Caloric restriction is the best known experimental procedure that extends lifespan and resistance to aging-related diseases. Part of these actions was found to be mediated by the NAD-dependent histone deacetylase Sir2/Sirt1. Resveratrol is a polyphenol found in the skin of grapes, which was identified as a Sirt1 activator and subsequently proposed as a caloric restriction mimetic. The aim of the present study was to determine how resveratrol affects the GH axis, which is central in the physiology of aging. Treating rat anterior pituitary cells in primary cell culture and GH3 GH-producing cells with resveratrol decreased GH secretion. GH promoter is regulated by the cAMP/PKA pathway through CREB-binding protein (CBP) bound to Pit1. Treatment with resveratrol decreased the binding of acetyl-histone 3 and Pit1 on the endogenous rat GH promoter. Furthermore Pit1 gene expression was found to be reduced in resveratrol treated GH3 cells. In rat cells Pit1 is under the control of itself and CREB. Resveratrol treatment decreased CREB acetylation and the specific Sirt1 activator NAD decreased CREB transcriptional activity. CREB is mainly acetylated by the histone acetyltransferase CBP. Sirt1 immunoprecipitated with CBP and resveratrol decreased CBP acetylation, an effect that results in diminishing its acetyltransferase activity. Interestingly, resveratrol also decreased CREB phosphorylation at Ser133. CREB is usually phosphorylated by the cAMP/PKA pathway. However, resveratrol treatment did not affect cAMP production. Other kinases, such as, Akt were also found to phosphorylate CREB. Indeed resveratrol treatment decreased pAkt-Ser473 levels in a mechanism involving mTOR but not PDK1. Altogether these data demonstrate that resveratrol decreases GH synthesis, similar to the situation observed in caloric restricted rodents, and provide a mechanism linking the lifespan regulator Sirt1 with the GH axis.
03 - 07 May 2008
European Society of Endocrinology