Hypothalamic Regulation of Energy Homeostasis

下丘脑能量稳态的调节

• 批准号: 6517729
• 负责人: Sharon L. Wardlaw
• 金额: $ 32.7万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-15 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6517729
• 关键词: RNase protection assay; appetite regulatory center; bioenergetics; body weight; brain mapping; cell population study; chemical structure function; dietary control; gene expression; genetically modified animals; high performance liquid chromatography; hormone receptor; hormone regulation /control mechanism; hypothalamic hormones; hypothalamic pituitary adrenal axis; hypothalamus; in situ hybridization; insulin; laboratory rat; leptin; neurons; neuropeptides; nutrition related tag; proopiomelanocortin; radioimmunoassay

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.

描述：（由申请人提供）该提案的长期目标是了解神经肽如何在大脑中相互作用以调节能量 体内平衡。瘦素和胰岛素都向身体发出能量储存水平的信号 大脑并激活下丘脑的神经肽中心，调节 食欲和体重。该提案将重点关注黑皮质素 神经肽系统是瘦素的重要靶点 下丘脑。研究将集中于阿片黑皮质素原的调节 (POMC) 和 POMC 衍生的肽、α-MSH、γ-MSH 和 β-EP 一起 新发现的刺豚鼠相关蛋白（AGRP）是在 下丘脑，是 MSH 肽的有效拮抗剂。 a-MSH 抑制 AGRP 是一种食欲肽，可拮抗 特定黑皮质素受体上的 α-MSH。尽管 lepthi 已被证明 刺激下丘脑 POMC 基因表达，目前尚不清楚 瘦素对 POMC 肽加工和释放的影响。这是一个重要的 考虑因素是因为 POMC 被加工成许多具有不同性质的肽 生物活性。人们对 AGRP 的监管知之甚少 下丘脑与食欲促进剂在相同的神经元中共表达 肽 NPY。几个目标将集中于 POMC、AGRP 和 NPY 的监管 瘦素和胰岛素对大鼠的影响以及 POMC 和胰岛素之间的相互作用 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分析来研究基因表达； 将通过凝胶过滤、HPLC 和井研究肽水平和加工 表征 RIA；肽释放将在经过充分验证的情况下进行研究 体外灌注系统。第三个目标将重点关注瘦素的作用和 POMC 肽在下丘脑-垂体-肾上腺 (HPA) 调节中的作用 轴，在能量稳态中起着关键作用，并且有着复杂的关系 瘦素缺乏动物的肥胖综合症。一个主要假设是 经测试，α-MSH 和 β-EP 抑制 HPA 反应并介导 瘦素对 HPA 轴的抑制作用。在最终目标中，效果 将研究转基因小鼠中 α-MSH 的过度表达 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 在人体能量稳态中发挥着重要作用。肥胖 最近有报道称，患有 P0MG 和黑皮质素受体的患者 突变。我们提出的啮齿动物 P0MG 调节和加工研究 因此应该对食物摄入和体重的调节产生影响 在人类中。