CB1 receptor antagonist AVE1625 affects primarily metabolic parameters independently of reduced food intake in Wistar rats

• Published in: American journal of physiology: endocrinology and metabolism 2007-09, Vol.293 (3), p.E826-E832
• Main Authors: Herling, Andreas W, Gossel, Matthias, Haschke, Guido, Stengelin, Siegfried, Kuhlmann, Johanna, Muller, Gunter, Schmoll, Dieter, Kramer, Werner
• Format: Article
• Language: English
• Subjects: Animals; Body Weight - drug effects; Body Weight - physiology; Diet; Eating - drug effects; Eating - physiology; Endocrine system; Endocrinology; Energy Intake - drug effects; Energy Intake - physiology; Energy Metabolism - drug effects; Energy Metabolism - physiology; Hydrocarbons, Halogenated - administration & dosage; Lipid Peroxidation - drug effects; Lipid Peroxidation - physiology; Male; Metabolism; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - metabolism; Rodents; Sulfonamides - administration & dosage
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00264.2007

Sanofi-Aventis Deutschland GmbH, Frankfurt/Main, Germany Submitted 27 April 2007 ; accepted in final form 18 June 2007 The objective of the present study was to investigate in fed Wistar rats whether the cannabinoid-1 (CB1) receptor antagonist AVE1625 causes primary effects on metabolic blood and tissue parameters as well as metabolic rate, which are independent of reduced caloric intake. After single administration to rats postprandially, AVE1625 caused a slight dose-dependent increase in basal lipolysis. Six hours after single administration, liver glycogen content was dose-dependently reduced to 60% of that of untreated controls. These findings demonstrate a primary acute effect of AVE1625 on induction of 1 ) lipolysis from fat tissue (increased FFA) and 2 ) glycogenolysis from the liver (reduced hepatic glycogen). Measured by indirect calorimetry, AVE1625 caused an immediate increase in total energy expenditure, a long-lasting increase of fat oxidation, and a transient increase of glucose oxidation, which were consistent with the acute findings on metabolic blood and tissue parameters. We conclude that, in addition to the well-investigated effects of CB1 receptor antagonists to reduce caloric intake and subsequently body weight, this pharmacological approach is additionally linked to inherently increased lipid oxidation. This oxidation is driven by persistently increased lipolysis from fat tissues, independently of reduced caloric intake, and might significantly contribute to the weight-reducing effect. cannabinoid receptors; lipolysis; glycogenolysis; energy expenditure Address for reprint requests and other correspondence: A. W. Herling, Therapeutic Dept. of Metabolism, Pharmacology, H 821, Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65926 Frankfurt/Main, Germany (e-mail: andreas.herling{at}sanofi-aventis.com )