Document Detail


Antibodies as pharmacologic tools for studies on the regulation of energy balance.
MedLine Citation:
PMID:  18662861     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Active immunization in rats may serve several purposes: the production of a disease-like phenotype, the generation of pharmacologic tools, and the development of clinically useful therapies. We selected the melanocortin-4 receptor (MC4R) as a target because its blockade could provide a treatment for anorexia and cachexia. METHODS: We used a sequence of the N-terminal (NT) domain of the MC4R as an antigen. Rats immunized against the NT peptide produced specific MC4R antibodies (Abs) that were purified and characterized in vitro and in vivo. RESULTS: The Abs acted as inverse agonists and reduced under basal conditions the production of cyclic adenosine monophosphate in HEK-293 cells expressing the human MC4R. Rats immunized against the NT peptide developed a phenotype consistent with hypothalamic MC4R blockade, i.e., increased food intake and body weight, liver and fat-pad weights, hepatic steatosis, and increased plasma triacylglycerols. With a high-fat diet, plasma insulin levels were significantly increased. In separate experiments an increase in food intake was observed after injection of purified MC4R Abs into the third ventricle. When lipopolysaccharide was administered in NT-immunized rats the reduction of food intake was partly prevented in this model of cytokine-induced anorexia. CONCLUSION: Our results show that active immunization of rats against the MC4R resulted in the generation of specific Abs that stimulated food intake by acting as inverse agonists of the hypothalamic MC4R. Pharmacologically active monoclonal MC4R Abs could be the starting point for the development of novel treatments for patients with anorexia or cachexia.
Authors:
Karl G Hofbauer; Anne-Catherine Lecourt; Jean-Christophe Peter
Publication Detail:
Type:  Journal Article     Date:  2008-07-26
Journal Detail:
Title:  Nutrition (Burbank, Los Angeles County, Calif.)     Volume:  24     ISSN:  0899-9007     ISO Abbreviation:  Nutrition     Publication Date:  2008 Sep 
Date Detail:
Created Date:  2008-08-26     Completed Date:  2009-01-28     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8802712     Medline TA:  Nutrition     Country:  United States    
Other Details:
Languages:  eng     Pagination:  791-7     Citation Subset:  IM    
Affiliation:
Applied Pharmacology, Biozentrum, University of Basel, Basel, Switzerland. karl.hofbauer@unibas.ch
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MeSH Terms
Descriptor/Qualifier:
Adenosine Monophosphate / immunology
Adipose Tissue / drug effects,  immunology
Animals
Anorexia / chemically induced,  immunology
Antibodies / immunology*,  pharmacology*
Body Weight / drug effects,  immunology
Diet / methods
Dietary Fats / immunology,  pharmacology
Disease Models, Animal
Energy Metabolism / drug effects,  immunology*
Fatty Liver / immunology
Feeding Behavior / drug effects
Humans
Insulin / blood,  immunology
Lipopolysaccharides / administration & dosage,  immunology,  pharmacology
Liver / drug effects,  immunology
Male
Organ Size / drug effects,  immunology
Rats
Rats, Sprague-Dawley
Receptor, Melanocortin, Type 4 / immunology
Sodium Chloride / administration & dosage
Triglycerides / blood,  immunology
Chemical
Reg. No./Substance:
0/Antibodies; 0/Dietary Fats; 0/Lipopolysaccharides; 0/Receptor, Melanocortin, Type 4; 0/Triglycerides; 11061-68-0/Insulin; 61-19-8/Adenosine Monophosphate; 7647-14-5/Sodium Chloride

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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