Mechanism for Metabolic Effects of Resveratrol Elucidated

Resveratrol inhibits phosphodiesterase 4 in mice, resulting in indirect activation of s irtuin 1

MONDAY, Feb. 6 (HealthDay News) -- By inhibiting phosphodiesterase (PDE) 4 in skeletal muscle, resveratrol triggers a series of intracellular events, including indirect activation of sirtuin 1 (Sirt1), according to an experimental study published in the Feb. 3 issue of Cell.

Sung-Jun Park, Ph.D., of the National Institutes of Health in Bethesda, Md., and colleagues investigated the metabolic effects of resveratrol on mice cells.

The researchers found that administration of resveratrol to mice resulted in increased cAMP, due to competitive inhibition of cAMP-degrading PDEs. The subsequent activation of Epac1, a cAMP effector protein, increased intracellular calcium (Ca²+) levels and activation of the CamKKβ-AMPK pathway via phospholipase C and the ryanodine receptor Ca²+-release channel. Consequently, NAD+ and Sirt1 activity were increased. The metabolic benefits of resveratrol were reproduced by inhibition of PDE4 with rolipram in mice, including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance.

"cAMP is a key mediator of metabolic regulation, and the identification of PDEs as resveratrol targets might explain how resveratrol mimics some aspects of calorie restriction," the authors write. "It is therefore possible that PDE4 inhibitors may be useful for treating metabolic diseases and other aging-related diseases in humans."

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