Role of Leptin Signaling in the Central Nervous System

描述：（由申请人提供）本提案旨在调查 瘦素受体（LEPR）在脑区的作用涉及的调节 的能量平衡，并表征微妙的表型效应， 部分瘦素受体下调。瘦素缺陷小鼠（ob/ob） 过度进食和肥胖，这是一种通过给予 瘦素LEPR的信号形式（LEPR-B）在细胞中高度表达。 下丘脑和LEPR-B（db/db）缺陷的小鼠同样肥胖，但 对瘦素没有反应。在LEPR缺陷杂合子小鼠中的几项研究 (db/+）表明LEPR水平降低引起部分表型 易患代谢失调该提案的具体目标是 评估前脑神经元对体重调节的贡献， 肥胖，并测试假设，基因剂量的LEPR在前脑 决定了肥胖表型的严重程度。在特定目标1中， 将表征前脑神经元中缺失的LEPR（Lepr null），以评估 瘦素信号对体重调节的作用。具体目标 2，LEPR-B将在前脑神经元中过表达， 四环素应答启动子（Tet-LEPR）拯救肥胖表型 LEPR缺陷小鼠。在特异性目的3中，LEPR-B表达将可逆地 在Tet-LEPR小鼠中抑制，以建立Lepr基因的剂量-反应曲线 剂量及其对几种代谢参数的影响。原位杂交 LEPR和调节体重的下丘脑肽（NPY、AGEP、POMC和 除了行为测试外，还将进行CART）。这些研究将 有助于我们进一步了解大脑LEPR信号和 LEPR表型杂合性。

DESCRIPTION: (Provided By Applicant) This proposal is designed to investigate the role of leptin receptor (LEPR) in brain areas implicated in the regulation of energy balance, and to characterize the subtler phenotypic effects of partial leptin receptor downregulatlon. Leptin-deficient mice (ob/ob) are hyperphagic and obese, a syndrome that is corrected by administration of leptin. The signaling form of LEPR (LEPR-B) is highly expressed in the hypothalamus, and mice deficient in LEPR-B (db/db) are likewise obese but are not leptin responsive. Several studies in mice heterozygous for LEPR deficiency (db/+) suggest that reduced levels of LEPR elicit a partial phenotype predisposed to metabolic dysregulation. The specific goals of this proposal are to assess the contribution of forebrain neurons to body weight regulation and adiposity, and to test the hypothesis that gene dosage of LEPR in the forebrain determines the severity of the obese phenotype. In Specific Aim 1, mice with LEPR deleted in forebrain neurons (Lepr null) will be characterized to assess the contribution of leptin signaling to body weight regulation. In Specific Aim 2, LEPR-B will be overexpressed in forebrain neurons using a tetracycline-responsive promoter (Tet-LEPR) to rescue the obese phenotype of LEPR-deficient mice. In Specific Aim 3, LEPR-B expression will be reversibly suppressed in Tet-LEPR mice to establish a dose-response curve for Lepr gene dosage and its impact on several metabolic parameters. In situ hybridization of LEPR and hypothalamic peptides that regulate body weight (NPY, AGEP, POMC and CART) will be performed in addition to behavioral tests. These studies will help to advance our understanding of brain LEPR signaling and the effects of LEPR heterozygosity on phenotype.