Antibodies as pharmacologic tools for studies on the regulation of energy balance.
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.


CONCLUSIONS
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.
Hofbauer
Karl G
KG
Applied Pharmacology, Biozentrum, University of Basel, Basel, Switzerland. karl.hofbauer@unibas.ch
Lecourt
Anne-Catherine
AC
Peter
Jean-Christophe
JC
D000249:Adenosine Monophosphate / Q000276:immunology; D000273:Adipose Tissue / Q000187:drug effects / Q000276:immunology; D000818:Animals; D000855:Anorexia / Q000139:chemically induced / Q000276:immunology; D000906:Antibodies / Q000276:immunology* / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects / Q000276:immunology; D004032:Diet / Q000379:methods; D004041:Dietary Fats / Q000276:immunology / Q000494:pharmacology; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects / Q000276:immunology*; D005234:Fatty Liver / Q000276:immunology; D005247:Feeding Behavior / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000097:blood / Q000276:immunology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000276:immunology; D008297:Male; D009929:Organ Size / Q000187:drug effects / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000276:immunology; D012965:Sodium Chloride / Q000008:administration & dosage; D014280:Triglycerides / Q000097:blood / Q000276:immunology
D000906:Antibodies; D004041:Dietary Fats; D007328:Insulin; D008070:Lipopolysaccharides; D044105:Receptor, Melanocortin, Type 4; D014280:Triglycerides; D000249:Adenosine Monophosphate; D012965:Sodium Chloride