Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Diabetes. 2017 May;66(5):1159-1171. doi: 10.2337/db16-1225. Epub 2017 Mar 1.
Sirt6 is an NAD-dependent deacetylase that is involved in the control of energy metabolism. However, the tissue-specific function of Sirt6 in the adipose tissue remains unknown. In this study, we showed that fat-specific Sirt6 knockout (FKO) sensitized mice to high-fat diet-induced obesity, which was attributed to adipocyte hypertrophy rather than adipocyte hyperplasia. The adipocyte hypertrophy in FKO mice likely resulted from compromised lipolytic activity as an outcome of decreased expression of adipose triglyceride lipase (ATGL), a key lipolytic enzyme. The suppression of ATGL in FKO mice was accounted for by the increased phosphorylation and acetylation of FoxO1, which compromises the transcriptional activity of this positive regulator of ATGL. Fat-specific Sirt6 KO also increased inflammation in the adipose tissue, which may have contributed to insulin resistance in high-fat diet-fed FKO mice. We also observed that in obese patients, the expression of Sirt6 expression is reduced, which is associated with a reduction of ATGL expression. Our results suggest Sirt6 as an attractive therapeutic target for treating obesity and obesity-related metabolic disorders.
Sirt6 是一种依赖 NAD 的去乙酰化酶，参与能量代谢的调控。然而，Sirt6 在脂肪组织中的组织特异性功能尚不清楚。在本研究中，我们表明脂肪特异性 Sirt6 敲除（FKO）使小鼠对高脂肪饮食诱导的肥胖敏感，这归因于脂肪细胞肥大而不是脂肪细胞增生。FKO 小鼠的脂肪细胞肥大可能是由于脂肪甘油三酯脂肪酶（ATGL）表达减少导致脂解活性受损所致，ATGL 是关键的脂解酶。FKO 小鼠中 ATGL 的抑制归因于 FoxO1 的磷酸化和乙酰化增加，这削弱了 ATGL 的这种阳性调节剂的转录活性。脂肪特异性 Sirt6 KO 还增加了脂肪组织中的炎症，这可能导致高脂肪饮食喂养的 FKO 小鼠胰岛素抵抗。我们还观察到，在肥胖患者中，Sirt6 的表达减少，这与 ATGL 表达减少有关。我们的研究结果表明 Sirt6 是治疗肥胖和肥胖相关代谢紊乱的有吸引力的治疗靶点。
