Stefanidis Aneta, Verty Aaron N A, Allen Andrew M, Owens Neil C, Cowley Michael A, Oldfield Brian J
Department of Physiology, Monash University, Clayton, Victoria, Australia.
Obesity (Silver Spring). 2009 Jan;17(1):16-24. doi: 10.1038/oby.2008.468. Epub 2008 Oct 30.
The administration of antipsychotic drugs to human patients or experimental animals leads to significant weight gain, which is widely presumed to be driven by hyperphagia; however, the contribution from energy expenditure remains unclear. These studies aim to examine the contribution of shifts in energy expenditure, particularly those involving centrally mediated changes in thermogenesis, to the body weight gain associated with the administration of olanzapine to female Sprague Dawley rats. Olanzapine (6 mg/kg/day orally) caused a transient increase in food intake but a maintained increase in body weight. When pair-fed rats were treated with olanzapine, body weight continued to rise compared to vehicle-treated rats, consistent with a reduction in energy expenditure. Brown adipose tissue (BAT) temperature, measured using biotelemetry devices, decreased immediately after the onset of olanzapine treatment and remained depressed, as did physical activity. UCP1 expression in interscapular BAT was reduced following chronic olanzapine treatment. An acute injection of olanzapine was preceded by an injection of a retrograde tracer into the spinal cord to evaluate the nature of the olanzapine-activated neural pathway. Levels of Fos protein in a number of spinally projecting neurons within discrete hypothalamic and brainstem sites were elevated in olanzapine-treated rats. Some of these neurons in the perifornical region of the lateral hypothalamus (LHA) were also Orexin A positive. These data collectively show a significant impact of thermogenesis (and physical activity) on the weight gain associated with olanzapine treatment. The anatomical studies provide an insight into the central neuroanatomical substrate that may subserve the altered thermogenic responses brought about by olanzapine.
给人类患者或实验动物使用抗精神病药物会导致显著体重增加，普遍认为这是由食欲亢进引起的；然而，能量消耗的作用仍不明确。这些研究旨在探讨能量消耗变化，特别是那些涉及中枢介导的产热变化，对雌性Sprague Dawley大鼠服用奥氮平后体重增加的影响。奥氮平（6毫克/千克/天，口服）导致食物摄入量短暂增加，但体重持续增加。当对成对喂养的大鼠使用奥氮平治疗时，与使用赋形剂治疗的大鼠相比，体重持续上升，这与能量消耗减少一致。使用生物遥测设备测量的棕色脂肪组织（BAT）温度在奥氮平治疗开始后立即下降，并一直保持较低水平，身体活动情况也是如此。长期使用奥氮平治疗后，肩胛间BAT中的解偶联蛋白1（UCP1）表达降低。在急性注射奥氮平之前，先向脊髓注射逆行示踪剂，以评估奥氮平激活的神经通路的性质。在奥氮平治疗的大鼠中，离散的下丘脑和脑干部位的一些脊髓投射神经元中的Fos蛋白水平升高。下丘脑外侧区（LHA）穹窿周区域的一些神经元也为食欲素A阳性。这些数据共同表明产热（和身体活动）对奥氮平治疗相关的体重增加有显著影响。解剖学研究为可能支持奥氮平引起的产热反应改变的中枢神经解剖学基础提供了见解。
