Effect of Atypical Antipsychotics on Fructose Metabolism and Weight Gain

说明(申请人提供)：抗精神病药物会导致体重显著增加，从而增加糖尿病、代谢综合征和心血管疾病等慢性健康问题的风险。抗精神病药物引起的体重增加导致用药不依从性，从而导致精神病复发。此外，精神障碍患者的死亡风险远远高于普通人群，其中60%的死亡是由于与肥胖有关的慢性健康问题。由于肥胖是糖尿病、代谢综合征和心血管疾病发展过程中的一个关键因素，因此确定抗精神病药物导致体重增加的机制非常重要。在这个R36项目中，我提出了一个新的假设，即抗精神病药物通过改变肠道中果糖的吸收和代谢而导致体重增加。该假说基于以下观察：(1)抗精神病药物的靶向受体，包括多巴胺、5-羟色胺和组胺受体在肠道中表达；(2)我们的初步结果表明，慢性氯氮平治疗使C57BL/6野生型小鼠的肠道果糖摄取增加；(3)我们的初步结果显示，在慢性氯氮平治疗后，野生型C57BL/6小鼠的体重显著增加；然而，在同样的实验范式下，具有相同遗传背景的GLUT5基因缺失的小鼠未能显示出任何由氯氮平诱导的体重增加。总之，我们的初步结果有力地表明，肠道GLUT5果糖转运体参与了氯氮平诱导的体重增加。在这个项目中，我将确定非典型抗精神病药物氯氮平导致体重增加的分子机制。我将侧重于肠道多巴胺受体调节GLUT5果糖转运体功能的机制，以及氯氮平如何调节肠道糖异生和脂肪生成途径中涉及的基因的表达。所有研究都将使用相同遗传背景的GLUT5缺失小鼠和野生型小鼠。该项目的结果将确定抗精神病药物在调节肠道果糖运输和新陈代谢中的新作用。识别与非典型抗精神病药物肠道感觉有关的新分子机制可能会导致突破治疗，从而导致抗精神病药物的改进。这将有助于改善那些患有神经精神障碍并依赖这些药物的人的生活质量。这篇R36论文提案针对NIMH成人翻译研究和治疗开发部门的一个高度优先的领域，因为它描述了特定精神药物产生不良代谢和心血管事件的机制。

DESCRIPTION (provided by applicant): Antipsychotics induce significant weight gain which increases the risk of chronic health problems such as diabetes, metabolic syndrome and cardiovascular disease. Antipsychotics-induced weight gain contributes to medication non-compliance which results in psychotic relapse. Additionally, the mortality risk of patients suffering from mental disorders is much higher than the general population and 60% of these deaths are due to the chronic health problems associated with obesity. Since obesity is a critical element in the progression towards the development of diabetes, metabolic syndrome and cardiovascular disease, it is important to determine the mechanisms by which antipsychotics induce weight gain. In this R36 project, I propose a novel hypothesis that antipsychotics induce weight gain by altering fructose absorption and metabolism in the intestine. The hypothesis is based on the following observations- (1) The target receptors for antipsychotics including dopamine, serotonin and histamine receptors are expressed in the intestine; (2) our preliminary result that chronic clozapine treatment increases intestinal fructose uptake in C57BL/6 wild type mice; (3) our preliminary result that wild type C57BL/6 mice show significant weight gain following chronic clozapine treatment; however, GLUT5 null mice of the same genetic background fail to show any clozapine-induced weight gain under the same experimental paradigm. Together our preliminary results strongly suggest that the intestinal GLUT5 fructose transporter is involved in clozapine-induced weight gain. In this project, I will determine the molecular mechanism by which, the atypical antipsychotic clozapine, induces weight gain. I will focus on the mechanisms by which enteric dopamine receptors regulate GLUT5 fructose transporter function and how clozapine modulates the expression of genes involved in the intestinal gluconeogenic and lipogenic pathways. All studies will be done using GLUT5 null mice and wild type littermates of the same genetic background. The results from this project will identify a novel role for antipsychotics in modulating intestinal fructose transport and metabolism. Identifying novel molecular mechanisms involved in the gut sensing of atypical antipsychotics may lead to break through therapies that will lead to improved antipsychotics. This will help improve the quality of life of those suffering from neuropsychiatric disorders and rely on these medications. This R36 dissertation proposal addresses an area of high priority for the Division of Adult Translational Research and Treatment Development at NIMH as it delineates the mechanisms through which specific psychotropic medications produce adverse metabolic and cardiovascular events.