1. ¹INSERM U 413, Laboratory of Cellular and Molecular Neuroendocrinology, University of Rouen, Mont-Saint-Aignan, France
2. ²International Associated Laboratory Samuel de Champlain, University of Rouen, Mont-Saint-Aignan, France
3. ³European Institute for Peptide Research (IFRMP 23), University of Rouen, Mont-Saint-Aignan, France
4. ⁴CNRS FRE 2735, Laboratory of Experimental Neuropsychopharmacology, IFRMP 23, Faculty of Medicine and Pharmacy, University of Rouen, Rouen, France
5. ⁵INRS, Institut Armand-Frappier, Laboratory of Peptide Pharmacology, University of Quebec, Pointe-Claire, QC, Canada
6. ⁶INSERM U 583, Physiopathologie et Thérapie des Déficits Sensoriels et Moteurs, Institut des Neurosciences de Montpellier, Hôpital Saint-Eloi, Montpellier, France
7. ⁷INSERM Avenir, Mechanisms and Treatments of Developmental Cerebral Disorders, Faculty of Medicine and Pharmacy, University of Rouen, Rouen, France

Correspondence: Dr S Jégou and Dr H Vaudry, INSERM U 413, Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (IFRMP 23), University of Rouen, 76821 Mont-Saint-Aignan, France. Tel: +33 2 3514 6624; Fax: +33 2 3514 6946; E-mail: sylvie.jegou@univ-rouen.fr or hubert.vaudry@univ-rouen.fr

⁸These authors contributed equally to this work, and should be considered as joint first authors.

Received 14 December 2007; Revised 26 March 2008; Accepted 7 April 2008; Published online 4 June 2008.

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) and the proopiomelanocortin (POMC)-derived peptide, -melanocyte-stimulating hormone (-MSH), exert anorexigenic activities. While -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.