The Central Sirtuin 1/p53 Pathway Is Essential for the Orexigenic Action of Ghrelin

Abstract

OBJECTIVEGhrelin is a stomach-derived peptide that increases food intake through the activation of hypothalamic AMP-activated protein kinase (AMPK). However, the molecular mechanisms initiated by the activation of the ghrelin receptor, which in turn lead to AMPK activation, remain unclear. Sirtuin 1 (SIRT1) is a deacetylase activated in response to calorie restriction that acts through the tumor suppressor gene p53. We tested the hypothesis that the central SIRT1/p53 pathway might be mediating the orexigenic action of ghrelin.RESEARCH DESIGN AND METHODSSIRT1 inhibitors, such as Ex527 and sirtinol, and AMPK activators, such as AICAR, were administered alongside ghrelin in the brain of rats and mice (wild-type versus p53 knockout [KO]). Their hypothalamic effects on lipid metabolism and changes in transcription factors and neuropeptides were assessed by Western blot and in situ hybridization.RESULTSThe central pretreatment with Ex527, a potent SIRT1 inhibitor, blunted the ghrelin-induced food intake in rats. Mice lacking p53, a target of SIRT1 action, failed to respond to ghrelin in feeding behavior. Ghrelin failed to phosphorylate hypothalamic AMPK when rats were pretreated with Ex527, as it did in p53 KO mice. It is noteworthy that the hypothalamic SIRT1/p53 pathway seems to be specific for mediating the orexigenic action of ghrelin, because central administration of AICAR, a potent AMPK activator, increased food intake in p53 KO mice. Finally, blockade of the central SIRT1 pathway did not modify ghrelin-induced growth hormone secretion.CONCLUSIONSGhrelin specifically triggers a central SIRT1/p53 pathway that is essential for its orexigenic action, but not for the release of growth hormone.

Ghrelin modulates hypothalamic fatty acid-sensing and control of food intake in rainbow trout

“…This is the first study in which the GHRL effect on the four main neuropeptides involved in the metabolic regulation of food intake have been assessed simultaneously. The observed changes are in concordance with those previously observed in mammals in which central GHRL administration resulted in consistent increases of NPY and AgRP expression (Andrews et al 2008, Sangiao-Alvarellos et al 2010, Martins et al 2013, Stark et al 2015 and, occasionally, in decreased POMC and CART mRNA levels (Velásquez et al 2011).…”

“…The orexigenic effect is in agreement with that observed in most fish species after IP or ICV GHRL treatments (Unniappan et al 2002, Tinoco et al 2014, and is in line to the effect of this peptide in other vertebrates, including mammals (Ló pez et al 2008, Sangiao-Alvarellos et al 2010, Velásquez et al 2011, Martins et al 2013, Stark et al 2015. It is surprising that GHRL did not also increase food intake 6 h after treatment.…”

“…This octanoylation is essential for binding to the growth hormone secretagogue receptor (GHS-R1a) present in several locations, including hypothalamic neurons (Perello & Dickson 2015, Al Massadi et al 2015. The binding elicits an orexigenic response through enhanced stimulation of NPY/AgRP and decreased POMC/CART gene expression (Velásquez et al 2011). This orexigenic effect is mediated by changes in fatty acid metabolism and other parameters related to fatty acid-sensing systems that basically reverse those elicited by raised levels of LCFA (Ló pez et al 2008, Sangiao-Alvarellos et al 2010, Martins et al 2013, Gao et al 2013, Stark et al 2015.…”

The role of ghrelin signalling in second-generation antipsychotic-induced weight gain

“…Finally, the postprandial suppression of AMPK was eliminated in UCP2 knockout but not in wild type mice (Andrews et al, 2008). More recent studies have also indicated the roles of Sirtuin 1 (SIRT1)/p53 (Velasquez et al, 2011) and CPT1c/ceramide (Ramirez et al, 2013) in the orexigenic effect of ghrelin signalling.…”

Calorie restriction and sirtuins revisited

“…Nonetheless, the weight of evidence indicates that SIRT1 in the agouti-related peptide-producing neurons (AgRPs) controls the response to the gut hormone ghrelin and feeding behavior (Dietrich et al 2010(Dietrich et al , 2012Sasaki et al 2010). In addition, SIRT1 in the ventromedial hypothalamic (VMH) neurons determines physiological outputs to ghrelin signaling (Velasquez et al 2011;Porteiro et al 2013). SIRT1 in the dorsomedial hypothalamus (DMH) and lateral hypothalamus (LH) is induced by CR and mediates outputs such as physical activity and body temperature by determining the levels of the orexin receptor 2 (Satoh et al 2010).…”