Abstract
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 Ca2+ levels and activates the CamKKβ-AMPK pathway via phospholipase C and the ryanodine receptor Ca2+-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.
Highlights
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
We report that the metabolic effects of resveratrol result from competitive inhibition of cAMP-degrading phosphodiesterases, leading to elevated cAMP levels
Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of resveratrol, including prevention of dietinduced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance in mice
Summary
Resveratrol, a polyphenol in red wine, has been reported as a calorie restriction mimetic with potential antiaging and antidiabetogenic properties. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases Sung-Jun Park1, Faiyaz Ahmad2, Andrew Philp4, Keith Baar4, Tishan Williams5, Haibin Luo6, Hengming Ke5, Holger Rehmann7, Ronald Taussig8, Alexandra L Brown1, Myung K Kim1, Michael A Beaven3, Alex B Burgin9, Vincent Manganiello2, Jay H Chung1*
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