GENETIC APPROACHES TO SEROTONIN AND FEEDING BEHAVIOR

血清素和喂养行为的遗传学方法

• 批准号: 6539115
• 负责人: Laurence H. Tecott
• 金额: $ 40.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6539115
• 关键词: appetite; behavioral /social science research tag; behavioral genetics; bioenergetics; body physical activity; brain mapping; eating disorders; genetic models; genetic susceptibility; laboratory mouse; mutant; neuroregulation; nutrient intake activity; nutrition related tag; obesity; serotonin receptor

DESCRIPTION: (Adapted from the Investigator's Abstract) Brain serotonin systems are strongly implicated in the regulation of normal feeding behavior and in the dysregulation of feeding observed in eating disorders. Several lines of evidence indicate that serotonin 5-HT2C receptor subtype contributes significantly to the serotonergic inhibition of food intake. Consistent with this, mice lacking functional setotonin 5-HT2C receptors display reduced sensitivity to appetite suppressant drugs that act through serotonin systems. In addition, these animals exhibit a dysregulation of feeding behavior leading to chronic elevations of food intake, late-onset ('middle-age") obesity and enhanced susceptibility to type 2 diabetes. Several features of this obesity syndrome are reminiscent of common forms of the human condition. It is proposed that 5-HT2C receptor mutants provide a unique genetic model in which obesity results from a primary defect in feeding behavior rather than a direct effect of the mutation on energy expenditure. In addition to testing this hypothesis, the neural mechanisms through which 5-HT2C receptors regulate feeding will be explored. In Aim 1, detailed studies of feeding behavior will be performed to test the hypothesis that 5-HT2C receptor mutants compensate for their overeating by increasing energy expenditure and that subsequent obesity results from an age dependent failure to maintain this compensation. In aim 3, mechanisms through which serotonin systems compensate for the 5-HT2C receptor mutation will be explored. Particular attention will be paid to potential compensation by the 5-HT1B receptor, including studies of feeding behavior and energy balance in "double-mutant" mice lacking both the 5-HT2C and 5-HT1B receptor subtypes. Studies of Aim 4 will identify brain regions and transmitter systems through which 5-HT2C receptors may regulate feeding. Hypotheses generated from the results of aim 4 will be tested in Aim 5 through the development of mice in which 5-HT2C receptor mutations are localized to restricted brain regions and cell types.

描述：（改编自研究者摘要）大脑血清素系统 与正常进食行为的调节和 饮食失调中观察到的喂养失调。几行 有证据表明血清素 5-HT2C 受体亚型有助于 显着地抑制食物摄入的血清素。符合 缺乏功能性血清素 5-HT2C 受体的小鼠表现出降低的 对通过血清素系统起作用的食欲抑制药物的敏感性。 此外，这些动物表现出进食行为失调，导致 食物摄入量长期增加、迟发性（“中年”）肥胖和 2 型糖尿病的易感性增加。这种肥胖的几个特点 综合症让人想起人类状况的常见形式。建议 5-HT2C受体突变体提供了一种独特的遗传模型，其中肥胖 由进食行为的主要缺陷引起，而不是直接影响 能量消耗的突变。除了检验这个假设之外， 5-HT2C受体调节摄食的神经机制将是 探索过。在目标 1 中，将对进食行为进行详细研究 检验 5-HT2C 受体突变体补偿其功能的假设 通过增加能量消耗而暴饮暴食，从而导致肥胖 由于年龄相关未能维持这种补偿。在目标 3 中， 血清素系统补偿 5-HT2C 受体的机制 将探索突变。将特别关注潜在的 5-HT1B 受体的补偿，包括摄食行为和 缺乏 5-HT2C 和 5-HT1B 的“双突变”小鼠的能量平衡 受体亚型。目标 4 的研究将确定大脑区域和发射器 5-HT2C 受体可调节摄食的系统。假设 目标 4 的结果生成的结果将在目标 5 中通过 5-HT2C 受体突变定位于小鼠的发育 受限的大脑区域和细胞类型。