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且尚未用于能量代谢时，进餐终止。虽然已经确定了各种预吸收反馈信号在胃肠道中的各个站点所产生的，其定量的喂养控制的贡献的评估需要考虑的整体背景下，这些信号产生。在进食过程中，多个胃肠道部位受到刺激，引发与营养特征，浓度和数量相关的各种信号。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。食物摄入量还受到参与整体能量平衡的下丘脑信号系统的活动的影响。瘦素是ob基因的蛋白产物，它的发现使我们对参与能量调节的下丘脑系统的组织结构的理解有了重大进展。这些下丘脑信号传导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响应来减少膳食量。拟议的实验将解决不同方面的整合信号参与控制的食物摄入量在不同的模型和不同的实验方法。拟议的实验是根据两个具体目标组织的。在第一个方面，我们将研究瘦素及其下游介质在调节餐内饱腹信号的神经和行为反应中的作用。我们将开始评估下丘脑信号肽在哪里以及如何影响膳食模式。对于减少进食量的行为，我们将评估这些信号调节孤束核（NTS）对餐内反馈信号的反应的能力。这些实验将采用c-fos和NTS神经激活的电生理学评估。最后，这些实验将使用电生理技术来评估下丘脑-NTS信号的肽候选物。第二个具体目标下的实验将侧重于量化响应于营养暴露的胃肠道肽分泌。这些实验将采用灵长类动物和大鼠模型。GI反馈信号的传统焦点一直是来自上肠的肽。最近的数据表明胃肽（生长激素释放肽）和下肠肽（PYY（3-36）和GLP-1在喂养控制中的作用）。肽释放的模式响应于定点营养输送尚未完全表征。了解这些肽分泌的背景将允许对餐内和餐间喂养控制的相对贡献进行知情评估。后者的数据将对理解减肥手术的喂养和减肥效果有影响。总的来说，这些实验将提供重要的信息的相对作用和肽系统参与摄食控制的综合行动。

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.