Neural regulation of protein ingestion

描述（由申请人提供）：许多观察结果支持监管系统的存在，该系统评估内源性蛋白质/氨基酸需求并改变食物摄入量以满足这一需求。负蛋白质平衡的设置导致食物摄入量显著增加，导致能量摄入过量，动物试图满足对蛋白质的需求，身体脂肪增加。因此，控制蛋白质摄入的调节系统足以压倒控制能量摄入的系统。然而，人们对调节蛋白质摄入的机制以及它们与能量平衡和肥胖的关系知之甚少。这个项目的长期目标是确定神经系统调节食物摄入，以响应不同的蛋白质平衡。最近的研究结果表明，氨基酸，特别是支链氨基酸亮氨酸，在下丘脑局部起作用，抑制食物摄入和促氧神经肽Npy和Agrp的表达。至少有两种信号通路介导了这种反应。一个涉及细胞内信号分子mTOR（哺乳动物雷帕霉素靶点）和amp活化蛋白激酶（AMPK）；第二种涉及局部大脑对亮氨酸的代谢。本项目将验证1)下丘脑特定区域氨基酸信号的减少导致负蛋白平衡导致贪食的假说；2)验证mTOR信号、AMPK信号和/或支链氨基酸代谢介导氨基酸对食物摄入和神经肽基因表达的影响的假说。这些研究的完成将大大增加我们对宏量营养素组成及其对食物摄入的影响的理解，并可能为控制或逆转肥胖的新干预措施奠定基础。

DESCRIPTION (provided by applicant): A number of observations support the existence of regulatory systems which assess endogenous protein/amino acid demand and alter food intake to meet this demand. Settings of negative protein balance lead to significant increases in food intake, resulting in excess energy intake and increased body adiposity as the animal attempts to meet the demand for protein. Thus regulatory systems governing protein intake are sufficient to override systems governing energy intake. Yet little is known about the mechanisms contributing to the regulation of protein intake or their relationship to energy balance and obesity. The long term goal of this project is to define the neuronal systems regulating food intake in response to varied protein balance. Results of recent studies indicate that amino acids, and specifically the branched-chain amino acid leucine, act locally in the hypothalamus to inhibit food intake and the expression of the orexigenic neuropeptides Npy and Agrp. At least two signaling pathways appear to mediate this response. One involves the intracellular signaling molecules mTOR (mammalian target of rapamycin) and AMP-activated protein kinase (AMPK); the second involves the local brain metabolism of leucine. The current project will 1) Test the hypothesis that reduced amino acid signaling within specific areas of the hypothalamus contributes to the hyperphagia induced by negative protein balance, and 2) Test the hypothesis that mTOR signaling, AMPK signaling, and/or branched-chain amino acid metabolism mediate the effect of amino acids on food intake and neuropeptide gene expression. Completion of these studies will dramatically increase our understanding of macronutrient composition and its impact on food intake and could lay the foundation for new interventions to control or reverse obesity.