Neural regulation of protein ingestion

描述(由申请人提供)：许多观察结果支持管理系统的存在，这些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会导致食物摄入量的显著增加，导致过量的能量摄入和增加身体肥胖，因为动物试图满足对蛋白质的需求。因此，管理蛋白质摄入的调控系统足以凌驾于控制能量摄入的系统之上。然而，人们对蛋白质摄入量的调节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调节食物摄入量的神经系统，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，抑制食物的摄入和促食欲素神经肽NPY和AgRP的表达。至少有两条信号通路似乎参与了这一反应。一个涉及细胞内信号分子mTOR(哺乳动物雷帕霉素的靶标)和AMP激活的蛋白激酶(AMPK)；第二个涉及大脑局部亮氨酸的代谢。目前的项目将1)检验下丘脑特定区域氨基酸信号减少导致蛋白质负平衡引起吞噬反应的假说，2)检验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量和神经肽基因表达的影响的假说。这些研究的完成将极大地提高我们对常量营养素组成及其对食物摄入量的影响的了解，并可能为控制或逆转肥胖的新干预措施奠定基础。 与公共健康相关：目前的项目试图澄清大脑控制摄食行为以应对蛋白质平衡变化的生物学基础。考虑到蛋白质平衡优先于能量平衡，这项工作尤其重要，因此利用这一调节系统将揭示调节食物摄入量和治疗肥胖症的新方法。相对于其他常量营养素，蛋白质摄入量受到严格的调控，但人们对大脑感知和调节蛋白质摄入量的机制知之甚少。考虑到这一调节系统在快速生长和高蛋白质需求时期特别重要，而且许多青少年食用低质量的饮食，调节蛋白质摄入量及其与能量摄入量的相互作用的机制可能与青少年肥胖有直接关系。

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. PUBLIC HEALTH RELEVANCE: The current project seeks to clarify the biological basis whereby the brain controls feeding behavior in response to variations in protein balance. This work is especially important considering that protein balance takes priority over energy balance, and thus tapping into this regulatory system will reveal novel approaches to regulate food intake and treat obesity. Protein intake is robustly regulated relative to other macronutrients, yet very little is known about the mechanisms by which the brain senses and regulates protein intake. Considering that this regulatory system is particularly important in periods of rapid growth and high protein demand and that many adolescents consume low quality diets, mechanisms regulating protein intake and their interaction with energy intake may have direct relevance to adolescent obesity.