Critical Role of Arcuate Y4 Receptors and the Melanocortin System in Pancreatic Polypeptide-Induced Reduction in Food Intake in Mice

Shu Lin,Herbert Herzog,Lei Zhang,Laurence Macia,Amy D Nguyen,Matthew J During,Aygul Aljanova,Yan-Chuan Shi,Ernie Yulyaningsih,En-Ju Deborah Lin,Amanda Sainsbury,Daniel Tomé

doi:10.1371/journal.pone.0008488

Abstract

BackgroundPancreatic polypeptide (PP) is a potent anti-obesity agent known to inhibit food intake in the absence of nausea, but the mechanism behind this process is unknown.Methodology/Principal FindingsHere we demonstrate that in response to i.p. injection of PP in wild type but not in Y4 receptor knockout mice, immunostaining for the neuronal activation marker c-Fos is induced specifically in neurons of the nucleus tractus solitarius and the area postrema in the brainstem, notably in cells also showing immunostaining for tyrosine hydroxylase. Importantly, strong c-Fos activation is also detected in the arcuate nucleus of the hypothalamus (ARC), particularly in neurons that co-express alpha melanocyte stimulating hormone (α-MSH), the anorexigenic product of the proopiomelanocortin (POMC) gene. Interestingly, other hypothalamic regions such as the paraventricular nucleus, the ventromedial nucleus and the lateral hypothalamic area also show c-Fos induction after PP injection. In addition to c-Fos activation, PP injection up-regulates POMC mRNA expression in the ARC as detected by in situ hybridization. These effects are a direct consequence of local Y4 signaling, since hypothalamus-specific conditional Y4 receptor knockout abolishes PP-induced ARC c-Fos activation and blocks the PP-induced increase in POMC mRNA expression. Additionally, the hypophagic effect of i.p. PP seen in wild type mice is completely absent in melanocortin 4 receptor knockout mice.Conclusions/SignificanceTaken together, these findings show that PP reduces food intake predominantly via stimulation of the anorexigenic α-MSH signaling pathway, and that this effect is mediated by direct action on local Y4 receptors within the ARC, highlighting a potential novel avenue for the treatment of obesity.

Highlights

The worldwide prevalence of obesity and type 2-diabetes are increasing at an alarming rate
This study demonstrates that reduction in food intake induced by Y4 receptor agonism with PP is mediated by activation of the POMC / alpha melanocyte stimulating hormone (a-MSH) signaling pathway, because PP-induced hypophagia is absent in MC4R2/2 mice
POMC, peripheral PP injection significantly inhibits expression of glutamic acid decarboxylase 65 (GAD65) with no effect on arcuate nucleus of the hypothalamus (ARC) neuropeptide Y (NPY) mRNA expression.Taken together, these findings suggest that peripheral PP may act on Y4 receptors within the ARC to activate a-MSH- and gammaaminobutyric acid (GABA)-ergic neurons and thereby stimulate POMC and inhibit GAD65 mRNA expression, increasing a-MSH action on melanocortin 4 receptor (MC4R) and reducing food intake

Summary

Introduction

The worldwide prevalence of obesity and type 2-diabetes are increasing at an alarming rate. Y2 receptors have been flagged as potential targets for novel anti-obesity agents, since PYY3-36, an endogenous Y2-preferring ligand, reduces food intake in lean [8] and obese [9] humans and reduces body weight and adiposity after chronic administration to obese rodents [10,11]. Like other gut-derived satiety hormones such as glucagon-like peptide-1, PYY3-36 has been shown to induce nausea or conditioned taste aversion at doses that reduce food intake [12,13,14]. This could limit the effectiveness of PYY3-36 or Y2-preferring agonists as treatments for obesity. Pancreatic polypeptide (PP) is a potent anti-obesity agent known to inhibit food intake in the absence of nausea, but the mechanism behind this process is unknown

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