SIRT1 Takes a Backseat to AMPK in the Regulation of Insulin Sensitivity by Resveratrol

Resveratrol is a polyphenol that is enriched in the skins of red grapes. Although scientists speculated for decades about the French paradox in which red wine appeared to protect against heart disease, the mechanisms mediating these effects remained a mystery. In 2003 Sinclair and colleagues (1) identified that resveratrol activated the nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase, SIRT1, whose yeast homolog (Sir2) was previously shown to enhance longevity in response to calorie restriction (2). Over the past several years studies in rodents have confirmed the powerful antiaging effects of resveratrol, which have been shown to range from improved exercise performance to correction of age- and obesity-induced dyslipidemia, cardiovascular dysfunction, and insulin resistance (3–5). Whereas SIRT1 has a diverse range of substrates, many of its metabolic actions are believed to be mediated by deacetylation and activation of peroxisome proliferator–activated receptor γ coactivator-α (PGC1α), which is a master regulator of mitochondrial biogenesis (4). These studies have suggested that resveratrol and SIRT1 may be the panacea for preventing the development of age-onset diseases. Resveratrol, like other polyphenols, also increases the activity of the AMP-activated protein kinase (AMPK) (3,6,7). AMPK is activated by cellular stress, including fasting and exercise, and is also regulated by circulating hormones and nutrients (8). The activation of AMPK increases fatty acid oxidation, an effect which may involve phosphorylation and inhibition of acetyl-CoA-carboxylase (ACC), reduced levels of malonyl-CoA, and increased mitochondrial fatty acid flux via carnitine palmitoyltransferase-1 (Fig. 1). At the same time, AMPK also phosphorylates …