SIRT1: A novel guardian of brown fat against metabolic damage.

Abstract

Enhancing the activity of brown, or brown-like, adipose tissue (both of them, herein, referred as BAT) could constitute a therapeutic strategy to improve insulin sensitivity and metabolic health in obese populations. The high abundance of mitochondria and the exclusive presence of the uncoupling protein 1 (UCP1) allow BAT to burn high levels of glucose and lipids and dissipate their energy as heat, thereby increasing energy expenditure. BAT in humans inversely correlates with body mass index, and “whitening” of brown fat tissue is observed in obese patients, rendering BAT dysfunctional (1). The molecular mechanisms contributing to obesity-linked BAT dysfunction, however, remain largely unknown. In this issue of Obesity, Fen et al. (2) might provide some new clues. Sirtuin 1 (SIRT1) is a protein deacetylase enzyme whose activation improves glucose homeostasis in mammals. Fen et al. aimed to understand the impact of SIRT1 loss-of-function on diet-induced-insulin resistance (2). For this, glucose homeostasis and thermogenesis were analyzed in SIRT1 heterozygous knockout mice (SIRT1+/−) fed a high-fat diet (HFD) for 16 weeks. Their observations initially indicated that SIRT1 deficiency exacerbates adiposity and glucose intolerance in HFD-fed mice. These effects were not related to alterations in activity or food intake, and they evoked the higher weight and fat mass observed in two different adipose-specific SIRT1 knockout models (3, 4). A second important finding of this study is that SIRT1 could play an important role in HFD-induced BAT dysfunction. SIRT1+/− mice on a HFD displayed thermogenic dysfunction. Further analyses showed a decrease in mitochondrial content associated with lower UCP1 levels in the BAT of SIRT1+/− mice. Fatty acid oxidation genes expression was also downregulated in BAT from SIRT1+/−. This is in line with the strong influence of SIRT1 on PPARα target genes, including UCP1, in BAT (5). Finally, SIRT1+/− mice on a HFD also displayed increased inflammation in the white adipose tissue (WAT) and higher lipid deposition in liver and muscle. This suggests that the aggravated insulin resistance observed in SIRT1+/− mice under HFD could be associated with systemic alterations in multiple tissues. It will be important, however, to fully understand whether BAT dysfunction is a causal event for ectopic lipid deposition in SIRT1+/− mice or just a parallel consequence of a whole-body metabolic failure. This work highlights the relevance of SIRT1 in brown fat biology, in agreement with previous findings indicating that SIRT1 gain-of-function enhances thermogenic capacity (5) and the browning of WAT depots (6). Hence, SIRT1 might not only influence the susceptibility to metabolic damage induced by HFDs, but also the effectiveness of body weight loss strategies relying on BAT activation. To date, human studies have suggested that regular exposure to mild cold may improve energy homeostasis. The ability to engage patients in protracted “cold-exposure” interventions, however, is doubtful. Hence, in the absence of selective pharmacological BAT activators, the ability of SIRT1 to amplify the BAT response to β3 agonists and to prevent BAT dysfunction in mice might have promising therapeutic implications.