Role of AMPK and mTOR in the hypothalamus and brainstem for the reduction of food intake by the amino acids leucine and serine

在西方文明社会中，高蛋白饮食在减肥方面的流行突显了人们对饮食蛋白质影响体重的看法，并强调了研究这种现象背后的机制的必要性。目前的提议试图澄清大脑控制进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。目前，关于单个氨基酸在大脑中的作用机制，或者大脑不同区域之间的潜在相互作用，如下丘脑和脑干，这两个主要的食物摄入调节中心，我们知之甚少。亮氨酸进入大脑后会抑制食物的摄入量，而丝氨酸被认为会影响食物的摄入量，这一点得到了很好的支持。因此，本研究的主要目的是研究氨基酸敏感系统哺乳动物雷帕霉素靶标(MTOR)和细胞能量敏感酶AMP激活的蛋白激酶(AMPK)作为下游分子的作用，它们可能协同或独立地介导氨基酸对食物摄取和神经肽基因表达的影响。这项研究将使用活体方法来确定AMPK和/或mTOR是否是下丘脑氨基酸，特别是亮氨酸和丝氨酸的关键检测器，以及脑干是否有助于氨基酸对食物摄入量的调节。因此，目前工作中提出的研究特别新颖，可以为调节食物摄入量和治疗肥胖症的新方法奠定基础。

The popularity of high protein diets for weight loss in society of Western civilization highlights the perception that dietary protein influences body weight, and underscores the need to study the mechanisms underlying this phenomenon. The current proposal 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. Currently we have very little information regarding the mechanisms through which individual amino acids may act within the brain, or the potential interaction between various brain areas such as the hypothalamus and brainstem, two major centers of food intake regulation. It is well supported that leucine suppresses food intake when administered into the brain and serine is supposed to influence food intake. Therefore, the main objective of the present study is to investigate the role of the amino acid-sensing system mammalian target of rapamycin (mTOR) and the cellular energy-sensing enzyme AMP-activated protein kinase (AMPK) as downstream molecules that may act in concert or independently to mediate the effects of amino acids on food intake and neuropeptide gene expression. This research will use in vivo approaches to determine whether AMPK and/or mTOR are critical detectors of hypothalamic amino acids, particularly leucin and serine, and whether the brainstem contributes to the amino acid-dependent regulation of food intake. As such, the studies proposed in the current work are particularly novel, and could lay the foundation for new approaches to the regulation of food intake and treatment of obesity.