Critical role of arcuate Y4 receptors and the melanocortin system in pancreatic polypeptide-induced reduction in food intake in mice.

Abstract

BACKGROUND:

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.

METHODOLOGY/PRINCIPAL FINDINGS:

Here 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 (alpha-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/SIGNIFICANCE:

Taken together, these findings show that PP reduces food intake predominantly via stimulation of the anorexigenic alpha-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.

• Authors: Shu Lin, Yan-Chuan Shi, Ernie Yulyaningsih, Aygul Aljanova, Lei Zhang, Laurence Macia, Amy D Nguyen, En-Ju Deborah Lin, Matthew J During, Herbert Herzog, Amanda Sainsbury
• Journal: PloS one (PLoS One) Vol. 4 Issue 12 Pg. e8488 (Dec 30 2009) ISSN: 1932-6203 [Electronic] United States
• PMID: 20041129 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Melanocortins
• Proto-Oncogene Proteins c-fos
• Receptor, Melanocortin, Type 4
• Receptors, Neuropeptide Y
• neuropeptide Y4 receptor
• alpha-MSH
• Pancreatic Polypeptide
• Pro-Opiomelanocortin
• Glutamate Decarboxylase
• glutamate decarboxylase 2

Topics

• Animals
• Arcuate Nucleus of Hypothalamus (cytology, drug effects, enzymology, metabolism)
• Brain Stem (cytology, drug effects, metabolism)
• Energy Metabolism (drug effects)
• Feeding Behavior (drug effects)
• Gene Expression Regulation (drug effects)
• Glutamate Decarboxylase (genetics, metabolism)
• Male
• Melanocortins (metabolism)
• Mice
• Neurons (cytology, drug effects, metabolism)
• Pancreatic Polypeptide (pharmacology)
• Pro-Opiomelanocortin (genetics, metabolism)
• Proto-Oncogene Proteins c-fos (metabolism)
• Receptor, Melanocortin, Type 4 (metabolism)
• Receptors, Neuropeptide Y (agonists, metabolism)
• Signal Transduction (drug effects)
• alpha-MSH (metabolism)