ANATOMIC AND PHYSIOLOGIC CHARACTERIZATION OF MCH ACTION

MCH 作用的解剖学和生理学特征

• 批准号: 2906216
• 负责人: ELEFTHERIA MARATOS-FLIER
• 金额: $ 31.25万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2906216
• 关键词: appetite regulatory center; biological signal transduction; enzyme induction /repression; fos protein; gene targeting; genetically modified animals; hormone receptor; hormone regulation /control mechanism; laboratory mouse; leptin; melanins; melanocyte stimulating hormone; neuropeptide receptor; neuropeptides; nutrient intake activity; nutrition related tag; obesity; phosphatidylinositol 3 kinase; polymerase chain reaction; stereotaxic techniques

DESCRIPTION (Adapted from the applicant's abstract): Obesity is a serious illness with a complex etiology and a major risk factor for type II diabetes. Although obesity is common, the causes of obesity are poorly understood. A number of peripheral hormones and central neuropeptides have been implicated in the pathogenesis of obesity. Using PCR-differential display, we recently discovered that the mRNA in the neuropeptide melanin- concentrating hormone (MCH) is increased in the hypothalamus of ob/ob mice. In addition, MCH mRNA levels are regulated by fasting. To confirm that MCH is also increased and functions as an orexigenic factor, rats were injected with MCH-treated analogs through cannulas placed in the lateral ventricle in both normal and ob/ob animals. MCH induces an acute and profound increase in chow consumption. MCH also interacts with the melanocortin system. In fish, MCH induces melanosome aggregation while MSH induces dispersion. In mammals, the two peptides are antagonistic on a number of behaviors, and we have found that MCH and MSH act as mutual antagonists in a feeding paradigm. Unlike agouti, another inhibitor of MSH, MCH does not act on any of the known melanocortin receptors. MCH neurons, which are localized to the lateral hypothalamus project diffusely throughout the brain. Little is known about which specific areas of the brain parenchyma may be important in mediation MCH action. Virtually nothing is known about the MCH receptor, or about MCH-mediated signal transduction. Our preliminary data in scales from the common carp indicate that MCH does not act through cAMP or cGMP, but that it stimulates PI 3- kinase activity. The investigators propose to analyze the neuroanatomical basis of MCH action by performing functional and mapping studies, and we will couple these studies with analysis aimed at understanding the mechanism of its physiological action. Finally, we will analyze the effect of MCH gene ablation in a MCH knockout mouse.

描述（改编自申请人的摘要）：肥胖是一种严重的疾病 病因复杂且是 II 型主要危险因素的疾病 糖尿病。肥胖虽然很常见，但引起肥胖的原因却很少 明白了。许多外周激素和中枢神经肽具有 与肥胖的发病机制有关。使用 PCR 差异 显示，我们最近发现神经肽黑色素中的 mRNA- ob/ob 下丘脑的浓缩激素 (MCH) 增加 老鼠。此外，MCH mRNA 水平受禁食调节。确认 大鼠的 MCH 也增加并起到食欲促进因素的作用 通过放置在 正常动物和 ob/ob 动物的侧脑室。 MCH 诱发急性 以及食物消费量的大幅增加。 MCH 还与 黑皮质素系统。在鱼类中，MCH 诱导黑素体聚集，而 MSH 引起分散。在哺乳动物中，这两种肽在 行为的数量，我们发现 MCH 和 MSH 是相互的 喂养范式中的拮抗剂。与agouti不同的是，另一种抑制剂 MSH、MCH 不作用于任何已知的黑皮质素受体。妇幼保健院 位于下丘脑外侧的神经元广泛投射 整个大脑。对于哪些特定领域知之甚少 脑实质可能在调节 MCH 作用中发挥重要作用。几乎 关于 MCH 受体或 MCH 介导的信号一无所知 转导。我们对鲤鱼鳞片的初步数据表明 MCH 不通过 cAMP 或 cGMP 起作用，但它刺激 PI 3- 激酶活性。研究人员建议分析神经解剖学 通过进行功能和绘图研究作为 MCH 行动的基础，我们 将把这些研究与旨在了解 其生理作用机制。最后我们来分析一下效果 MCH 基因敲除小鼠中的 MCH 基因消融。