Adipose-specific knockdown of Sirt1 results in obesity and insulin resistance by promoting exosomes release
Adipose-specific knockdown of Sirt1 results in obesity and insulin resistance by promoting exosomes release
复制标题
Sirt1 的脂肪特异性敲低通过促进外泌体释放导致肥胖和胰岛素抵抗
DOI：
10.1080/15384101.2019.1638694
复制
发表时间：
2019-07-14
期刊：
影响因子：
4.3
通讯作者：
Sun, Hongzhi
中科院分区：
文献类型：
--
作者：
Li, Fang;Li, Huixia;Sun, Hongzhi
SIRT 1是近年来发现的一种重要的糖代谢和胰岛素敏感性调节因子。然而，其潜在机制尚未完全阐明。在这项研究中，我们研究了SIRT 1在肥胖和胰岛素抵抗的发展中的作用，通过产生脂肪特异性消融Sirt 1的小鼠（Ad-Sirt 1-/-小鼠）。Ad-Sirt 1-/-小鼠表现出脂肪量增加、葡萄糖耐量受损、胰岛素敏感性减弱和外泌体增加，而给予外泌体抑制剂有效地改善了Ad-Sirt 1-/-小鼠受损的代谢特征。此外，增加的外泌体被证明是Ad-Sirt 1-/-小鼠中自噬活性缺陷的结果，并且SIRT 1活性的恢复有效地改善了体外代谢谱。进一步的研究表明Sirt 1缺陷诱导的exosomes至少部分通过TLR 4/NF-κB信号通路调节胰岛素敏感性。因此，我们的研究结果暗示SIRT 1是代谢调节的关键因素，脂肪Sirt 1缺乏可能通过促进外泌体释放对肥胖和胰岛素抵抗的发展产生影响。
ABSTRACT Sirtuin1 (SIRT1) has recently emerged as a pivotal regulator of glucose metabolism and insulin sensitivity. However, the underlying mechanism has not been fully elucidated. In this study, we investigated the role of SIRT1 in the development of obesity and insulin resistance by generating mice with adipose-specific ablation of Sirt1 (Ad-Sirt1-/- mice). Ad-Sirt1-/- mice exhibited increased fat mass, impaired glucose tolerance, attenuated insulin sensitivity, and increased exosomes, whereas the administration of exosomes inhibitor effectively ameliorated the impaired metabolic profile in Ad-Sirt1-/- mice. Moreover, the increased exosomes were proved to be a result of defective autophagy activity in Ad-Sirt1-/- mice and restoration of SIRT1 activity efficiently improved metabolic profiles in vitro. Further study demonstrated that Sirt1 deficiency-induced exosomes modulated insulin sensitivity at least partially via the TLR4/NF-κB signaling pathway. Therefore, our findings implicated SIRT1 as a key factor in metabolic regulation, and adipose Sirt1 deficiency could exert an effect on the development of obesity and insulin resistance by promoting exosome release.