The Role of Glutamate in the Control of Food Intake

描述(申请人提供)：膳食大小是食物总摄入量和能量平衡的主要决定因素。在大鼠和人类中，增加食量与正能量平衡和肥胖的发展有关。肥胖已被几乎所有主要公共卫生组织确定为发病率和死亡率的主要贡献者。了解饱腹感发生的神经机制和控制进食量对剖析肥胖的病理生理学具有重要意义。来自胃肠道的机械、化学和内分泌信号有助于终止进餐和确定进餐大小。这些胃肠道信号由迷走神经的传入神经元传递到后脑。因此，迷走神经为大脑提供了有关有机体营养状况的信息，甚至在营养同化发生之前就是如此。氨基酸谷氨酸是迷走神经传入神经元的主要神经递质。尽管它对迷走神经传递很重要，但迷走神经和后脑谷氨酸受体在控制食物摄入量中的作用很少被研究。然而，我们证明了系统地或后脑注射NMDA型谷氨酸受体拮抗剂的拮抗剂会增加进食量。这种食量的增加需要完整的中央迷走神经传入过程。目前应用的目的是：1.通过手术或神经毒性损毁迷走神经传入神经以确定参与迷走神经和后脑对食物摄取的调控的特定亚群(S)；2.利用生理操作，结合药理学和免疫组织化学方法，确定后脑中的N-甲基-D-天冬氨酸受体是否特异性地调节胃信号对食物摄取的抑制；以及3.在胃肠道动脉附近应用N-甲基-D-天冬氨酸激动剂和拮抗剂，以确定迷走神经外周传入元件上的谷氨酸受体是否参与控制食物摄入量。控制膳食大小是总热量摄入量和能量平衡的主要决定因素。直接向大脑传递胃肠道信息的迷走神经控制着食物的大小。该项目旨在确定NMDA型谷氨酸受体在迷走神经控制食物大小中的作用。

DESCRIPTION (provided by applicant): Meal size is a major determinant of total food intake and energy balance. Increased meal size is associated with positive energy balance and development of obesity in in rats and humans. Obesity has been identified as a major contributor to morbidity and mortality by virtually all major public health organizations. Understanding the neural mechanisms through which satiation occurs and meal size is controlled is seminal to the dissecting the pathophysiology of obesity. Mechanical, chemical and endocrine signals originating from the gastrointestinal tract contribute to meal termination and determination of meal size. These gastrointestinal signals are carried to the hindbrain by the afferent neurons of the vagus nerve. The vagus, therefore, provides the brain with information on the nutritional status of the organism, even before nutrient assimilation occurs. The amino acid, glutamate, is the principal neurotransmitter of vagal afferent neurons. In spite of its importance to vagal neurotransmission, the contribution of vagal and hindbrain glutamate receptors in the control of food intake is little investigated. However, we demonstrated that injection of antagonists of NMDA-type glutamate receptor antagonists systemically or into the hindbrain increases meal size. This increase in meal size requires intact central vagal afferent processes. The aims of the current application are 1. to employ surgical or neurotoxic destruction of vagal afferents to identify the specific subpopulation(s) that participates in NMDA receptor-mediated control of food intake by the vagus nerve and hindbrain, 2. to use physiological manipulation, together with pharmacological and immunohistochemical methods to determine whether NMDA receptors in the hindbrain specifically modulate inhibition of food intake by gastric signals, and 3. to utilize near arterial application of NMDA agonists and antagonists to the gastrointestinal tract to determine whether glutamate receptors on peripheral vagal afferent elements participate in control food intake. Control of meal size is a principal determinant of total caloric intake and energy balance. The vagus nerve, which directly conveys gastrointestinal information to the brain controls meal size. This project aims to determine the role of NMDA-type glutamate receptors in the control of meal size by the vagus nerve.