Starting a Beneficial Path

Science Signaling  07 Feb 2012:
Vol. 5, Issue 210, pp. ec40
DOI: 10.1126/scisignal.2002928

The polyphenol resveratrol, which is found in red wine, appears to mimic the beneficial effects of calorie restriction on aging and age-associated metabolic disorders. These effects of resveratrol are thought to involve activation of the NAD+ (the oxidized form of nicotinamide adenine dinucleotide)–dependent deacetylase Sirt1 downstream of the energy-sensing enzyme AMPK [adenosine 5'-monophosphate (AMP)–activated protein kinase]; however, the direct target of resveratrol—and the pathway whereby it activates AMPK—have been unclear (see Tennen et al.). Park et al. found that oral administration of resveratrol to mice increased cyclic AMP (cAMP) abundance in skeletal muscle and white adipose tissue and that direct exposure to resveratrol increased cAMP in cultured C2C12 myotubes. Pharmacological and knockdown analyses indicated that resveratrol activated AMPK by way of the cAMP effector Epac1; resveratrol increased Epac activity in C2C12 myotubes, and assays of Epac1 activity in the presence or absence of resveratrol confirmed that its ability to do so was indirect. AMPK increases NAD+ abundance, and the ability of resveratrol to do so was blocked by siRNA directed against Epac1, as was its ability to promote deacetylation of the Sirt1 target PGC-1α (a transcriptional coactivator that promotes mitochondrial biogenesis and respiration). Conversely, an Epac agonist increased myotube mitochondrial content and oxygen consumption and, like resveratrol, decreased the abundance of reactive oxygen species. AMPK activation depends on its phosphorylation by either LKB1 (liver kinase B1) or CamKKβ (calcium/calmodulin-dependent kinase kinase β). The authors used a combination of calcium chelation, knockdown, and pharmacological analysis to determine how resveratrol’s activation of Epac led to activation of AMPK and found that this occurred by way of phospholipase C, ryanodine receptor 2, and CamKKβ. Returning to the question of how resveratrol increases cAMP, the authors determined that, whereas it had no effect on the activities of the enzymes that synthesize cAMP, it acted as a competitive inhibitor of several phosphodiesterases (PDEs, enzymes that hydrolyze cyclic nucleotides). Remarkably, the PDE4 inhibitor rolipram not only mimicked resveratrol’s activity in vitro (stimulating AMPK phosphorylation and activity by way of Epac1, increasing NAD+ abundance and PGC-1α deacetylation, and increasing mitochondrial biogenesis), it also reproduced its beneficial effects in vivo. Mice treated with rolipram showed increased exercise tolerance, increased metabolic activity, increased glucose tolerance, and resistance to diet-induced obesity. Thus, the authors conclude that resveratrol acts as a competitive phosphodiesterase inhibitor to initiate the pathways mediating its beneficial effects on aging-related metabolic disorders.

S.-J. Park, F. Ahmad, A. Philp, K. Baar, T. Williams, H. Luo, H. Ke, H. Rehmann, R. Taussig, A. L. Brown, M. K. Kim, M. A. Beaven, A. B. Burgin, V. Manganiello, J. H. Chung, Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148, 421–433 (2012). [Online Journal]

R. I. Tennen, E. Michishita-Kioi, K. F. Chua, Finding a target for resveratrol. Cell 148, 387–389 (2012). [Online Journal]