Brainstem nutrient sensing in the integrative control of food intake

 描述（由申请人提供）：必需氨基酸L-亮氨酸的中枢营养素感知是食物摄入量和膳食量的关键决定因素。我们已经证明：1）亮氨酸的内源性中枢水平在餐后迅速升高，2）阻断内侧基底下丘脑（MBH）内的内源性亮氨酸催化剂，从而促进局部亮氨酸利用度，减少食物摄入，3）MBH亮氨酸施用通过减少膳食量来减少食物摄入，4）阻断MBH中亮氨酸信号传导的下游细胞内级联促进进食，而5）MBH中这些下游途径的慢性激活限制了高脂饮食的过度进食和相关的体重增加。这些作用似乎由两种细胞内信号通路介导：哺乳动物雷帕霉素靶蛋白（mTOR）-丝氨酸/苏氨酸激酶p70 S6 K（S6 K）通路和细胞外信号调节激酶1/2（ERK 1/2）通路。进食抑制剂量的MBH亮氨酸还激活尾侧脑干的脑干背侧迷走神经复合体，特别是孤束核的尾内侧区（cmNTS），在这里，与膳食相关的肠道负反馈信号会聚并整合以介导膳食的神经控制。我们最近发表的和初步的结果支持的cmNTS作为一个网站，其中本地亮氨酸的行为，以减少食物摄入量，通过限制膳食的大小，并通过增加CCK的喂养抑制效力的鉴定。这些作用似乎也由mTOR-S6 K和ERK途径介导。此外，饮食诱导的肥胖症（DIO）减弱cmNTS亮氨酸的摄食抑制作用。总之，这些数据表明了一种新的脑干营养感测能力，以及其与膳食大小直接控制的新颖整合。该提案中的研究将采用行为，神经生理学，药理学，免疫组织化学和分子遗传学方法的协调组合，以确定和表征脑干营养感测控制摄食的神经和分子机制，它如何在DIO中被破坏，以及它如何有针对性地控制肥胖症的食物摄入量和体重。

 DESCRIPTION (provided by applicant): Central nutrient sensing of the essential amino acid l-leucine is a critical determinant of food intake and meal size. We have shown that: 1) endogenous central levels of leucine are rapidly elevated after a meal, 2) blocking endogenous leucine catabolism within the mediobasal hypothalamus (MBH), thereby promoting local leucine availability, reduces food intake, 3) MBH leucine administration reduces food intake by reducing meal size, 4) blocking downstream intracellular cascades of leucine signaling in the MBH promote feeding, while 5) chronic activation of these downstream pathways in the MBH limit high fat diet hyperphagia and associated weight gain. These actions appear to be mediated by two intracellular signaling pathways: the mammalian target of rapamycin (mTOR) - serine/threonine kinase p70S6K (S6K) pathway, and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. MBH leucine at feeding inhibitory doses also activates the brainstem dorsal vagal complex of the caudal brainstem, particularly the caudomedial region of the nucleus of the solitary tract (cmNTS), where meal-related gut negative feedback signals converge and are integrated to mediate the neural control of meal size. Our recent published and preliminary results support the identification of the cmNTS as a site where local leucine acts to reduce food intake by limiting meal size and by increasing the feeding inhibitory potency of CCK. These actions appear to be mediated by both mTOR-S6K and ERK pathways as well. Furthermore, diet induced obesity (DIO) attenuates cmNTS leucine's feeding inhibitory actions. Taken together, these data suggest a new brainstem nutrient sensing capability, and its novel integration with direct controls of meal size. Studies in this proposal will apply a coordinated combination of behavioral, neurophysiological, pharmacological, immunohistochemical and molecular genetic approaches to identify and characterize the neural and molecular mechanisms underlying brainstem nutrient sensing in the control of feeding, how it is disrupted in DIO, and how it can be targeted to control food intake and body weight in obesity.