Specific Sirt1 Activator-mediated Improvement in Glucose Homeostasis Requires Sirt1-Independent Activation of AMPK.
Specific Sirt1 Activator-mediated Improvement in Glucose Homeostasis Requires Sirt1-Independent Activation of AMPK.
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DOI：
10.1016/j.ebiom.2017.03.019
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发表时间：
2017-04
期刊：
影响因子：
11.1
通讯作者：
Chung JH
中科院分区：
文献类型：
--
作者：
Park SJ;Ahmad F;Um JH;Brown AL;Xu X;Kang H;Ke H;Feng X;Ryall J;Philp A;Schenk S;Kim MK;Sartorelli V;Chung JH
特异性 Sirt1 激活剂 SRT1720 可能通过激活 Sirt1 来增强骨骼肌中的线粒体功能。然而，Sirt1 的功能获得并不会增加线粒体功能，这引发了关于 Sirt1 在 SRT1720 作用中的核心作用的问题。此外，据信SRT1720的代谢作用独立于AMP激活蛋白激酶（AMPK）而发生，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 以不依赖 Sirt1 的方式激活 AMPK，并且 SRT1720 通过以竞争性方式抑制 cAMP 降解磷酸二酯酶 (PDE) 来激活 AMPK。抑制 cAMP 效应蛋白 Epac 可阻止 SRT1720 激活肌管中的 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，与目前的看法相反，SRT1720 产生的代谢效应需要 AMPK，而 AMPK 可以独立于 Sirt1 被激活。 SRT1720 以独立于 Sirt1 的方式激活 AMPK。 SRT1720 通过抑制 cAMP 磷酸二酯酶来激活 AMPK。 SRT1720 介导的葡萄糖稳态改善需要 AMPK。 SRT1720 导致的体重减轻不足以改善葡萄糖稳态。肥胖已成为一种流行病，2型糖尿病等与肥胖相关的疾病呈上升趋势。因此，发现这些疾病的新疗法将对公共卫生产生巨大影响。 Sirt1 激活化合物（例如 SRT1720）可以预防肥胖和葡萄糖不耐受，但它们带来这些健康益处的机制尚不清楚。我们发现 SRT1720 独立于 Sirt1 激活能量传感器 AMPK，并以 AMPK 依赖性方式增加线粒体功能和葡萄糖耐量。 SRT1720通过直接抑制cAMP磷酸二酯酶来激活AMPK，这表明cAMP磷酸二酯酶可能是肥胖相关疾病的潜在药物靶点。
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. SRT1720 activates AMPK in a Sirt1-independent manner. SRT1720 activates AMPK by inhibiting cAMP phosphodiesterase. SRT1720-mediated improvement in glucose homeostasis requires AMPK. Weight loss due to SRT1720 is not sufficient for improved glucose homeostasis. Obesity has become an epidemic and obesity-related diseases such as type 2 diabetes are on the rise. Therefore, discovering novel therapies for these diseases will have great public health impact. Sirt1 activating compounds such as SRT1720 protect against obesity and glucose intolerance, but the mechanism by which they confer these health benefits has been unclear. We discovered that SRT1720 activates energy sensor AMPK, independent of Sirt1, and increases mitochondrial function and glucose tolerance in an AMPK-dependent manner. SRT1720 activates AMPK by directly inhibiting cAMP phosphodiesterases, suggesting that cAMP phosphodiesterases may be potential drug targets for obesity-related diseases.