Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases

Park, Sung-Jun; Ahmad, Faiyaz; Philp, Andrew; Baar, Keith; Williams, Tishan; Luo, Hai‐Bin; Ke, Hengming; Rehmann, Holger; Taussig, Ronald; Brown, Alexandra L.; Kim, Myung K.; Beaven, Michael A.; Burgin, Alex B.; Manganiello, Vincent C.; Chung, Jay H.

doi:10.1186/1753-6561-6-s3-p73

Cited by 192 publications

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“…Resveratrol was recently shown to block cAMP phosphodiesterases and increase cAMP in muscle and adipose tissue (51). In contrast, in pituitary cells, no significant changes in cAMP levels were detected after resveratrol treatment or Sirt1 siRNA.…”

Section: Discussionmentioning

confidence: 96%

Sirt1 inhibits the transcription factor CREB to regulate pituitary growth hormone synthesis

et al. 2013

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Growth hormone (GH) is a major anabolic hormone and the primary regulator of organism growth. Its transcription is triggered by GH-releasing hormone (GHRH) through the transcription factor cAMP response element-binding protein (CREB) and by caloric intake. In contrast, the deacetylase Sirt1 is activated by caloric restriction. Therefore, the present study investigates how Sirt1 affects CREB function and GH synthesis. Sirt1 pharmacological activation with resveratrol (IC₅₀=87 μM) suppressed GHRH-induced GH secretion from rat anterior pituitary cells in vivo and in vitro, while vehicle controls showed no effect. Resveratrol's effects were abolished after knocking down Sirt1 with RNA interference, but not in control scrambled siRNA-transfected rat somatotrophs, confirming the Sirt1 specificity. Sirt1 activation and overexpression suppressed forskolin-induced CREB-Ser(133) phosphorylation, but no effect was seen with vehicle and empty plasmid controls. The deacetylase-dead mutant Sirt1 retained CREB-Ser(133) phosphorylation by keeping protein phosphatase protein phosphatase 1 activity low. Sirt1 activation suppressed glycogen synthase kinase 3 β acetylation, and a mutation on the GSK3β-Lys(205) residue mimicking a hypoacetylated form revealed increased activity. In summary, this is a novel mechanism through which Sirt1 intercepts the cAMP pathway by suppressing CREB transcriptional activation, resulting in decreased GH synthesis.

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Section: Discussionmentioning

confidence: 96%

Sirt1 inhibits the transcription factor CREB to regulate pituitary growth hormone synthesis

et al. 2013

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“…The subsequent concerted action of both activated AMPK and SIRT1 on PGC-1α activates this coactivator, resulting in the induction of mitochondrial biogenesis (Canto et al, 2009). Recently, a direct inhibition of cAMP PDEs by resveratrol was demonstrated, which may be an important aspect in its mechanism of action (Park et al, 2012). Then again, the large number of proteins that are able to interact with resveratrol makes it very difficult to interpret the contribution of the effect of direct inhibition of PDEs by this compound, in the overall scheme of interactions (Pacholec et al, 2010).…”

Section: Induction Of Mitochondrial Biogenesis Via Sirt1 Activation: mentioning

confidence: 99%

Turn up the power – pharmacological activation of mitochondrial biogenesis in mouse models

Komen

Thorburn

2014

British J Pharmacology

125

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The oxidative phosphorylation (OXPHOS) system in mitochondria is responsible for the generation of the majority of cellular energy in the form of ATP. Patients with genetic OXPHOS disorders form the largest group of inborn errors of metabolism. Unfortunately, there is still a lack of efficient therapies for these disorders other than management of symptoms. Developing therapies has been complicated because, although the total group of OXPHOS patients is relatively large, there is enormous clinical and genetic heterogeneity within this patient population. Thus there has been a lot of interest in generating relevant mouse models for the different kinds of OXPHOS disorders. The most common treatment strategies tested in these mouse models have aimed to up-regulate mitochondrial biogenesis, in order to increase the residual OXPHOS activity present in affected animals and thereby to ameliorate the energy deficiency. Drugs such as bezafibrate, resveratrol and AICAR target the master regulator of mitochondrial biogenesis PGC-1α either directly or indirectly to manipulate mitochondrial metabolism. This review will summarize the outcome of preclinical treatment trials with these drugs in mouse models of OXPHOS disorders and discuss similar treatments in a number of mouse models of common diseases in which pathology is closely linked to mitochondrial dysfunction. In the majority of these studies the pharmacological activation of the PGC-1α axis shows true potential as therapy; however, other effects besides mitochondrial biogenesis may be contributing to this as well. LINKED ARTICLESThis article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi. org/10.1111/bph.2014.171.issue-8 Abbreviations AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; AMPK, AMP-activated kinase; BAT, brown adipose tissue; CI-V, complex I-V; DMD, Duchenne muscular dystrophy; FAO, fatty acid oxidation; HD, Huntington's disease; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; mtDNA, mitochondrial DNA; nDNA, nuclear DNA; NRF, nuclear respiratory factor; OXPHOS, oxidative phosphorylation; PD, Parkinson's disease; PGC-1, PPAR-γ coactivator 1; POLG, polymerase γ; SIRT1, silent information regulator two (Sir2) protein 1, sirtuin 1 Mitochondria as the powerhouse and mitochondrial diseaseMitochondria are involved in numerous processes but they are best known for their role as the powerhouse of the cell. The oxidative phosphorylation (OXPHOS) system located in the mitochondrial inner membrane integrates the production of cellular energy in the form of ATP, with all the major catabolic pathways including fatty acid oxidation (FAO), the tricarboxylic acid cycle and amino acid oxidation. The OXPHOS system consists of five multimeric protein complexes, complex I-V (CI-V). Although critical OXPHOS subunits are encoded by the circular DNA molecules residing inside mitochondria (mtDNA), the majority of the subunits, together with all the proteins required fo...

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“…A priority in future studies is to identify the direct molecular targets of RV, upstream of AMPK, as well as other molecular targets independent of AMPK activation [17]. Recently published findings indicate RV targets upstream regulators of AMPK, include cAMP-degrading phosphodiesterases, which activate CamKK␤ an upstream regulator of AMPK [46]. In conclusion, we present evidence that RV activates AMPK and downstream targets involved in regulating diabetes-related metabolic changes in db/db mice, which naturally develop type 2 diabetes.…”

Section: Adiponectin and Other Mediators Of Rv-induced Diabetes-relatmentioning

confidence: 99%

Resveratrol ameliorates diabetes‐related metabolic changes via activation of AMP‐activated protein kinase and its downstream targets in db/db mice

Jung

Park

et al. 2012

Molecular Nutrition Food Res

136

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Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases

Abstract: Park et al.: Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. BMC Proceedings 2012 6(Suppl 3):P73.

Cited by 192 publications

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Sirt1 inhibits the transcription factor CREB to regulate pituitary growth hormone synthesis

Sirt1 inhibits the transcription factor CREB to regulate pituitary growth hormone synthesis

Turn up the power – pharmacological activation of mitochondrial biogenesis in mouse models

Resveratrol ameliorates diabetes‐related metabolic changes via activation of AMP‐activated protein kinase and its downstream targets in db/db mice

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