Hypothalamic Regulation of Energy Homeostasis

描述：(申请人提供)这项建议的长期目标是了解神经肽如何在大脑中相互作用来调节能量 动态平衡。瘦素和胰岛素都将能量储存的水平传递给 大脑和下丘脑中激活的神经肽中心 食欲和体重。这项提案将重点放在黑素皮质素 神经肽系统是瘦素的一个重要靶点 下丘脑。研究将集中在前阿片黑素皮质素的调节上 (POMC)和POMC标记的多肽-α-MSH、γ-MSH和β-EP一起 与新发现的刺鼠相关蛋白(AGRP)，它是在 下丘脑，是MSH多肽的有效拮抗剂。A-MSH抑制 摄食和AGRP是一种食欲肽，它能拮抗 α-MSH作用于特定的黑素皮质素受体。尽管Lepthi已经被证明 刺激下丘脑POMC基因的表达，对此我们一无所知 瘦素对POMC多肽加工和释放的影响。这是一个重要的 考虑因素，因为POMC被加工成许多不同的多肽 生物活动。对AGRP的调控知之甚少。 与食欲素缺乏症在同一神经元中共表达的下丘脑 多肽NPY。几个目标将集中在POMC、AGRP和NPY的调节上 瘦素和胰岛素对大鼠的影响及其与POMC的相互作用 AgRP神经元本身都表达黑素皮质素受体。神经肽 基因表达将通过敏感的溶液杂交分析进行研究； 多肽的水平和加工将通过凝胶过滤、高效液相色谱法和Well进行研究。 特征化的RIA；多肽释放将在经过良好验证的 体外灌流系统。第三个目标将集中在瘦素的作用和 POMC多肽对下丘脑-垂体-肾上腺(HPA)的调节 轴，它在能量平衡中起着关键作用，并且与 瘦素缺乏动物的肥胖综合征。一个重要的假设是 测试表明，α-MSH和β-EP抑制HPA反应并调节 瘦素对HPA轴的抑制作用。在最终的目标中， 将在转基因小鼠中研究Alpha-MSH的过度表达 能量平衡、神经肽基因表达和HPA反应。的确有 越来越多的证据表明，POMC在人类能量平衡中发挥了作用。肥胖 最近报道了患有P0 MG和黑素皮质素受体的患者 突变。啮齿动物体内P0-MG调控和加工的研究 因此应该对食物摄入量和体重的调节产生影响 在人类身上。

DESCRIPTION: (provided by applicant) The long-term objective of this proposal is to understand how neuropeptides interact in the brain to regulate energy homeostasis. Both leptin and insulin signal the level of energy stores to the brain and activate neuropeptide centers in the hypothalamus which modulate appetite and body weight. This proposal will focus on the melanocortin neuropeptide system which is an important target for leptin in the hypothalamus. Studies will center on the regulation of proopiomelanocortin (POMC) and the POMC-denved peptides, alpha-MSH, gamma-MSH and beta-EP, together with the newly discovered agouti related protein (AGRP) which is synthesized in the hypothalamus and is a potent antagonist of the MSH peptides. a-MSH inhibits feeding and AGRP is an orexigemc peptide which antagonizes the actions of alpha-MSH at specific melanocortin receptors. Although lepthi has been shown to stimulate POMC gene expression in the hypothalamus, nothing is known about the effects of leptin on POMC peptide processing and release. This is an important consideration because POMC is processed to a number of peptides with different biological activities. Little is known about the regulation of AGRP in the hypothalamus which is coexpressed in the same neurons with the orexigenic peptide NPY. Several Aims will focus on the regulation of POMC, AGRP and NPY in the rat by both leptin and insulin and on interactions between the POMC and AGRP neurons themselves which both express melanocortin receptors. Neuropeptide gene expression will be studied by sensitive solution hybridization assays; peptide levels and processing will be studied by gel filtration, HPLC and well characterized RIAs; peptide release will be studied in a well validated in vitro perifusion system. The third Aim will focus on the role of leptin and the POMC peptides in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis, which plays a key role in energy homeostasis, and is intricately related to the obesity syndromes in leptin deficient animals. A major hypothesis to be tested is that alpha-MSH and beta-EP inhibit the HPA response and mediate inhibitory effects of leptin on the HPA axis. In the final Aim, the effects of alpha-MSH overexpression in transgenic mice will be studied with respect to energy homeostasis, neuropeptide gene expression and HPA responses. There is growing evidence that POMC plays a role in human energy homeostasis. Obesity has recently been reported in patients with P0MG and melanocortin receptor mutations. Our proposed studies of P0MG regulation and processing in the rodent should thus have implications for the regulation of food intake and body weight in the human.