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

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.

Y4 receptors and pancreatic polypeptide regulate food intake via hypothalamic orexin and brain-derived neurotropic factor dependent pathways

“…The data obtained in this study suggest that peripherally administered PP can control food intake by modulating neuronal activity and expression levels of key molecules in hypothalamic centers that control feeding (the LHA) and satiety (the VMH). This is also consistent with recent data using the same technologies showing altered c-Fos activation in other parts of the hypothalamus coinciding with the reduction of food intake (Lin et al, 2009). Here we show that PP injection induced c-Fos activation in orexin immunoreactive neurons in the LHA and down-regulated orexin mRNA expression in this region via Y4 receptor-mediated processes.…”

“…This is also consistent with recent data using the same technologies showing altered c-Fos activation in other parts of the hypothala- mus coinciding with the reduction of food intake (Lin et al, 2009). Here we show that PP injection induced c-Fos activation in orexin immunoreactive neurons in the LHA and down-regulated orexin mRNA expression in this region via Y4 receptor-mediated processes.…”

“…PP dose-dependently reduces food intake in freely fed and fasted mice, and this is mediated through the Y4 receptor since the effect is abolished in Y4 receptor knockout mice (Balasubramaniam et al, 2006 andLin et al, 2009).…”

Central and peripheral control of food intake

“…Th e peripheral administration of PP has been shown to decrease the food intake in rodents and humans Jesudason et al 2007). PP is thought to reduce food intake through the following mechanisms 1) stimulation of Y4 and Y5 receptors in the dorsal vagal complex, including the area postrema (AP), the nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus (DMV) (Whitcomb et al 1997;Lin et al 2009); 2) sending anorexigenic signals via the brainstem and hypothalamic neuropeptides (Hankir et al 2011); 3) modulation of the expression of other peripheral peptides such as ghrelin, and 4) delay in gastric emptying that seemed to occur only in animal models and not in humans. Th e anorectic eff ects of PP and PYY (3-36) are abolished in abdominal vagotomised rats, suggesting that PP and PYY (3-36) induce anorexia via vagal aff erent nerves (Iwasaki et al 2013).…”

Peptides and Their Potential Role in the Treatment of Diabetes and Obesity

“…The orexigenic effects of NPY are mediated by central Y1 and Y5 receptors, as discussed above. In contrast, the Y2 and Y4 receptors mediate anorectic effects of PYY and PP, respectively [81][82][83]. PYY is an anorectic gut hormone expressed in enteroendocrine L-cells throughout the GI tract, with highest tissue content in the terminal ileum, colon, and rectum [84,85].…”