Hypothalamic Regulation of Energy Homeostasis

描述：（由申请人提供）本提案的长期目标 是了解神经肽如何在大脑中相互作用来调节能量 体内平衡瘦素和胰岛素都能向机体发出能量储存水平的信号， 激活下丘脑中的神经肽中心， 食欲和体重。这项提案将重点放在黑皮质素 神经肽系统是瘦素的重要靶点， 下丘脑研究将集中在前阿黑皮素的调节上 （POMC）和POMC-衍生肽，α-MSH，γ-MSH和β-EP，一起 与新发现的AGRP相关蛋白（AGRP）， 是MSH肽的有效拮抗剂。a-MSH抑制 AGRP是一种食欲抑制肽， α-MSH在特定的黑皮质素受体。尽管已经证明瘦体 刺激POMC基因在下丘脑的表达，没有什么是已知的， 瘦素对POMC肽加工和释放的影响。这是一个重要 考虑，因为POMC被加工成许多具有不同 生物活动。关于AGRP在人类中的调节知之甚少。 下丘脑，其在与食欲素相同的神经元中共表达。 肽NPY。几个目标将集中在POMC，AGRP和NPY的调节， 大鼠瘦素和胰岛素和POMC之间的相互作用， AGRP神经元本身都表达黑皮质素受体。神经肽 将通过灵敏的溶液杂交测定来研究基因表达; 肽水平和处理将通过凝胶过滤、HPLC和微孔滤膜进行研究。 特征的RIA;肽释放将在一个经过充分验证的 体外灌流系统第三个目标将集中在瘦素的作用和 POMC肽对下丘脑-垂体-肾上腺（HPA）的调节 轴，在能量稳态中起着关键作用，并且与 瘦素缺乏动物的肥胖综合征。一个主要的假设是 测试的是，α-MSH和β-EP抑制HPA反应并介导 瘦素对HPA轴的抑制作用。在最后的目标中， 将研究转基因小鼠中α-MSH的过表达， 能量稳态、神经肽基因表达和HPA反应。有 越来越多的证据表明POMC在人体能量平衡中起作用。肥胖 最近在P0 MG和黑素皮质素受体患者中报道 突变。我们提出的研究P0 MG的调节和加工在啮齿类动物 因此应该对食物摄入和体重的调节有影响 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.