Brainstem nutrient sensing in the integrative control of food intake

脑干营养传感在食物摄入综合控制中的应用

基本信息

批准号：
8876024
负责人：
GARY J SCHWARTZ
金额：
$ 13.38万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-15 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8876024
关键词：
70-kDa Ribosomal Protein S6 Kinases Address Adipose tissue Affect Amino Acids Animals Attenuated Automobile Driving Behavioral Body Weight Brain Stem Cardiovascular Diseases Catabolism Cells Cholecystokinin Chronic Comorbidity Complex Data Development Diabetes Mellitus Diet Dorsal Dose Eating Endocrine Energy Intake Energy Metabolism Energy-Generating Resources Epidemic Equilibrium Essential Amino Acids Event FOS gene Fatty acid glycerol esters Feedback Feeding behaviors Food Food Energy Gastrointestinal tract structure Health Hormones Human Hyperphagia Hypertension Hypothalamic structure Impairment Individual Ingestion Intestines Learning Leptin Leucine Maintenance Malignant Neoplasms Mammals Measures Mediating Metabolic Metabolism Mitogen-Activated Protein Kinases Molecular Molecular Genetics Neurobiology Neurons Nucleus solitarius Nutrient Obesity Oral Pathway interactions Peptides Physical activity Physiological Property Protein-Serine-Threonine Kinases Publishing Risk Satiation Signal Pathway Signal Transduction Site Stimulus Stomach Stroke United States Weight Gain Work cardiovascular disorder risk detection of nutrient energy balance extracellular feeding genetic approach mTOR protein mortality neurophysiology neuroregulation neurotransmission novel public health relevance relating to nervous system research study

项目摘要

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.

描述（由申请人提供）：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量的关键决定因素。我们已经证明：1) 餐后亮氨酸的内源中枢水平迅速升高，2)。阻断中基底下丘脑 (MBH) 内的内源性亮氨酸分解代谢，从而促进局部亮氨酸可用性，减少食物摄入量，3) MBH 通过减少进餐亮氨酸施用食物摄入量大小，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高脂肪饮食过度进食和相关的体重增加，这些作用似乎是由两种细胞内信号传导途径介导的。：哺乳动物雷帕霉素靶标 (mTOR) - 丝氨酸/苏氨酸激酶 p70S6K (S6K) 途径，以及细胞外信号调节激酶 1/2 (ERK1/2) 途径。进食抑制剂量的 MBH 亮氨酸还会激活尾部脑干的脑干背侧迷走神经复合体，特别是孤束核 (cmNTS) 的尾内侧区域，这里是与进餐相关的肠道负反馈信号汇聚和的区域。我们最近发表的初步结果支持 cmNTS 是局部亮氨酸通过限制膳食量来减少食物摄入的位点。这些数据似乎也通过 mTOR-S6K 和 ERK 途径介导，从而减弱了 cmNTS 亮氨酸的摄食抑制作用。脑干营养传感能力及其与直接控制膳食量的新颖整合本提案中的研究将应用神经生理学、药理学、免疫组织化学和分子遗传学方法的协调组合来识别。并描述了脑干营养感应在进食控制中的神经和分子机制、它在 DIO 中如何被破坏，以及如何有针对性地控制肥胖症的食物摄入和体重。