Carta Acesso aberto Revisado por pares

Finding a Target for Resveratrol

2012; Cell Press; Volume: 148; Issue: 3 Linguagem: Inglês

10.1016/j.cell.2012.01.032

ISSN

1097-4172

Autores

Ruth I. Tennen, Eriko Michishita-Kioi, Katrin F. Chua,

Tópico(s)

Autophagy in Disease and Therapy

Resumo

Despite resveratrol's well-documented health benefits, its mechanism of action remains controversial. In particular, the direct molecular target of resveratrol has been elusive. Park et al. now show that resveratrol directly inhibits cAMP-dependent phosphodiesterases, triggering a cascade of events that converge on the important energy-sensing metabolic regulators AMPK, SIRT1, and PGC-1α. Despite resveratrol's well-documented health benefits, its mechanism of action remains controversial. In particular, the direct molecular target of resveratrol has been elusive. Park et al. now show that resveratrol directly inhibits cAMP-dependent phosphodiesterases, triggering a cascade of events that converge on the important energy-sensing metabolic regulators AMPK, SIRT1, and PGC-1α. For nearly 75 years, calorie restriction (CR) has been the most consistent behavioral intervention capable of extending life span and protecting against age-associated metabolic disease. Since the report that resveratrol—a polyphenol found in the skin of grapes—mimics the life-span-extending effects of CR in budding yeast (Howitz et al., 2003Howitz K.T. Bitterman K.J. Cohen H.Y. Lamming D.W. Lavu S. Wood J.G. Zipkin R.E. Chung P. Kisielewski A. Zhang L.L. et al.Nature. 2003; 425: 191-196Crossref PubMed Scopus (3149) Google Scholar), this compound has been studied intensely. Debate about the direct targets, downstream effectors, and molecular mechanism by which resveratrol improves health span has ensued. In this issue, Park et al., 2012Park S.-J. Ahmad F. Philp A. Baar K. Williams T. Luo H. Ke H. Rehmann H. Taussig R. Brown A.L. et al.Cell. 2012; 148 (this issue): 487-501Abstract Full Text Full Text PDF PubMed Scopus (1044) Google Scholar identify phosphodiesterase (PDE) enzymes as direct targets of resveratrol and propose that resveratrol indirectly activates the sirtuin SIRT1 through a signaling cascade involving cAMP, Epac1, and AMPK. Resveratrol burst into the news nearly 20 years ago, when it was proposed to account for the unique effects of red wine on life span and health. Subsequently, resveratrol was linked to myriad physiological benefits, including protection against cardiovascular disease, cancer, age-related deterioration, and the pathological consequences of high-fat diets (Baur, 2010Baur J.A. Mech. Ageing Dev. 2010; 131: 261-269Crossref PubMed Scopus (172) Google Scholar). Resveratrol was reported to exert its effects by directly activating the yeast Sir2 protein and its mammalian homolog SIRT1 (Howitz et al., 2003Howitz K.T. Bitterman K.J. Cohen H.Y. Lamming D.W. Lavu S. Wood J.G. Zipkin R.E. Chung P. Kisielewski A. Zhang L.L. et al.Nature. 2003; 425: 191-196Crossref PubMed Scopus (3149) Google Scholar). These members of the sirtuin family catalyze NAD+-dependent deacetylation reactions. The resveratrol-sirtuin connection sparked a torrent of excitement, in part because sirtuins had been independently linked to life span regulation in budding yeast (Kaeberlein et al., 1999Kaeberlein M. McVey M. Guarente L. Genes Dev. 1999; 13: 2570-2580Crossref PubMed Scopus (1758) Google Scholar). Over the last decade, fundamental roles for mammalian sirtuins in numerous cellular processes that impact metabolism, genomic stability, and aging-related disease have been demonstrated (Nakagawa and Guarente, 2011Nakagawa T. Guarente L. J. Cell Sci. 2011; 124: 833-838Crossref PubMed Scopus (232) Google Scholar). Among these functions, SIRT1 deacetylates and activates PGC-1α, a master transcriptional regulator of genes involved in energy control, ultimately leading to improved mitochondrial function and protection against metabolic disease (Lagouge et al., 2006Lagouge M. Argmann C. Gerhart-Hines Z. Meziane H. Lerin C. Daussin F. Messadeq N. Milne J. Lambert P. Elliott P. et al.Cell. 2006; 127: 1109-1122Abstract Full Text Full Text PDF PubMed Scopus (3314) Google Scholar). Thus, the notion that resveratrol acts as a CR mimetic by activating sirtuins seemed promising. However, the observed activation of SIRT1 by resveratrol in vitro now appears to be an artifact of the assay used, casting doubt on the direct resveratrol-SIRT1 connection (Baur, 2010Baur J.A. Mech. Ageing Dev. 2010; 131: 261-269Crossref PubMed Scopus (172) Google Scholar). This raises two important questions: How does resveratrol lead to SIRT1 activation in vivo, and what is the direct cellular target of resveratrol? A series of studies provided some initial answers by showing that resveratrol can activate SIRT1 indirectly through AMPK, another energy-sensing enzyme that is required for many of the adaptations triggered by CR (Cantó et al., 2010Cantó C. Jiang L.Q. Deshmukh A.S. Mataki C. Coste A. Lagouge M. Zierath J.R. Auwerx J. Cell Metab. 2010; 11: 213-219Abstract Full Text Full Text PDF PubMed Scopus (667) Google Scholar, Um et al., 2010Um J.H. Park S.J. Kang H. Yang S. Foretz M. McBurney M.W. Kim M.K. Viollet B. Chung J.H. Diabetes. 2010; 59: 554-563Crossref PubMed Scopus (535) Google Scholar). AMPK promotes the activation of PGC-1α by SIRT1 through several mechanisms, including a priming phosphorylation that is required for its deacetylation by SIRT1 and an increase in NAD+ concentration, which is rate limiting for SIRT1 activity (Cantó and Auwerx, 2010Cantó C. Auwerx J. Cell Mol. Life Sci. 2010; 67: 3407-3423Crossref PubMed Scopus (303) Google Scholar). Until now, AMPK activation was the most upstream signaling event known to be triggered by resveratrol, but like SIRT1, AMPK did not appear to be a direct resveratrol target. Now, Park and colleagues (Park et al., 2012Park S.-J. Ahmad F. Philp A. Baar K. Williams T. Luo H. Ke H. Rehmann H. Taussig R. Brown A.L. et al.Cell. 2012; 148 (this issue): 487-501Abstract Full Text Full Text PDF PubMed Scopus (1044) Google Scholar) seem to have found the missing link between resveratrol and AMPK. The authors provide evidence that resveratrol directly inhibits several PDE enzymes, and they systematically delineate the steps that lead from PDE inhibition to AMPK activation (Figure 1). These steps include increased levels of the ubiquitous second messenger cAMP, activation of the cAMP-dependent guanine nucleotide exchange factor Epac1, and increased intracellular calcium to activate CamKKβ, which phosphorylates and activates AMPK. Importantly, the PDE4 inhibitor rolipram phenocopies the cellular signaling events induced by resveratrol, including increased cAMP levels, Epac1-dependent activation of AMPK, increased NAD+, and increased deacetylation of PGC-1α. Park et al. complement this comprehensive pathway dissection with compelling in vivo experiments in mice. When fed to mice on a high-fat diet, rolipram induced a gene expression pattern that mirrors that induced by resveratrol in multiple mouse tissues. And like resveratrol-treated mice, rolipram-treated mice showed improved mitochondrial function, increased physical endurance, increased basal metabolism, and protection against diet-induced obesity and glucose intolerance. Together, these data paint a detailed picture of how resveratrol activates AMPK and SIRT1 to produce metabolic benefits, with some interesting mechanistic and clinical implications. Resveratrol is thought to produce its health benefits by mimicking CR. Does CR produce beneficial health effects by activating the same signaling cascade as resveratrol (cAMP-Epac1-CamKKβ-AMPK)? Can this network of proteins be exploited to develop CR mimetics with higher specificity and efficacy? A number of sirtuin-activating compounds (STACs) have been developed as promising therapeutic agents, and like resveratrol, these STACs appear to influence SIRT1 activity indirectly (Baur, 2010Baur J.A. Mech. Ageing Dev. 2010; 131: 261-269Crossref PubMed Scopus (172) Google Scholar). Do any of these molecules also function by directly inhibiting PDEs? Alternatively, by identifying PDEs as direct resveratrol targets, the authors' findings (Park et al., 2012Park S.-J. Ahmad F. Philp A. Baar K. Williams T. Luo H. Ke H. Rehmann H. Taussig R. Brown A.L. et al.Cell. 2012; 148 (this issue): 487-501Abstract Full Text Full Text PDF PubMed Scopus (1044) Google Scholar) may open the door to new uses for previously identified pharmacologic agents. For example, many of the players in the resveratrol-responsive signaling cascade also play anti-inflammatory and neuroprotective roles (Nakagawa and Guarente, 2011Nakagawa T. Guarente L. J. Cell Sci. 2011; 124: 833-838Crossref PubMed Scopus (232) Google Scholar), and highly selective PDE inhibitors are currently being investigated as treatments for a wide range of pathologic conditions including psychiatric and neurodegenerative diseases as well as inflammatory disorders such as chronic obstructive pulmonary disease (Houslay et al., 2005Houslay M.D. Schafer P. Zhang K.Y. Drug Discov. Today. 2005; 10: 1503-1519Crossref PubMed Scopus (560) Google Scholar). The complex narrative of how resveratrol works also provides exciting new directions for future research. For example, how does the cAMP-Epac1-CamKKβ-AMPK signaling cascade intersect with other well-characterized pathways induced in different physiologic contexts such as fasting, cold exposure, exercise, and acute stress, all of which can lead to a "fight-or-flight" β-adrenergic response? These physiologic triggers activate many of the same factors involved in the response to resveratrol but involve different inputs and connections, generating a seemingly tangled web of interconnected pathways. For example, β-adrenergic activation of the cAMP/PKA cascade by acute stress results in the rapid phosphorylation and activation of SIRT1 independent of both AMPK and NAD+ concentration changes (Gerhart-Hines et al., 2011Gerhart-Hines Z. Dominy Jr., J.E. Blättler S.M. Jedrychowski M.P. Banks A.S. Lim J.H. Chim H. Gygi S.P. Puigserver P. Mol. Cell. 2011; 44: 851-863Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar). Occurring within minutes, this signaling pathway allows increased fat utilization and adaptive thermogenesis in response to acute nutritional stress or cold exposure. Although the study by Park et al., 2012Park S.-J. Ahmad F. Philp A. Baar K. Williams T. Luo H. Ke H. Rehmann H. Taussig R. Brown A.L. et al.Cell. 2012; 148 (this issue): 487-501Abstract Full Text Full Text PDF PubMed Scopus (1044) Google Scholar focuses on the changes that occur over hours to weeks, it seems plausible that PDE inhibition by resveratrol might also be useful in modulating physiologic responses to acute stress. Questions of output specificity do, however, remain. For instance, given the numerous roles for cAMP and calcium in intracellular signaling, which downstream pathways are triggered by resveratrol? With the increase in NAD+, are other NAD+-dependent enzymes—such as the six other mammalian sirtuins and the many poly(ADP-ribose) polymerases (PARPs)—also downstream resveratrol effectors? Finally, it will be interesting to learn whether the Epac1-AMPK-SIRT1 pathway operates in cell types besides muscle and white adipose tissue. For example, although PDEs regulate cAMP signaling in cardiac myocytes, resveratrol does not appear to alter PGC-1α acetylation or mitochondrial biogenesis in these cells (Lagouge et al., 2006Lagouge M. Argmann C. Gerhart-Hines Z. Meziane H. Lerin C. Daussin F. Messadeq N. Milne J. Lambert P. Elliott P. et al.Cell. 2006; 127: 1109-1122Abstract Full Text Full Text PDF PubMed Scopus (3314) Google Scholar), and inactivation of Pde4 in mice results in heart defects such as progressive cardiomyopathy (Houslay et al., 2005Houslay M.D. Schafer P. Zhang K.Y. Drug Discov. Today. 2005; 10: 1503-1519Crossref PubMed Scopus (560) Google Scholar), suggesting that tissue-varying responses might limit the efficacy of pharmacologic intervention. From molecular details to in vivo characterization, the biochemical circuit described by Park et al., 2012Park S.-J. Ahmad F. Philp A. Baar K. Williams T. Luo H. Ke H. Rehmann H. Taussig R. Brown A.L. et al.Cell. 2012; 148 (this issue): 487-501Abstract Full Text Full Text PDF PubMed Scopus (1044) Google Scholar provides important insight into the mechanism by which resveratrol promotes metabolic health. But in the intensely controversial, complex, and rapidly evolving field of resveratrol and sirtuins, the identification of PDEs as the putative "missing link" is certainly not the end of the story. Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP PhosphodiesterasesPark et al.CellFebruary 03, 2012In BriefThe antiaging, antidiabetic polyphenol in red wine indirectly activates Sirt1 via competitive inhibition of cAMP-phosphodiesterases to ultimately increase NAD+ levels. This suggests that PDEs are potential therapeutic targets for aging-related metabolic disorders. Full-Text PDF Open Archive

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