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Antibodies against the melanocortin-4 receptor act as inverse agonists in vitro and in vivo
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 155598
Author(s) Peter, Jean-Christophe; Nicholson, Janet R; Heydet, Déborah; Lecourt, Anne-Catherine; Hoebeke, Johan; Hofbauer, Karl G
Author(s) at UniBasel Hofbauer, Karl G.
Year 2007
Title Antibodies against the melanocortin-4 receptor act as inverse agonists in vitro and in vivo
Journal American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Volume 292
Number 6
Pages / Article-Number R2151-8
Keywords food intake, G protein-coupled receptor, body weight, agouti-related, protein, immunization
Abstract 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.
Publisher American Physiological Society
ISSN/ISBN 0002-9513
edoc-URL http://edoc.unibas.ch/dok/A5258610
Full Text on edoc No
Digital Object Identifier DOI 10.1152/ajpregu.00878.2006
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/17322114
ISI-Number WOS:000247725300007
Document type (ISI) Article
 
   

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