Identifying Novel Targets of Resveratrol

RESEARCH HIGHLIGHTS

METABOLIC DISEASE Identifying novel targets of resveratrol

Resveratrol is thought to mimic the receptor 2 (RYR2), and Chung’s team effects of caloric restriction to confer showed that resveratrol required anti-ageing and antidiabetogenic active EPAC1 to activate RYR2. So, properties, but its mechanism of resveratrol, via the EPAC1–PLC– action has remained controversial. RYR2 pathway, promotes CaMKKβ- Chung and colleagues now report mediated activation of AMPK. The that resveratrol increases cyclic authors point out that, depending on AMP levels by competitively the condition and the cell type, the inhibiting phosphodiesterases alternative cAMP effector protein (PDEs), ultimately leading to the kinase A might also be involved in activation of AMP-activated pro- resveratrol-mediated activation of tein kinase (AMPK) and positive AMPK by activating LKB1. metabolic effects. The key issue, however, is how Chung and his team had previ- resveratrol raises cAMP levels. ously shown that AMPK was a key Chung and colleagues showed that mediator of the metabolic effects of it did not stimulate the activity of resveratrol but not a direct target adenylyl cyclases, prompting them of this polyphenol. In the present to investigate potential inhibitory study, published in Cell, they con- effects on the cAMP-selective PDEs. firmed a previously reported increase Resveratrol inhibited the activity of in cAMP levels in response to resver- PDE1, PDE3 and PDE4 by compet- atrol, before showing that inhibition ing with cAMP for PDE binding. of adenylyl cyclase prevented AMPK Given these results, PDE inhibi- phosphorylation. They then dem- tors would be expected to mimic BRAND X PICTURES onstrated that the cAMP-regulated the metabolic effects of resveratrol, guanine nucleotide exchange factor and so — on the basis that PDE4 is controls. Notably, both resveratrol EPAC1 was required for AMPK responsible for most PDE activity and rolipram also increased levels of activation in HeLa cells, and that res- in myotubes and skeletal muscles glucagon-like peptide 1, which has veratrol indirectly increased EPAC1 — Chung’s team treated these cells antidiabetogenic activities. activity. EPAC1 was also required for with rolipram, a PDE4 inhibitor. So, not only have Chung and the resveratrol-mediated increase in Like resveratrol, rolipram increased colleagues identified a direct target the levels of NAD+ and the activity of cAMP levels and NAD+ levels, of resveratrol and elucidated a bio- the sirtuin 1 deacetylase. stimulated AMPK phosphorylation chemical pathway by which it confers Calcium/calmodulin-dependent and induced deacetylation of a metabolic benefits, they have also kinase kinase-β (CaMKKβ) and liver sirtuin 1 substrate. Mice that were demonstrated that the PDE4 inhibi- kinase B1 (LKB1) are two upstream fed a high-fat diet and treated with tor rolipram reproduces all of these kinases that phosphorylate and rolipram exhibited increased mRNA benefits. And with improved mem- thereby activate AMPK. EPAC1 levels of genes known to be induced ory and protection against ageing- can increase cytosolic Ca2+ levels by resveratrol, as well as enhanced related diseases having already been via CaMKKβ in a phospholipase mitochondrial biogenesis. The mice demonstrated for PDE4 inhibitors in C (PLC)-dependent manner, and were also resistant to weight gain, animal models, these agents seem to treatment with a calcium chelator, which resulted from an increased have strong therapeutic potential. a CaMKKβ inhibitor or a PLC basal metabolic rate. Furthermore, Katrin Legg inhibitor decreased AMPK phospho- as expected from the metabolic ORIGINAL RESEARCH PAPER Park, S.‑J. et al. rylation in response to resveratrol. changes induced by rolipram, treat- Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP EPAC1 also induces calcium release ment with this inhibitor increased phosphodiesterases. Cell 148, 421–433 (2012) from internal stores via ryanodine glucose tolerance compared with