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Effects of rimonabant, a cannabinoid CB1 receptor ligand, on energy expenditure in lean rats
1F Hoffmann-La Roche Pharmaceuticals Ltd, Department of Metabolic and Vascular Diseases, Basel, Switzerland.
Objective:
To determine the effect of rimonabant on energy expenditure (O2 consumption) in rats at different metabolic states and in cannabinoid CB1 receptor-deficient (CB1R-/-) mice.
Design:
Animals were exposed to light-dark cycles and fed only during dark cycles. Rimonabant or vehicle was administered together with food (absorptive), following overnight feeding (postabsorptive) or following a whole day of no food (fasting). Indirect calorimetric measurements, physical activity and food intake were measured continuously.
Results:
Compared with vehicle-treated rats, rats administered 3 and 10 mg kg(-1) rimonabant showed an 18 and 49% increase in O2 consumption, respectively after 3 h. A second dose of rimonabant administered 9-14.5 h after the first one failed to affect O2 consumption, suggesting the development of tolerance. Similarly, stereotypic behaviors and ambulatory activity increased following the first dose but these effects were not observed after the second dose. Respiratory quotients revealed no effect of rimonabant on rates of carbohydrate and fat oxidation. Analysis of the correlation between O2 consumption and physical activity indicated that factors other than increased physical activity may contribute to the increase in O2 consumption. Similar studies in mice demonstrated that wild type but not CB1R-/- mice showed a change in O2 consumption and physical activity following rimonabant administration, suggesting that these effects are mediated by the cannabinoid CB1 receptor.
Conclusion:
Previous studies suggested that reduced food intake alone may not explain the weight reduction observed with rimonabant. Our studies suggest that rimonabant stimulates significant acute energy expenditure in non-obese rodents, which could not be completely accounted for by an increase in physical activity. However, with the observation that there is rapid development of tolerance, these results suggest that there may be additional mechanism(s) that lead to weight loss in these rodents.
