Increased Energy Expenditure Contributes More to the Body Weight-Reducing Effect of Rimonabant than Reduced Food Intake in Candy-Fed Wistar Rats

• Published in: Endocrinology (Philadelphia) 2008-05, Vol.149 (5), p.2557-2566
• Main Authors: Herling, Andreas W, Kilp, Susanne, Elvert, Ralf, Haschke, Guido, Kramer, Werner
• Format: Article
• Language: English
• Subjects: Animals; Anti-Obesity Agents - pharmacology; Biological and medical sciences; Blood Glucose - analysis; Blood Glucose - drug effects; Body weight; Body Weight - drug effects; Bomb calorimetry; Calorimetry; Candy; Cannabinoid CB1 receptors; Confectionery; Diet; Dosage; Eating - drug effects; Endocannabinoid system; Energy; Energy balance; Energy expenditure; Energy intake; Energy Metabolism - drug effects; Energy Metabolism - physiology; Fatty Acids, Nonesterified - blood; Female; Food; Food intake; Fundamental and applied biological sciences. Psychology; Lipolysis; Liver Glycogen - analysis; Male; Oxidation; Photoperiod; Piperidines - pharmacology; Pyrazoles - pharmacology; Rats; Rats, Wistar; Time Factors; Vertebrates: endocrinology; Weight Loss - drug effects; Weight Loss - physiology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2007-1515

The CB1 receptor antagonist, rimonabant, affects the endocannabinoid system and causes a sustained reduction in body weight (BW) despite the transient nature of the reduction in food intake. Therefore, in a multiple-dose study, female candy-fed Wistar rats were treated with rimonabant (10 mg/kg) and matched with pair-fed rats to distinguish between hypophagic action and hypothesized effects on energy expenditure. Within the first week of treatment, rimonabant reduced BW nearly to levels of standard rat chow-fed rats. Evaluation of energy balance (energy expenditure measured by indirect calorimetry in relation to metabolizable energy intake calculated by bomb calorimetry) revealed that increased energy expenditure based on increased fat oxidation contributed more to sustained BW reduction than reduced food intake. A mere food reduction through pair feeding did not result in comparable effects because animals reduced their energy expenditure to save energy stores. Because fat oxidation measured by indirect calorimetry increased immediately after dosing in the postprandial state, the acute effect of rimonabant on lipolysis was investigated in postprandial male rats. Rimonabant elevated free fatty acids postprandially, demonstrating an inherent pharmacological activity of rimonabant to induce lipolysis and not secondarily postabsorptively due to reduced food intake. We conclude that the weight-reducing effect of rimonabant was due to continuously elevated energy expenditure based on increased fat oxidation driven by lipolysis from fat tissue as long as fat stores were elevated. When the amount of endogenous fat stores declined, rimonabant-induced increased energy expenditure was maintained by a re-increase in food intake.