The Role of Glutamate in the Control of Food Intake

谷氨酸在控制食物摄入量中的作用

• 批准号: 8370480
• 负责人: Robert C Ritter
• 金额: $ 32.37万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8370480
• 关键词: Afferent Neurons; Agonist; Area; Attenuated; Behavioral; Brain; Cholecystokinin; Coupling; Data; Development; Eating; Eating Disorders; Endocrine; Esthesia; Event; Excitatory Amino Acid Antagonists; Extracellular Signal Regulated Kinases; Fiber; Frequencies; Gastrointestinal tract structure; Glutamate Receptor; Glutamates; Goals; Health; Human; Hypothalamic structure; Injection of therapeutic agent; Intervention; Investigation; Lead; Ligands; Link; MAP Kinase Gene; MAPK3 gene; Mediating; Melanocortin 4 Receptor; Methods; Modification; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Nucleus solitarius; Obesity; Pathogenesis; Peptides; Phosphorylation; Play; Preparation; Process; Progress Reports; Property; Protein Kinase; Receptor Activation; Reporting; Research Personnel; Role; Satiation; Seminal; Signal Transduction; Site; Source; Synapses; Synapsins; Synaptic Transmission; Synaptic Vesicles; System; Testing; Therapeutic Intervention; Time; U-0126; Work; computerized data processing; feeding; food quality; gastrointestinal; hindbrain; in vivo; insight; interest; melanocortin receptor; neuromechanism; neurotransmitter release; prevent; receptor; receptor function; relating to nervous system; response; synaptic function; transmission process

DESCRIPTION (provided by applicant): The gastrointestinal (GI) tract informs the brain of the quantity and quality of food consumed during meals. Hence, GI signals drive satiation, and are seminal to control of food intake, regardless of the conditions that initiate it. This application or renewal continues an enduring interest in neural mechanisms by which satiation signals are communicated to the hindbrain nucleus of the solitary tract (NTS) and integrated with other controls of food intake. Glutamate is the principal neurotransmitter released by vagal afferent terminals in the NTS. As such, glutamate receptors in the NTS are pivotal to the transmission and processing of vagal satiation signals. Our prior investigations revealed that activation of NMDA-type glutamate receptors in the NTS participate in control of meal size. Moreover, delay of meal termination by NTS injection of NMDAr antagonists depends on intact vagal afferent terminals in the NTS. Finally, activation NMDAr in the NTS is required for CCK-evoked MAPK signaling and consequent reduction of food intake by cholecystokinin (CCK), the archetypical GI satiation peptide. Nevertheless, we remain ignorant of the specific mechanisms by which NMDAr enable CCK- induced reduction of food intake. Therefore, one aim of this application is to use multiple in vivo and ex vivo preparations to test the nested hypotheses that reduction of food intake by CCK requires NMDAr-dependent activation of MAPK signaling in vagal afferent terminals in the NTS; that MAPK signaling results in pERK1/2- mediated phosphorylation of synapsin 1 in vagal afferent terminals; and leads to strengthened vagal afferent synaptic function in the NTS with consequent reduction of food intake. Other investigators have reported that hindbrain melanocortin receptor activation (MC4r) contributes to CCK-evoked MAPK signaling in the hindbrain and reduction of food intake. This report, taken together with our findings that NTS NMDAr activation is necessary for reduction of feeding by CCK, suggests an important interaction between NTS MC4r and NMDAr in control of food intake. Therefore, the second aim of this application is to establish a basic relationship between NTS NMDAr and MC4r that makes both crucial for CCK-induced reduction of food intake. Specifically we will apply pharmacological and immunochemical methods to determine whether NTS NMDAr activation is functionally upstream or downstream of NTS MC4r in control of food intake by CCK. In addition we will assess the possibility that NTS NMDAr participate in control of food intake by endogenous MC4r ligands in the NTS, and thereby may participate in the integration of melanocortinergic controls of food intake with those arising from vagal afferent activation. Our long-term goal is to determine how the unique properties of NMDAr contribute to the process of satiation and integration of GI satiation signals with other controls of food intake. Detailed appreciation of NTS NMDAr contributions to control of food intake is of significance to human health because it may provide avenues for therapeutic intervention in eating disorders and obesity. PUBLIC HEALTH RELEVANCE: Glutamate is the principal neurotransmitter released by vagal afferent neurons, which communicate information from the GI tract to the hindbrain. The NMDA-type glutamate receptor participates in the control of food intake by GI signals in the hindbrain. The proposed work will delineate the neural mechanisms by which hindbrain NMDA receptors contribute to the processes that reduce food intake, and determine how these receptors interact with other hindbrain receptors involved in control of food intake. Results will provide new insights into the process of satiation and potential points for therapeutic intervention in eating disorders and development of obesity.

描述（由申请人提供）：胃肠道（GI）告知大脑进餐时消耗的食物的数量和质量。因此，胃肠道信号会驱动饱腹感，并且对于控制食物摄入量至关重要，无论引发它的条件如何。这种应用或更新延续了人们对神经机制的持久兴趣，通过这种机制将饱足信号传递到孤束的后脑核（NTS）并与其他食物摄入控制相结合。谷氨酸是 NTS 迷走神经传入末梢释放的主要神经递质。因此，NTS 中的谷氨酸受体对于迷走神经饱足信号的传输和处理至关重要。我们之前的研究表明，NTS 中 NMDA 型谷氨酸受体的激活参与了膳食量的控制。此外，NTS 注射 NMDAr 拮抗剂延迟进餐终止取决于 NTS 中完整的迷走神经传入末梢。最后，CCK 诱发的 MAPK 信号传导需要激活 NTS 中的 NMDAr，并随后通过缩胆囊素 (CCK)（典型的胃肠道饱足肽）减少食物摄入。然而，我们仍然不知道 NMDAr 使 CCK 诱导的食物摄入量减少的具体机制。因此，本申请的一个目的是使用多种体内和离体制剂来测试嵌套假设，即 CCK 减少食物摄入需要 NTS 迷走神经传入末梢中 MAPK 信号的 NMDAr 依赖性激活； MAPK 信号传导导致迷走神经传入末梢 pERK1/2 介导的突触蛋白 1 磷酸化；并导致 NTS 中迷走神经传入突触功能增强，从而减少食物摄入。其他研究人员报告称，后脑黑皮质素受体激活 (MC4r) 有助于后脑中 CCK 诱发的 MAPK 信号传导并减少食物摄入。该报告与我们的研究结果（NTS NMDAr 激活对于减少 CCK 摄食是必要的）相结合，表明 NTS MC4r 和 NMDAr 在控制食物摄入方面存在重要的相互作用。因此，该应用的第二个目标是建立 NTS NMDAr 和 MC4r 之间的基本关系，这使得两者对于 CCK 诱导的食物摄入减少至关重要。具体来说，我们将应用药理学和免疫化学方法来确定 NTS NMDAr 激活在功能上是 NTS MC4r 的上游还是下游，以控制 CCK 的食物摄入。此外，我们将评估 NTS NMDAr 参与 NTS 中内源性 MC4r 配体控制食物摄入的可能性，从而可能参与黑皮质素能食物摄入控制与迷走神经传入激活引起的食物摄入控制的整合。我们的 长期目标是确定 NMDAr 的独特特性如何促进饱足过程以及胃肠道饱足信号与其他食物摄入控制的整合。详细了解 NTS NMDAr 对控制食物摄入的贡献对人类健康具有重要意义，因为它可能为饮食失调和肥胖症的治疗干预提供途径。 公共健康相关性：谷氨酸是迷走神经传入神经元释放的主要神经递质，其将信息从胃肠道传递到后脑。 NMDA 型谷氨酸受体通过后脑中的胃肠道信号参与食物摄入的控制。拟议的工作将描述后脑 NMDA 受体参与减少食物摄入过程的神经机制，并确定这些受体如何与参与控制食物摄入的其他后脑受体相互作用。结果将为饱足过程提供新的见解，并为饮食失调和肥胖的发展提供治疗干预的潜在要点。