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.
Cell. 2012 Feb 3;148(3):421-33. doi: 10.1016/j.cell.2012.01.017.
Resveratrol, a polyphenol in red wine, has been reported as a calorie restriction mimetic with potential antiaging and antidiabetogenic properties. It is widely consumed as a nutritional supplement, but its mechanism of action remains a mystery. Here, we report that the metabolic effects of resveratrol result from competitive inhibition of cAMP-degrading phosphodiesterases, leading to elevated cAMP levels. The resulting activation of Epac1, a cAMP effector protein, increases intracellular Ca(2+) levels and activates the CamKKβ-AMPK pathway via phospholipase C and the ryanodine receptor Ca(2+)-release channel. As a consequence, resveratrol increases NAD(+) and the activity of Sirt1. Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of resveratrol, including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance in mice. Therefore, administration of PDE4 inhibitors may also protect against and ameliorate the symptoms of metabolic diseases associated with aging.
白藜芦醇是红酒中的一种多酚，具有潜在的抗衰老和抗糖尿病特性，被报道为一种卡路里限制模拟物。它被广泛用作营养补充剂，但它的作用机制仍然是个谜。在这里，我们报告说，白藜芦醇的代谢作用是由于竞争性抑制 cAMP 降解磷酸二酯酶，导致 cAMP 水平升高。由此产生的 cAMP 效应蛋白 Epac1 的激活增加细胞内 Ca(2+)水平，并通过磷脂酶 C 和肌醇 1,4,5-三磷酸受体 Ca(2+)释放通道激活 CamKKβ-AMPK 途径。结果，白藜芦醇增加 NAD(+)和 Sirt1 的活性。用罗利普兰抑制 PDE4 可重现白藜芦醇的所有代谢益处，包括预防饮食诱导的肥胖和增加线粒体功能、体力和葡萄糖耐量在小鼠。因此，PDE4 抑制剂的给药也可能预防和改善与衰老相关的代谢疾病的症状。
