LEPTIN ACTION ON HYPOTHALAMIC PEPTIDES GOVERNING FEEDING

这个项目的目标是了解食物摄入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。 由于肥胖的人和通过饮食控制肥胖的小鼠具有升高的循环瘦素水平，但保持正常的食物摄入，因此认为肥胖个体对内源性瘦素相对不敏感。 在啮齿类动物中，长期输注瘦素会产生对瘦素饱腹作用的抵抗。 下丘脑对瘦素的饱腹感作用产生抵抗的机制尚不清楚。 这个问题将在这里解决的慢性瘦素输注大鼠。 一个简单的假设，即模型食欲，神经肽Y（NPY）和厌食，神经降压素（NT），肽的分泌和行动的改变，基础上的阻力瘦素的饱腹感的作用将被测试。 将讨论以下具体目标。 具体目标1：为了确定NPY分泌减少是否弓状核（ARC）-室旁核（PVN）途径中的NT分泌增加和/或合成和释放增加可以解释急性瘦素诱导的食物摄入减少;以及是否也涉及对NPY和NT作用的反应性的变化;具体目的2：确定是否在慢性瘦素暴露下逆转了作为瘦素急性效应基础的NPY和NT的分泌和作用的变化，并导致对瘦素饱腹作用的抗性的发展;具体目的3：确定在由瘦素诱导的急性食欲减退期间和在对瘦素的饱腹作用的抗性的发展期间瘦素受体活性和基因表达的变化;具体目的4：为了描述与摄食过多相关的神经肽Y和神经降压肽系统的活性以及瘦素受体功能的逆转，并随后恢复到正常饮食状态，控制条件下撤出慢性瘦素输注。 将通过评估合成潜力（mRNA）、释放可用性（肽含量）和输出（体内和体外释放）来评价肽神经分泌。 将通过RIA测量肽和激素。 通过原位杂交技术测量神经肽及其受体以及瘦素受体的前原mRNA。 NPY和NT受体活性将通过配体结合试验进行评估。 这些研究将进一步了解下丘脑中与进食相关的瘦素信号传导，因此将与饮食失调治疗方法的开发相关。

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.