CNS GLP-1 signaling in energy and glucose homeostasis

CNS GLP-1 信号在能量和葡萄糖稳态中的作用

基本信息

批准号：
7643201
负责人：
RANDY J SEELEY
金额：
$ 31.34万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7643201
关键词：
Afferent Neurons Agonist Amygdaloid structure Anorexia Appetite Depressants Behavioral Blood Blood Glucose Body Weight Body Weight decreased Brain Brain Stem Carbohydrates Complement Data Diabetes Mellitus Eating Funding GLP-I receptor Genetic Genetic Models Genetic Techniques Glucose Goals Hepatic Human Hypothalamic structure Ingestion Intestines Islets of Langerhans Link Location Measures Mediating Metabolism Mus Neurons Neurosecretory Systems Nutrient Obesity Output Peptides Peripheral Pharmacologic Substance Physiology Play Population Portal vein structure Publishing Regulation Relative (related person)Research Personnel Rodent Role Satiation Signal Transduction Site Stress System Testing Tissues Visceral blood glucose regulation clinical care cost energy balance exenatide glucagon like peptide glucagon-like peptide glucagon-like peptide 1 glucose metabolism glucose tolerance hindbrain improved insulin secretion peptide I programs receptor relating to nervous system response

项目摘要

DESCRIPTION (provided by applicant): Rates of both obesity and diabetes continue to escalate and with them come rising monetary and human costs. Growing evidence links gut secreted factors as crucial for regulating both food intake and the levels of glucose in the blood. Glucagon-like-peptide-I (GLP-I) is a gut peptide with a broad role in the regulation of nutrient ingestion and disposition. GLP-I is produced in the intestine as well as in a restricted set of neurons in the hindbrain, and a single GLP-I receptor (GLP-I R) is expressed in pancreatic islets as well as neurons controlling autonomic and neuroendocrine function in the hypothalamus, amygdala and caudal brainstem. Previously it was thought that intestinal GLP-I and central GLP-I operated as independent systems, the former regulating glucose metabolism and the latter behavioral responses, particularly food intake. Recent evidence has challenged this view and it is increasingly apparent that there is overlapping activity between the peripheral and CNS GLP-I systems. In particular, it now appears that signaling through CNS GLP-I receptors regulates blood glucose, although it is not yet clear whether the signal is from GLP-I secreted in the brain, the gut or both. Moreover, peripherally administered GLP-I R agonists, like exendin-4 (Ex-4), cause weight loss in rodents and humans in addition to improving glucose tolerance, but it is unclear how this effect is mediated. The specific populations of CNS GLP-I receptors responsible for regulating blood glucose and the anorectic actions of Ex-4 remain unclear. Thus, the overarching goal of this proposal is to determine how the peripheral and central GLP-I systems interact to control food intake and glucose metabolism. Our first aim will be to determine the key sites of endogenous GLP-I and exogenous Ex-4 to regulate food intake and body weight using both pharmacological and tissue specific genetic knockdowns. Our second aim will be to determine the key sites of endogenous GLP-I and exogenous Ex-4 to regulate peripheral glucose levels. Again we will use a combination of site-specific delivery of pharmacological antagonists and tissue-specific genetic knockdowns of the GLP-I receptor. Determining the mechanisms of CNS GLP-I signaling is important for understanding carbohydrate and energy balance. Furthermore, the advent of pharmaceuticals that utilize GLP-I R signaling to treat diabetes makes understanding the physiology of GLP-I directly applicable to clinical care.

描述（由申请人提供）：肥胖和糖尿病的比率不断升级，随着它们的货币和人为成本的上涨。越来越多的证据将肠道分泌的因素与调节食物摄入和血液中的葡萄糖水平有关。胰高血糖素样肽-I（GLP-I）是一种肠道肽，在养分摄入和处置的调节中起着广泛的作用。 GLP-I在肠道以及后脑中的一组受限神经元中产生，单个GLP-I受体（GLP-I R）在胰岛以及控制下丘脑，amyygdala和Caudal Brainsyst的自主和神经内分泌功能的神经元中表达。以前据认为，肠道GLP-I和中央GLP-I作为独立系统，前者调节葡萄糖代谢以及后一种行为反应，尤其是食物摄入量。最近的证据挑战了这一观点，越来越明显的是，外围和CNS GLP-I系统之间存在重叠的活动。特别是，现在看来通过CNS GLP-I受体发出的信号调节血糖，尽管尚不清楚该信号是来自大脑，肠道还是两者兼而有之的GLP-I。此外，除Exendin-4（Ex-4）等外围施用的GLP-I R激动剂外，除了提高葡萄糖耐受性外，还会导致啮齿动物和人的体重减轻，但尚不清楚该作用如何介导。 CNS GLP-I受体的特定种群负责调节血糖和EX-4的厌食症作用尚不清楚。因此，该提案的总体目标是确定外围和中央GLP-I系统如何相互作用以控制食物摄入和葡萄糖代谢。我们的第一个目的是确定内源性GLP-I和外源性EX-4的关键部位，以使用药理学和组织特异性遗传敲低来调节食物摄入和体重。我们的第二个目标是确定内源性GLP-I和外源性EX-4的关键部位以调节外周葡萄糖水平。同样，我们将使用GLP-I受体的药理学拮抗剂和组织特异性遗传敲低的位点特异性递送的组合。确定CNS GLP-I信号传导的机制对于理解碳水化合物和能量平衡很重要。此外，利用GLP-1信号来治疗糖尿病的药物的出现使得了解GLP-I直接适用于临床护理的生理学。