ENERGY BALANCE IN THE OBESE CCK A RECEPTOR DEFICIENT RAT

肥胖CCK受体缺陷大鼠的能量平衡

• 批准号: 6849246
• 负责人: Timothy H Moran
• 金额: $ 30.69万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6849246
• 关键词: appetite; bioenergetics; cholecystokinin; dietary lipid; gene targeting; genetically modified animals; hormone receptor; hormone regulation /control mechanism; laboratory rat; nutrition related tag; obesity; overeating; satiations; tube feeding

DESCRIPTION: Obesity has reached epidemic proportions in the United States, and both genetic and environmental contributions to the development and maintenance of obesity have been identified in human studies and animal models. Recent rodent models of genetic obesity have hypothalamic signaling pathways related to the overall control of metabolism and energy balance. Unlike these strains, the obese Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a unique genetic model of obesity with an identified deficit in a peripheral gut-brain peptide signaling pathway critical to the within meal control of food intake. OLETF rats spontaneously lack the promoter region for the gene that encodes for the cholecystokinin (CCK) A receptor, the subtype that mediates the satiety actions of this meal-elicited peptide. OLETF rats are obese and hyperphagic, and we have shown that their hyperphagia is characterized by increased meal size, consistent with the lack of a meal related signal important in the negative feedback control of food intake. In this proposal, we hypothesize that OLETF hyperphagia and obesity: 1) depends upon their genetically determined inability to detect meal-related CCK negative feedback signals critical in the control of meal size, and 2) is not dependent on altered central nervous system processing of other metabolic and hypothalamic signals important in the overall control of energy balance. Experiments in this proposal are designed to address multiple aspects of this hypothesis. Specifically, we will: 1) identify the roles of increased meal size and hyperphagia in the development of obesity in OLETF rats, 2) characterize metabolic profiles and patterns of hypothalamic gene expression in ad lib and pair fed OLETF rats, 3) identify potential interactions between exercise and disordered patterns of food intake in OLETF rats, 4) characterize OLETF feeding and metabolic responses to high fat and macronutrient selection diets and 5) compare the OLETF rat to a newly available CCK-A knockout mouse that does not develop obesity. Together, results from these studies will: 1) identify and characterize the ways in which a unique genetic deficit in a peripheral satiety signaling pathway interacts with a range of environmental factors (exercise, dietary restriction, diet composition) to modulate the development and maintenance of obesity, and 2) identify how such a satiety deficit interacts with central hypothalamic pathways mediating the control of energy balance.

描述：肥胖在美国已经达到流行病的程度， 遗传和环境对发育和维持的贡献 肥胖症已经在人类研究和动物模型中得到证实。最近 遗传性肥胖的啮齿类动物模型具有下丘脑信号通路相关的 对新陈代谢和能量平衡的整体控制。与这些菌株不同， 肥胖大冢龙-埃文斯德岛脂肪（OLETF）大鼠是一种独特的遗传 外周肠脑肽缺陷的肥胖模型 信号通路对食物摄入的餐内控制至关重要。OLETF 大鼠自发地缺乏编码该基因的启动子区域， 胆囊收缩素（CCK）A受体，介导饱腹感作用的亚型 这种食物引发的肽。OLETF大鼠肥胖且贪食， 已经表明它们的暴食症的特征在于增加的膳食量， 与缺乏与饮食相关的信号相一致， 食物摄入的反馈控制。在这个建议中，我们假设OLETF 暴食症和肥胖症：1）取决于他们的遗传决定的能力 检测与膳食相关的CCK负反馈信号， 膳食大小，2）不依赖于中枢神经系统处理的改变 其他代谢和下丘脑信号的重要性，在整体控制 能量平衡本提案中的实验旨在解决多个 这个假设的各个方面。具体而言，我们将：1）确定 在OLETF肥胖症的发展过程中，膳食量增加和食欲过盛 大鼠，2）表征下丘脑基因的代谢谱和模式 在随意和成对喂养的OLETF大鼠中表达，3）鉴定潜在的 OLETF中运动与食物摄入紊乱模式之间的相互作用 大鼠，4）表征OLETF喂养和对高脂肪的代谢反应， 常量营养素选择饮食和5）将OLETF大鼠与新获得的 CCK基因敲除小鼠，不发生肥胖。共同的结果， 这些研究将：1）确定和描述一个独特的 外周饱腹感信号通路中的遗传缺陷与 一系列环境因素（运动、饮食限制、饮食 2）在某些实施方案中，本发明的组合物（例如，药物组合物）调节肥胖的发展和维持，以及 确定这种饱腹感缺陷如何与中枢下丘脑相互作用 调节能量平衡的途径。