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


RESULTS
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
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.
Lin
Shu
S
Neuroscience Program, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, New South Wales, Australia.
Shi
Yan-Chuan
YC
Yulyaningsih
Ernie
E
Aljanova
Aygul
A
Zhang
Lei
L
Macia
Laurence
L
Nguyen
Amy D
AD
Lin
En-Ju Deborah
EJ
During
Matthew J
MJ
Herzog
Herbert
H
Sainsbury
Amanda
A
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D001933:Brain Stem / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D008297:Male; D053486:Melanocortins / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010191:Pancreatic Polypeptide / Q000494:pharmacology*; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000521:alpha-MSH / Q000378:metabolism
D053486:Melanocortins; D016760:Proto-Oncogene Proteins c-fos; D044105:Receptor, Melanocortin, Type 4; D017476:Receptors, Neuropeptide Y; C109491:neuropeptide Y4 receptor; D000521:alpha-MSH; D010191:Pancreatic Polypeptide; D011333:Pro-Opiomelanocortin; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2