HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 292/6/R2151    most recent 00878.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Peter, J.-C. Articles by Hofbauer, K. G. Search for Related Content PubMed PubMed Citation Articles by Peter, J.-C. Articles by Hofbauer, K. G.

APPETITE, OBESITY, DIGESTION, AND METABOLISM

Antibodies against the melanocortin-4 receptor act as inverse agonists in vitro and in vivo

¹Applied Pharmacology, Biozentrum, University of Basel, Basel, Switzerland; and ²Centre National de la Recherche Scientifique UPR 9021, Laboratory of Immunological and Therapeutical Chemistry, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France

Submitted 18 December 2006 ; accepted in final form 20 February 2007

Functionally active antibodies (Abs) against central G-protein-coupled receptors have not yet been reported. We selected the hypothalamic melanocortin-4 receptor (MC4-R) as a target because of its crucial role in the regulation of energy homeostasis. A 15 amino acid sequence of the N-terminal (NT) domain was used as an antigen. This peptide showed functional activity in surface plasmon resonance experiments and in studies on HEK-293 cells overexpressing the human MC4-R (hMC4-R). Rats immunized against the NT peptide produced specific antibodies, which were purified and characterized in vitro. In HEK-293 cells, rat anti-NT Abs showed specific immunofluorescence labeling of hMC4-R. They reduced the production of cAMP under basal conditions and after stimulation with a synthetic MC4-R agonist. Rats immunized against the NT peptide developed a phenotype consistent with MC4-R blockade, that is, increased food intake and body weight, increased liver and fat pad weight, and elevated plasma triglycerides. In a separate experiment in rats, an increase in food intake could be produced after injection of purified Abs into the third ventricle. Similar results were obtained in rats injected with anti-NT Abs raised in rabbits. Our data show for the first time that active immunization of rats against the NT sequence of the MC4-R results in specific Abs, which appear to stimulate food intake by acting as inverse agonists in the hypothalamus.

food intake; G protein-coupled receptor; body weight; agouti-related protein; immunization

This article has been cited by other articles:

				V. Tolle and M. J. Low In Vivo Evidence for Inverse Agonism of Agouti-Related Peptide in the Central Nervous System of Proopiomelanocortin-Deficient Mice Diabetes, January 1, 2008; 57(1): 86 - 94. [Abstract] [Full Text] [PDF]