Role of Leptin Signaling in the Central Nervous System

描述：(申请人提供)本提案旨在调查 瘦素受体(LEPR)在参与调节的脑区的作用 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)是 过度充血和肥胖，这是一种可以通过服用 瘦素。LEPR的信号形式(LEPR-B)在 下丘脑和LEPR-B缺乏的小鼠(db/db)也同样肥胖，但 而不是瘦素反应。LEPR缺乏症杂合子小鼠的几项研究 (Db/+)提示LEPR水平降低会导致部分表型 易患代谢失调的。这项提议的具体目标是 评估前脑神经元对体重调节和 肥胖症，并检验前脑LEPR基因剂量的假设 决定肥胖表型的严重程度。在特定目标1中，小鼠 前脑神经元中缺失的Lepr(Lepr空)将表征为评估 瘦素信号在体重调节中的作用。以特定的目标 2，LEPR-B将在前脑神经元中过表达 四环素反应启动子(Tet-LEPR)拯救肥胖表型的研究 Lepr缺陷小鼠。在特定目标3中，LEPR-B的表达将是可逆的 在Tet-LEPR小鼠体内抑制建立Lepr基因的剂量-反应曲线 剂量及其对几个代谢参数的影响。原位杂交法 调节体重的Lepr和下丘脑肽(NPY、AGEP、POMC和 除行为测试外，还将执行Cart)。这些研究将 有助于促进我们对大脑LEPR信号和脑内LEPR信号的影响的理解 表型上的LEPR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.