Brainstem nutrient sensing in the integrative control of food intake

 描述(申请人提供)：必需氨基酸L亮氨酸的中枢营养感应是食物摄入量和膳食大小的关键决定因素。我们发现：1)餐后内源性中枢亮氨酸水平迅速升高，2)阻断下丘脑内侧基底区(MBH)内内源性亮氨酸分解代谢，从而促进局部亮氨酸供应，减少食物摄入量，3)MBH亮氨酸投药通过减少进食量减少食物摄入量，4)阻断MBH细胞内亮氨酸信号的下游级联促进摄食，而5)MBH这些下游通路的慢性激活限制了高脂饮食的过度吞噬和相关的体重增加。这些作用似乎由两条细胞内信号通路介导：哺乳动物靶标雷帕霉素(MTOR)-丝氨酸/苏氨酸激酶p70S6K(S6K)通路和细胞外信号调节激酶1/2(ERK1/2)通路。在摄食抑制剂量下，MBH亮氨酸也激活尾侧脑干的脑干迷走神经复合体，特别是孤束核(CmNTS)的尾内侧区，在那里与进食有关的肠道负反馈信号汇聚并整合，介导对进食大小的神经控制。我们最近发表的和初步的结果支持cmNTS是一个局部亮氨酸通过限制进食大小和增加CCK的摄食抑制效力来减少食物摄入量的位置。这些作用似乎也由mTOR-S6K和ERK通路介导。此外，饮食诱导的肥胖(DIO)减弱了cmNTS亮氨酸的摄食抑制作用。综上所述，这些数据表明了一种新的脑干营养传感能力，以及它与直接控制膳食大小的新颖集成。这项建议中的研究将应用行为、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应在控制摄食方面的神经和分子机制，它在DIO中是如何被干扰的，以及如何针对它来控制肥胖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.