investigate the precise role of SIRT1 in the communications between mitochondria and ER.