Profiling of energy metabolism in olanzapine-induced weight gain in rats and its prevention by the CB1-antagonist AVE1625

This is the first study to examine the effect of subchronic olanzapine (OLZ) on energy homeostasis in rats, covering all aspects of energy balance, including energy intake as metabolizable energy, storage, and expenditure. We further analyzed whether, and by which mechanism, the CB1-antagonist AVE1625 might attenuate OLZ-induced body weight gain. For this purpose, we selected juvenile female Hanover Wistar rats that robustly and reproducibly demonstrated weight gain on OLZ treatment, accepting limitations to model the aberrations on lipid and carbohydrate metabolism. Rats received 2 mg/kg OLZ orally twice daily for 12 days. Body weight and body composition were analyzed. Moreover daily food intake, energy expenditure, and substrate oxidation were determined in parallel to motility and body core temperature. OLZ treatment resulted in substantial body weight gain, in which lean and fat mass increased significantly. OLZ-treated rats showed hyperphagia that manifested in increased carbohydrate oxidation and lowered fat oxidation (FO). Energy expenditure was increased, motility decreased, but there was no indication for hypothermia in OLZ-treated rats. Coadministration of OLZ and AVE1625 (10 mg/kg orally once daily) attenuated body weight gain, diminishing the enhanced food intake while maintaining increased energy expenditure and decreased motility. Our data reveal that energy expenditure was enhanced in OLZ-treated rats, an effect not critically influenced by motility. Energy uptake, however, exceeded energy expenditure and led to a positive energy balance, confirming hyperphagia as the major driving factor for OLZ-induced weight gain. Combination of OLZ treatment with the CB1-antagonist AVE1625 attenuated body weight gain in rats.