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

PLoS One. 2009 Dec 30;4(12):e8488. doi: 10.1371/journal.pone.0008488.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • 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