NEURAL SUBSTRATES OF PEPTIDE INDUCED SATIETY

肽诱导饱腹感的神经基质

• 批准号: 6477306
• 负责人: Robert C Ritter
• 金额: $ 26.29万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-04-01 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6477306
• 关键词: NMDA receptors; appetite regulatory center; behavior test; calcitonin gene related peptide; capsaicin; cholecystokinin; glutamates; hormone receptor; hormone regulation /control mechanism; immunocytochemistry; laboratory rat; neural information processing; neural transmission; neuroendocrine system; nutrient intake activity; nutrition related tag; satiations; sham feeding; vagus nerve; visceral afferent nerve

DESCRIPTION: (Adapted From The Applicant's Abstract) This application is a revised version for a competitive renewal of a research program aimed at defining the neuromechanisms through which gastrointestinal peptides especially cholecystokinin, CCK, reduce food intake and ultimately to appreciate how these substrates are involved in the physiology and pathology of food intake. CCK is released by intestinal mucosal I cells, in response to nutrients in the intestine. We discovered that exogenous CCK and intestinally infused nutrients reduce food intake by acting on similar, if not identical, capsacin sensitive, vagal fibers. Furthermore, reduction of feeding by exogenous CCK and intestinal nutrient infusions is blocked by receptor antagonist acting at CCKA but not CCKB receptors. These results suggest that peripheral CCK receptors and small unmyelinated vagal sensory neurons participate in the reduction of food intake by exogenous CCK and intestinal nutrients. They also suggest that endogenous CCK plays an important role in reduction of food intake by intestinal nutrients. Although it is now known that capsaicin sensitive vagal fibers mediate the reduction of food intake by both CCK and intestinal nutrients, we do not know the neurotransmitter(s) used to communicate these satiety signals from vagal fibers to the brain. Furthermore, we do not know how other gastrointestinal peptides may participate in activation of vagal sensory fibers in the intestinal wall. Our recent work suggests that glutamate, acting at NMDA receptors, may be involved in transmitting satiety signals from the vagus to brain. Also, we have some evidence that the peptide, CGRP, may participate in initiating satiety signals at the intestinal end of the vagus. Finally, we have little understanding of how CCK may respond to dietary changes to alter sensitivity of satiety signals. However, our recent results suggest that adaptation to certain diets, notably high fat diets, may cause marked reduction of response to CCK and other satiety signals. Therefore, the experiments proposed are designed to: 1) use intracranial injections together with intestinal infusions to evaluate the participation of glutamatergic transmission in the reduction of food by CCK and intestinal nutrients; 2) use behavioral, pharmacological and biochemical approaches to assess participation of gut CGRP in vagal activation leading to reduction of food intake and 3) to use dietary manipulations, behavioral testing, immunohistochemical and biochemical techniques to assess the role of dietary macronutrients in altering responsiveness to exogenous CCK and to evaluate participation of endogenous CCK in alterations of responsiveness to intestinal nutrients.

描述：（改编自申请人摘要） 此申请是一个修订版本的竞争性续期 一项旨在确定神经机制的研究计划， 胃肠道肽，特别是胆囊收缩素，CCK，减少食物 摄入量，并最终了解这些基板是如何参与 在食物摄取的生理学和病理学上。CCK是由 肠粘膜I细胞，对肠内的营养物质作出反应。 我们发现外源性CCK和脑内注入的营养素 通过作用于相似的（如果不是相同的）辣椒素来减少食物摄入 敏感的迷走神经纤维此外，减少外源性 受体拮抗剂阻断CCK和肠内营养输注 作用于CCKA而非CCKB受体。这些结果表明 外周CCK受体和小的无髓鞘迷走神经感觉神经元 通过外源性CCK参与减少食物摄入， 肠道营养素他们还认为内源性CCK在 肠道营养素在减少食物摄入中的重要作用。 虽然现在已知辣椒素敏感迷走神经纤维介导 CCK和肠道营养素减少食物摄入， 我不知道用来传递这些饱腹感的神经递质 从迷走神经纤维到大脑的信号。此外，我们不知道如何 其它胃肠肽可参与迷走神经的激活， 肠壁的感觉纤维我们最近的研究表明， 作用于NMDA受体的谷氨酸可能参与传递 饱腹感信号从迷走神经传递到大脑。另外，我们有证据表明 这种肽CGRP可能参与引发饱腹感信号 在迷走神经的肠端最后，我们几乎没有 了解CCK如何对饮食变化做出反应， 饱足感信号的敏感性。然而，我们最近的研究结果表明， 适应某些饮食，尤其是高脂肪饮食，可能会导致显着的 降低对CCK和其他饱腹感信号的反应。因此 提出的实验设计为：1）使用颅内注射 与肠道输注一起评估参与 胆囊收缩素减少食物中的代谢能传递， 肠道营养素; 2）使用行为，药理学和生物化学 评估肠CGRP参与迷走神经激活的方法 导致食物摄入减少和3）使用饮食操纵， 行为测试，免疫组织化学和生化技术， 评估膳食常量营养素在改变对以下物质的反应中的作用： 外源性CCK，并评估内源性CCK参与 对肠道营养素的反应性改变。