Pituitary adenylate cyclase-activating polypeptide inhibits food intake in mice through activation of the hypothalamic melanocortin system.
Pituitary adenylate cyclase-activating polypeptide (PACAP) and the proopiomelanocortin (POMC)-derived peptide, alpha-melanocyte-stimulating hormone (alpha-MSH), exert anorexigenic activities. While alpha-MSH is known to inhibit food intake and stimulate catabolism via activation of the central melanocortin-receptor MC4-R, little is known regarding the mechanism by which PACAP inhibits food consumption. We have recently found that, in the arcuate nucleus of the hypothalamus, a high proportion of POMC neurons express PACAP receptors. This observation led us to investigate whether PACAP may inhibit food intake through a POMC-dependent mechanism. In mice deprived of food for 18 h, intracerebroventricular administration of PACAP significantly reduced food intake after 30 min, and this effect was reversed by the PACAP antagonist PACAP6-38. In contrast, vasoactive intestinal polypeptide did not affect feeding behavior. Pretreatment with the MC3-R/MC4-R antagonist SHU9119 significantly reduced the effect of PACAP on food consumption. Central administration of PACAP induced c-Fos mRNA expression and increased the proportion of POMC neuron-expressing c-Fos mRNA in the arcuate nucleus. Furthermore, PACAP provoked an increase in POMC and MC4-R mRNA expression in the hypothalamus, while MC3-R mRNA level was not affected. POMC mRNA level in the arcuate nucleus of PACAP-specific receptor (PAC1-R) knock-out mice was reduced as compared with wild-type animals. Finally, i.c.v. injection of PACAP provoked a significant increase in plasma glucose level. Altogether, these results indicate that PACAP, acting through PAC1-R, may inhibit food intake via a melanocortin-dependent pathway. These data also suggest a central action of PACAP in the control of glucose metabolism.
INSERM U 413, Laboratory of Cellular and Molecular Neuroendocrinology, University of Rouen, Mont-Saint-Aignan, France.
Lourdes
L
Mounien
Jean-Claude
JC
Do Rego
Patrice
P
Bizet
Isabelle
I
Boutelet
Guillaume
G
Gourcerol
Alain
A
Fournier
Philippe
P
Brabet
Jean
J
Costentin
Hubert
H
Vaudry
Sylvie
S
Jégou
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D001786:Blood Glucose / Q000032:analysis; D003345:Corticosterone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009478:Neuropeptide Y / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D044104:Receptor, Melanocortin, Type 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000235:genetics; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D001786:Blood Glucose; D009478:Neuropeptide Y; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; C075647:pituitary adenylate-cyclase-activating-peptide (6-38); C103272:SHU 9119; D014660:Vasoactive Intestinal Peptide; D011333:Pro-Opiomelanocortin; D009074:Melanocyte-Stimulating Hormones; D003345:Corticosterone