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

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

*Corresponding author for this work

Research output: Contribution to journalArticle

53 Citations (Scopus)

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.

Original languageEnglish
Article number8488
Pages (from-to)1-10
Number of pages10
JournalPLoS ONE
Volume4
Issue number12
DOIs
Publication statusPublished - 30 Dec 2009
Externally publishedYes

Keywords

  • SUBTYPE MESSENGER-RNAS
  • PRADER-WILLI SYNDROME
  • NEUROPEPTIDE-Y
  • PEPTIDE YY3-36
  • WEIGHT-LOSS
  • BODY-WEIGHT
  • RAT-BRAIN
  • NUCLEUS
  • OBESITY
  • HYPOTHALAMUS

Cite this

Lin, S., Shi, Y-C., Yulyaningsih, E., Aljanova, A., Zhang, L., Macia, L., ... Sainsbury, A. (2009). Critical role of arcuate Y4 receptors and the melanocortin system in pancreatic polypeptide-induced reduction in food intake in mice. PLoS ONE, 4(12), 1-10. [8488]. https://doi.org/10.1371/journal.pone.0008488