Skrede Silje, González-García Ismael, Martins Luís, Berge Rolf Kristian, Nogueiras Ruben, Tena-Sempere Manuel, Mellgren Gunnar, Steen Vidar Martin, López Miguel, Fernø Johan
The Norwegian Centre for Mental Disorders Research and the K.G. Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway; Department of Physiology, Research Center of Molecular Medicine and Chronic Diseases, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain; The Lipid Research Group, Section for Medical Biochemistry, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Instituto Maimónides de Investigación Biomédica/Hospital Reina Sofía, Córdoba, Spain; KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Hormone Laboratory, Haukeland University Hospital, Bergen, Norway; Section of Clinical Pharmacology, Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway.
Int J Neuropsychopharmacol. 2017 Dec 1;20(12):1005-1012. doi: 10.1093/ijnp/pyx073.
Olanzapine is an orexigenic antipsychotic drug associated with serious metabolic adverse effects in humans. Development of valid rodent models for antipsychotic-induced metabolic adverse effects is hampered by the fact that such effects occur in females only. Estradiol is a predominant female hormone that regulates energy balance. We hypothesized that the female-specific hyperphagia and weight gain induced by olanzapine in the rat are dependent on the presence of estrogens.
Female sham-operated or ovariectomized rats were treated with a single injection of olanzapine depot formulation. Food intake, body weight, plasma lipids, lipogenic gene expression, energy expenditure, and thermogenic markers including brown adipose tissue uncoupling protein 1 protein levels were measured. Olanzapine was also administered to ovariectomized rats receiving estradiol replacement via the subcutaneous (peripheral) or intracerebroventricular route.
Orexigenic effects of olanzapine were lost in ovariectomized female rats. Ovariectomized rats treated with olanzapine had less pronounced weight gain than expected from their food intake. Accordingly, brown adipose tissue temperature and protein levels of uncoupling protein 1 were elevated. Replacement in ovariectomized rats with either peripherally or centrally administered estradiol reduced food intake and body weight. Cotreatment with olanzapine blocked the anorexigenic effect of peripheral, but not central estradiol.
Our results indicate that the ovarian hormone estradiol plays an important role in olanzapine-induced hyperphagia in female rats and pinpoint the complex effects of olanzapine on the balance between energy intake and thermogenesis.
奥氮平是一种致食欲的抗精神病药物，与人类严重的代谢不良反应相关。由于此类效应仅在雌性个体中出现，因此有效的抗精神病药物诱导代谢不良反应的啮齿动物模型的开发受到阻碍。雌二醇是调节能量平衡的主要雌性激素。我们假设奥氮平在大鼠中诱导的雌性特异性食欲亢进和体重增加依赖于雌激素的存在。
对假手术或卵巢切除的雌性大鼠单次注射奥氮平长效制剂。测量食物摄入量、体重、血浆脂质、脂肪生成基因表达、能量消耗以及包括棕色脂肪组织解偶联蛋白1蛋白水平在内的产热标志物。奥氮平也被给予通过皮下（外周）或脑室内途径接受雌二醇替代的卵巢切除大鼠。
奥氮平的致食欲作用在卵巢切除的雌性大鼠中消失。用奥氮平治疗的卵巢切除大鼠的体重增加不如根据其食物摄入量预期的明显。相应地，棕色脂肪组织温度和解偶联蛋白1的蛋白水平升高。用外周或中枢给予的雌二醇替代卵巢切除大鼠可减少食物摄入量和体重。与奥氮平联合治疗可阻断外周而非中枢雌二醇的厌食作用。
我们的结果表明，卵巢激素雌二醇在奥氮平诱导的雌性大鼠食欲亢进中起重要作用，并明确了奥氮平对能量摄入和产热之间平衡的复杂影响。
