Laboratory of Obesity and Aging Research, Genetics and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Translational Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
EBioMedicine. 2017 Apr;18:128-138. doi: 10.1016/j.ebiom.2017.03.019. Epub 2017 Mar 14.
The specific Sirt1 activator SRT1720 increases mitochondrial function in skeletal muscle, presumably by activating Sirt1. However, Sirt1 gain of function does not increase mitochondrial function, which raises a question about the central role of Sirt1 in SRT1720 action. Moreover, it is believed that the metabolic effects of SRT1720 occur independently of AMP-activated protein kinase (AMPK), an important metabolic regulator that increases mitochondrial function. Here, we show that SRT1720 activates AMPK in a Sirt1-independent manner and SRT1720 activates AMPK by inhibiting a cAMP degrading phosphodiesterase (PDE) in a competitive manner. Inhibiting the cAMP effector protein Epac prevents SRT1720 from activating AMPK or Sirt1 in myotubes. Moreover, SRT1720 does not increase mitochondrial function or improve glucose tolerance in AMPKα2 knockout mice. Interestingly, weight loss induced by SRT1720 is not sufficient to improve glucose tolerance. Therefore, contrary to current belief, the metabolic effects produced by SRT1720 require AMPK, which can be activated independently of Sirt1.
特定的 Sirt1 激活剂 SRT1720 通过激活 Sirt1 增加骨骼肌中的线粒体功能。然而，Sirt1 功能获得并不能增加线粒体功能，这就提出了一个问题，即 Sirt1 在 SRT1720 作用中的核心作用。此外，人们认为 SRT1720 的代谢作用独立于 AMP 激活的蛋白激酶（AMPK）发生，AMPK 是一种增加线粒体功能的重要代谢调节剂。在这里，我们表明 SRT1720 以 Sirt1 非依赖性的方式激活 AMPK，并且 SRT1720 通过竞争性抑制 cAMP 降解磷酸二酯酶（PDE）来激活 AMPK。抑制 cAMP 效应蛋白 Epac 可防止 SRT1720 在肌管中激活 AMPK 或 Sirt1。此外，SRT1720 不会增加 AMPKα2 敲除小鼠的线粒体功能或改善葡萄糖耐量。有趣的是，SRT1720 引起的体重减轻不足以改善葡萄糖耐量。因此，与当前的观点相反，SRT1720 产生的代谢作用需要 AMPK，而 AMPK 可以独立于 Sirt1 激活。
