Therapeutic Department Metabolism, Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany.
Obesity (Silver Spring). 2010 Oct;18(10):1952-8. doi: 10.1038/oby.2010.17. Epub 2010 Feb 18.
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.
这是第一项研究，旨在探讨亚慢性奥氮平（OLZ）对大鼠能量平衡的影响，涵盖了能量平衡的各个方面，包括可代谢能量的能量摄入、储存和支出。我们进一步分析了大麻素 1 型受体拮抗剂 AVE1625 是否以及通过何种机制减轻 OLZ 引起的体重增加。为此，我们选择了幼年雌性汉诺威威斯特伐利亚大鼠，这些大鼠在 OLZ 治疗中表现出明显且可重复的体重增加，接受了限制模型来模拟脂质和碳水化合物代谢的异常。大鼠每天口服 2mg/kg OLZ，每天两次，共 12 天。分析体重和身体成分。此外，在平行测定运动和身体核心温度的同时，还测定了每日食物摄入量、能量消耗和底物氧化。OLZ 治疗导致体重显著增加，其中瘦体重和脂肪量显著增加。OLZ 治疗的大鼠表现出贪食症，表现为碳水化合物氧化增加和脂肪氧化（FO）降低。能量消耗增加，运动减少，但 OLZ 治疗的大鼠没有出现体温过低的迹象。OLZ 和 AVE1625（每天口服 10mg/kg）联合给药可减轻体重增加，减少增强的食物摄入，同时维持增加的能量消耗和减少的运动。我们的数据表明，OLZ 治疗的大鼠能量消耗增加，而运动对其影响不大。然而，能量摄入超过能量消耗，导致正能量平衡，证实贪食症是 OLZ 引起体重增加的主要驱动因素。OLZ 治疗与大麻素 1 型受体拮抗剂 AVE1625 联合可减轻大鼠体重增加。
