LEPTIN ACTION ON HYPOTHALAMIC PEPTIDES GOVERNING FEEDING

瘦素对控制进食的下丘脑肽的作用

• 批准号: 2902563
• 负责人: ABHIRAM SAHU
• 金额: $ 23.58万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2902563
• 关键词: eating; gene expression; hormone receptor; hormone regulation /control mechanism; hypothalamus; in situ hybridization; laboratory rat; leptin; neuroendocrine system; neuropeptide Y; neurotensin; nutrition related tag; paraventricular nucleus; receptor binding; receptor expression; satiations; secretion

The goal of this project is to understand the neurobiological basis of food intake and body weight regulation. Leptin, a product of the obese gene in fat cells, is one of the most important peripheral satiety factors that inhibits food intake and body weight by acting in the brain. Since obese humans, and mice made obese by dietary manipulation, have elevated levels of circulating leptin but maintain a normal food intake, it is thought that obese individuals are relatively insensitive to endogenous leptin. In rodents, chronic leptin infusion produces resistance to the satiety action of leptin. The hypothalamic mechanisms for the development of resistance to leptin's satiety action are unknown. This problem will be addressed here in a chronic leptin infused rat. A simple hypothesis that alterations in the secretion and actions of a model orexigenic, neuropeptide Y (NPY), and anorectic, neurotensin (NT), peptide underlies the resistance to leptin's satiety action will be tested. The following Specific Aims will be addressed. Specific Aim 1: To determine whether decreased NPY secretion (synthesis and release) and/or increased NT secretion in the arcuate nucleus (ARC)- paraventricular nucleus (PVN) pathway can account for the acute leptin induced decrease in food intake; and whether changes in responsiveness to the actions of NPY and NT are also involved; Specific Aim 2: To determine whether the changes in secretion and action of NPY and NT that are established to underlie the acute effects of leptin are reversed with chronic leptin exposure and lead to the development of resistance to leptin's satiety action; Specific Aim 3: To determine the changes in leptin receptor activity and gene expression during the acute hypophagia induced by leptin and during the development of resistance to leptin's satiety action; Specific Aim 4: To describe the reversals in activities of the NPY and NT systems and in leptin receptor function that may be anticipated to occur in association with the hyperphagia and subsequent return to the control condition that follows withdrawl from chronic leptin infusion. Peptide neurosecretion will be evaluated by assessing synthetic potential (mRNA), availability for release (peptide content), and output (in vivo and in vitro release). Peptides and hormones will be measured by RIA. Prepro-mRNAs for neuropeptides and their receptors, and for leptin receptors will be measured by in situ hybridization technique. NPY and NT receptor activities will be assessed by ligand-binding assay. These studies will further our understanding of leptin signaling in the hypothalamus in relation to feeding, and therefore will be relevant to the development of therapeutic approaches to eating disorders.

这个项目的目标是了解食物摄入量和体重调节的神经生物学基础。瘦素是脂肪细胞中肥胖基因的产物，是最重要的外周饱腹感因子之一，通过作用于大脑来抑制食物摄入和体重。由于肥胖的人类和通过饮食控制而变得肥胖的小鼠循环中的瘦素水平升高，但保持正常的食物摄入量，因此人们认为肥胖者对内源性瘦素相对不敏感。在啮齿动物中，长期输注瘦素会对瘦素的饱腹感产生抵抗。下丘脑对瘦素的饱腹感产生抵抗的机制尚不清楚。这个问题将在一只长期注射瘦素的大鼠身上得到解决。一个简单的假设是，模型促食欲素神经肽Y(NPY)和厌食性神经降压素(NT)肽的分泌和作用的变化是抵抗瘦素的饱腹感作用的基础。将实现以下具体目标。具体目的1：确定弓状核(ARC)-室旁核(PVN)途径NPY分泌减少(合成和释放)和/或NT分泌增加是否可以解释急性瘦素引起的摄食量减少；以及对NPY和NT作用的反应性改变是否也参与其中；具体目的2：确定作为瘦素急性作用基础的NPY和NT的分泌和作用变化是否随着瘦素的慢性暴露而逆转，并导致对瘦素饱腹感的抵抗；具体目的3：确定瘦素引起的急性吞噬功能低下和对瘦素的饱足作用产生抵抗的过程中瘦素受体活性和基因表达的变化；具体目的4：描述NPY和NT系统的活性逆转以及瘦素受体功能的逆转，这些逆转可能与长期停用瘦素后的吞噬亢进和随后恢复到对照状态有关。多肽神经分泌将通过评估合成潜力(信使核糖核酸)、释放的有效性(肽含量)和产量(体内和体外释放)来评估。多肽和激素将通过放射免疫法进行测定。神经肽及其受体和瘦素受体的前原mRNAs将通过原位杂交技术进行检测。NPY和NT受体活性将通过配体结合试验进行评估。这些研究将进一步加深我们对下丘脑中瘦素信号与进食的关系的理解，因此将与饮食障碍治疗方法的发展相关。