SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function.
SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function.
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DOI：
10.1016/j.cmet.2012.04.003
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发表时间：
2012-05-02
期刊：
影响因子：
29
通讯作者：
Sinclair DA
中科院分区：
文献类型：
--
作者：
Price NL;Gomes AP;Ling AJ;Duarte FV;Martin-Montalvo A;North BJ;Agarwal B;Ye L;Ramadori G;Teodoro JS;Hubbard BP;Varela AT;Davis JG;Varamini B;Hafner A;Moaddel R;Rolo AP;Coppari R;Palmeira CM;de Cabo R;Baur JA;Sinclair DA
白藜芦醇诱导线粒体生物合成并防止代谢下降，但SIRT1是否介导这些益处是争论的主题。为了避免生殖系SIRT1基因敲除的发育缺陷，我们开发了第一个可诱导系统，允许成年小鼠全身缺失SIRT1。用中等剂量白藜芦醇治疗的小鼠显示出线粒体生物发生和功能增加，AMPK活化和骨骼肌中NAD+水平增加，而SIRT1敲除则没有显示出这些益处。过表达SIRT1的小鼠模仿了这些效应。高剂量的白藜芦醇以不依赖SIRT1的方式激活AMPK，表明白藜芦醇剂量是一个关键因素。重要的是，在缺乏SIRT1的动物中，两种剂量的白藜芦醇都没有观察到线粒体功能的改善。总之，这些数据表明，SIRT1在中等剂量的白藜芦醇刺激AMPK和改善体外和体内线粒体功能的能力中起着至关重要的作用。
Resveratrol induces mitochondrial biogenesis and protects against metabolic decline but whether SIRT1 mediates these benefits is the subject of debate. To circumvent the developmental defects of germ-line SIRT1 knockouts, we have developed the first inducible system that permits whole-body deletion of SIRT1 in adult mice. Mice treated with a moderate dose of resveratrol showed increased mitochondrial biogenesis and function, AMPK activation and increased NAD+ levels in skeletal muscle, whereas SIRT1 knockouts displayed none of these benefits. A mouse overexpressing SIRT1 mimicked these effects. A high dose of resveratrol activated AMPK in a SIRT1-independent manner, demonstrating that resveratrol dosage is a critical factor. Importantly, at both doses of resveratrol no improvements in mitochondrial function were observed in animals lacking SIRT1. Together these data indicate that SIRT1 plays an essential role in the ability of moderate doses of resveratrol to stimulate AMPK and improve mitochondrial function both in vitro and in vivo.
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