Diet-Induced Obesity and Insulin Resistance are Associated with Brown Fat Degeneration in SIRT1-Deficient Mice

Objective: Recent studies have revealed that SIRT1 gain-of-function could promote adipose tissue browning for the adaptive thermogenesis under normal diet. This study investigated the role of SIRT1 loss-of-function in diet-induced obesity and insulin resistance and the mechanism involved in adipose tissue thermogenesis. Methods: Male SIRT1(+/-) and wild-type (WT) mice were fed with a high-fat diet (HFD) for 16 weeks to induce obesity and insulin resistance, while mice on a chow diet were used as lean controls. The phenotype data were collected, and different adipose tissue depots were used for mechanism research. Results: Compared with WT mice, SIRT1(+/-) mice exhibited increased adiposity and more severe insulin resistance with less thermogenesis under HFD challenge. Strikingly. SIRT1(+/-) mice displayed an exacerbated brown adipose tissue (BAT) degeneration phenotype, which was characterized by lower thermogenic activity, aggravated nnitochondrial dysfunction, and more nnitochondrial loss. In addition, SIRT1 mice showed aggravated inflammation and dysfunction in epididymal adipose tissue after HFD intervention, which also contributed to the systemic insulin resistance. Conclusions: Diet-induced obesity and insulin resistance are associated with BAT degeneration in SIRT1-deficient mice, which further underlined the beneficial role of SIRT1 in obesity-associated metabolic disorders.