Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Mol Psychiatry. 2011 May;16(5):569-81. doi: 10.1038/mp.2010.33. Epub 2010 Mar 23.
Olanzapine and other atypical antipsychotics cause metabolic side effects leading to obesity and diabetes; although these continue to be an important public health concern, their underlying mechanisms remain elusive. Therefore, an animal model of these side effects was developed in male Sprague-Dawley rats. Chronic administration of olanzapine elevated fasting glucose, impaired glucose and insulin tolerance, increased fat mass but, in contrast to female rats, did not increase body weight or food intake. Acute studies were conducted to delineate the mechanisms responsible for these effects. Olanzapine markedly decreased physical activity without a compensatory decline in food intake. It also acutely elevated fasting glucose and worsened oral glucose and insulin tolerance, suggesting that these effects are adiposity independent. Hyperinsulinemic-euglycemic clamp studies measuring (14)C-2-deoxyglucose uptake revealed tissue-specific insulin resistance. Insulin sensitivity was impaired in skeletal muscle, but either unchanged or increased in adipose tissue depots. Consistent with the olanzapine-induced hyperglycemia, there was a tendency for increased (14)C-2-deoxyglucose uptake into fat depots of fed rats and, surprisingly, free fatty acid (FFA) uptake into fat depots was elevated approximately twofold. The increased glucose and FFA uptake into adipose tissue was coupled with increased adipose tissue lipogenesis. Finally, olanzapine lowered fasting plasma FFA, and as it had no effect on isoproterenol-stimulated rises in plasma glucose, it blunted isoproterenol-stimulated in vivo lipolysis in fed rats. Collectively, these results suggest that olanzapine exerts several metabolic effects that together favor increased accumulation of fuel into adipose tissue, thereby increasing adiposity.
奥氮平及其他非典型抗精神病药可引起代谢副作用，导致肥胖和糖尿病；尽管这些仍然是一个重要的公共卫生关注点，但它们的潜在机制仍不清楚。因此，在雄性 Sprague-Dawley 大鼠中开发了一种这些副作用的动物模型。奥氮平的慢性给药会升高空腹血糖，损害葡萄糖和胰岛素耐量，增加脂肪量，但与雌性大鼠不同的是，它不会增加体重或食物摄入量。进行了急性研究以阐明导致这些作用的机制。奥氮平明显降低了体力活动，而没有相应的食物摄入量下降。它还会急性升高空腹血糖并恶化口服葡萄糖和胰岛素耐量，表明这些作用与肥胖无关。测量（14）C-2-脱氧葡萄糖摄取的高胰岛素-正葡萄糖钳夹研究表明存在组织特异性胰岛素抵抗。胰岛素敏感性在骨骼肌中受损，但在脂肪组织中不变或增加。与奥氮平引起的高血糖一致，进食大鼠的（14）C-2-脱氧葡萄糖摄取量有增加的趋势，而且令人惊讶的是，脂肪组织摄取的游离脂肪酸（FFA）增加了约两倍。葡萄糖和 FFA 进入脂肪组织的增加与脂肪组织脂肪生成的增加有关。最后，奥氮平降低了空腹血浆 FFA，并且由于它对异丙肾上腺素刺激的血糖升高没有影响，因此它削弱了进食大鼠体内异丙肾上腺素刺激的脂肪分解作用。总之，这些结果表明，奥氮平具有几种代谢作用，共同有利于燃料更有效地积累到脂肪组织中，从而增加肥胖度。
