Resveratrol

SIRT1 Is Required for AMPK Activation and the Beneficial Effects of Resveratrol on Mitochondrial Function

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Cell Metabolism, Volume 15, Issue 5, 675-690, 2 May 2012
Copyright  2012 Elsevier Inc. All rights reserved.
10.1016/j.cmet.2012.04.003

Referred to by: Fortifying the Link between SIRT1, Resve...

Authors

Nathan L. Price,Ana P. Gomes,Alvin J.Y. Ling,Filipe V. Duarte,Alejandro Martin-Montalvo,Brian J. North,Beamon Agarwal,Lan Ye,Giorgio Ramadori,Joao S. Teodoro,Basil P. Hubbard,Ana T. Varela,James G. Davis,Behzad Varamini,Angela Hafner,Ruin Moaddel,Anabela P. Rolo,Roberto Coppari,Carlos M. Palmeira,Rafael de Cabo,Joseph A. Baur,David A. SinclairSee Affiliations

• Highlights
• Resveratrol's ability to improve mitochondrial function requires SIRT1 in vivo
• Moderate doses of resveratrol activate AMPK and raise NAD⁺ in a SIRT1-dependent manner
• Activation of AMPK in the absence of SIRT1 does not improve mitochondrial function
• Overexpression of SIRT1 mimics resveratrol's effects on AMPK and mitochondria

Summary

Resveratrol induces mitochondrial biogenesis and protects against metabolic decline, but whether SIRT1 mediates these benefits is the subject of debate. To circumvent the developmental defects of germline SIRT1 knockouts, we have developed an inducible system that permits whole-body deletion of SIRT1 in adult mice. Mice treated with a moderate dose of resveratrol showed increased mitochondrial biogenesis and function, AMPK activation, and increased NAD⁺ levels in skeletal muscle, whereas SIRT1 knockouts displayed none of these benefits. A mouse overexpressing SIRT1mimicked these effects. A high dose of resveratrol activated AMPK in a SIRT1-independent manner, demonstrating that resveratrol dosage is a critical factor. Importantly, at both doses of resveratrolno improvements in mitochondrial function were observed in animals lacking SIRT1. Together these data indicate that SIRT1 plays an essential role in the ability of moderate doses of resveratrol to stimulate AMPK and improve mitochondrial function both in vitro and in vivo.