Fat-Specific Sirt6 Ablation Sensitizes Mice to High-Fat Diet-Induced Obesity and Insulin Resistance by Inhibiting Lipolysis
Fat-Specific Sirt6 Ablation Sensitizes Mice to High-Fat Diet-Induced Obesity and Insulin Resistance by Inhibiting Lipolysis
复制标题
脂肪特异性 Sirt6 消融通过抑制脂肪分解使小鼠对高脂肪饮食引起的肥胖和胰岛素抵抗敏感
DOI：
10.2337/db16-1225
复制
发表时间：
2017-05-01
期刊：
影响因子：
7.7
通讯作者：
He, Jinhan
中科院分区：
文献类型：
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作者：
Kuang, Jiangying;Zhang, Yuwei;He, Jinhan
Sirt6是一种NAD（+）依赖性脱乙酰酶，参与能量代谢的控制。然而，Sirt6在脂肪组织中的组织特异性功能仍然未知。在这项研究中，我们发现脂肪特异性Sirt6敲除（FKO）使小鼠对高脂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三酸甘油酯脂肪酶（ATGL）（一种关键的脂肪分解酶）表达减少而导致脂肪分解活性受损所致。FKO小鼠中ATGL的抑制是由FoxO1的磷酸化和乙酰化增加引起的，FoxO1的磷酸化和乙酰化降低了ATGL的正调节因子的转录活性。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小鼠的胰岛素抵抗。我们还观察到，在肥胖患者中，Sirt6表达减少，这与ATGL表达减少有关。我们的研究结果表明，Sirt6作为一个有吸引力的治疗目标，用于治疗肥胖和肥胖相关的代谢紊乱。
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.