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: 6286970
• 负责人: Timothy H Moran
• 金额: $ 35.14万
• 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/6286970
• 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：肥胖症在美国已经达到流行的程度， 遗传和环境对开发和维护的贡献 在人类研究和动物模型中已经确定了肥胖的可能性。近期 遗传性肥胖的啮齿动物模型与下丘脑信号通路相关 到全面控制新陈代谢和能量平衡。与这些菌株不同， 肥胖的大冢长埃文斯德岛肥胖(OLETF)大鼠是一种独特的遗传 存在外周肠脑多肽缺陷的肥胖模型 信号通路对膳食内食物摄入量的控制至关重要。OLETF 大鼠自发地缺乏编码该基因的启动子区域 CCK A受体，介导饱腹感作用的亚型 这种由食物引发的多肽。OLETF大鼠肥胖，食欲不振，我们 研究表明，它们的吞噬过多的特征是食物体积增加， 与缺乏与进餐有关的信号一致，这是一个重要的负面信号 食物摄入量的反馈控制。在该提案中，我们假设OLETF 吞噬过度和肥胖：1)取决于他们的基因决定的能力 检测与膳食相关的CCK负反馈信号对控制 食物的大小，以及2)不依赖于改变的中枢神经系统处理 其他代谢信号和下丘脑信号在整体控制 能量平衡。该方案中的实验旨在解决多个 这一假说的各个方面。具体地说，我们将：1)确定 食量增加和吞噬功能亢进与OLETF肥胖的发生 大鼠，2)下丘脑基因代谢谱和模式的特征 随机和配对喂养的OLETF大鼠的表达，3)识别潜力 OLETF运动与食物摄取紊乱模式的相互作用 大鼠，4)表征OLETF对高脂肪和高脂肪的摄食和代谢反应 大量营养素选择饮食和5)比较OLETF大鼠和新获得的 CCK-一种不会患肥胖症的基因敲除小鼠。总而言之，结果来自 这些研究将：1)识别和表征独一无二的 外周饱腹感信号通路中的遗传缺陷与 环境因素的范围(锻炼、饮食限制、饮食 成分)调节肥胖症的发展和维持，以及2) 确定这种饱腹感不足如何与中央下丘脑相互作用 调节能量平衡的途径。