Gastrointestinal Integration and Feeding

描述（由申请人提供）：当大部分摄入的营养物质仍在胃肠道中，尚未用于能量代谢时，用餐终止。虽然已经确定了来自胃肠道不同部位的各种吸收前反馈信号，但要评估它们对摄食控制的定量贡献，需要考虑这些信号产生的总体背景。在进食过程中，多个胃肠道部位受到刺激，产生各种与营养物质特性、浓度和数量相关的信号。这些营养刺激信号对持续的食物摄入产生主要的负反馈影响。食物摄入也受下丘脑信号系统活动的影响，该系统涉及整体能量平衡。瘦素（ob基因的蛋白质产物）的发现使我们对参与能量调节的下丘脑系统的组织的理解取得了重大进展。这些下丘脑信号系统可能对食物摄入产生影响的一种方式是通过调节对餐内饱腹感信号的反应来减少餐量。所提出的实验将在不同的模型和不同的实验方法中解决与食物摄入控制有关的信号整合的不同方面。拟议的实验是根据两个具体目标组织的。首先，我们将研究瘦素及其下游介质在调节膳食饱腹感信号的神经和行为反应中的作用。我们将从评估下丘脑信号肽在哪里以及如何影响饮食模式开始。对于减少进食量的行为，我们将评估这些信号调节孤立束核（NTS）对进食反馈信号的反应的能力。这些实验将采用c-fos和NTS神经激活的电生理评估。最后，这些实验将使用电生理技术来评估下丘脑- nts信号的候选肽。第二个特定目标下的实验将集中于定量胃肠道对营养暴露的肽分泌。这些实验将采用灵长类动物和大鼠模型。胃肠道反馈信号的传统焦点一直是来自上肠的肽。最近的数据表明胃（饥饿素）和下肠肽(PYY（3-36）和GLP-1在喂养控制中的作用。肽释放响应于定点营养输送的模式尚未完全表征。了解这些多肽分泌的环境将有助于对餐内和餐间饲养控制的相对贡献进行知情评估。这些数据将有助于理解减肥手术的喂养和减肥效果。总之，这些实验将提供有关肽系统在摄食控制中的相关作用和综合作用的重要信息。

DESCRIPTION (provided by applicant): Meals terminate when the majority of ingested nutrients are still in the gastrointestinal tract and not yet available for energy metabolism. Although a variety of preabsorptive feedback signals arising from various sites in the GI tract have been identified, an assessment of their quantitative contribution to feeding control requires a consideration of the overall context in which these signals are produced. During feeding, multiple gastrointestinal sites are stimulated, provoking a variety of signals related to nutrient character, concentration and quantity. These nutrient stimulated signals exert major negative feedback influences on ongoing food intake. Food intake is also affected by the activity of hypothalamic signaling systems involved in overall energy balance. The discovery of leptin, the protein product of the ob gene, has produced significant advances in our understanding of the organization of hypothalamic systems involved in energy regulation. One way in which these hypothalamic signaling systems may exert their effects on food intake is by modulating responsivity to within meal satiety signals to reduce meal size. The proposed experiments will address different aspects of the integration of signals involved in the control of food intake in different models and with diverse experimental approaches. The proposed experiments are organized under two specific aims. Under the first, we will examine the actions of leptin and its down stream mediators in modulating neural and behavioral response to within meal satiety signaling. We will begin with assessments of where and how hypothalamic signaling peptides affect meal patterns. For actions that reduce meal size, we will evaluate the ability of these signals to modulate nucleus of the solitary tract (NTS) responses to within meal feedback signaling. These experiments will employ both c-fos and electrophysiological assessments of NTS neural activation. Finally, these experiments will use electrophysiological techniques to evaluate peptide candidates for hypothalamic-NTS signaling. Experiments under the second specific aim will focus on quantifying peptide secretion from the gastrointestinal tract in response to nutrient exposure. These experiments will employ both primate and rat models. The traditional focus for GI feedback signaling has been on peptides from the upper intestine. Recent data has suggested roles for gastric (ghrelin) and lower intestinal peptides (PYY (3-36) and GLP-1 in feeding control). Patterns of peptide release in response to site directed nutrient delivery have not been completely characterized. An understanding of the context within which these peptides are secreted will allow informed assessments of the relative contributions to both within meal and across meal feeding control. These latter data will have implications for understanding the feeding and weight loss effects of bariatric surgery. Overall, these experiments will provide important information on the relative roles and integrative actions of peptide systems involved in feeding control.