Central Serotonergic Pathways Regulating Energy Balance

调节能量平衡的中枢血清素通路

• 批准号: 6676662
• 负责人: Lora K Heisler
• 金额: $ 19.3万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6676662
• 关键词: bioenergetics; biological signal transduction; body composition; body weight; eating; electrophysiology; fenfluramine; genetically modified animals; homeostasis; hypothalamus; laboratory mouse; melanocyte stimulating hormone; neuropeptide receptor; neuropharmacology; neuroregulation; noninsulin dependent diabetes mellitus; obesity; pharmacokinetics; receptor expression; respiratory function; serotonin; serotonin receptor

DESCRIPTION (provided by applicant): Elucidating the basic neurobiology of energy homeostasis is paramount in the prevention and treatment of obesity and type II diabetes. Drugs that increase the activity of central serotonin (5-hydroxytryptamine, 5-HT) have been widely used as appetite suppressants. However, these drugs often elicit unwanted side effects because they target multiple 5-HT pathways and receptors. A notable example is d-fenfluramine (d-Fen), a drug that blocks the reuptake of 5-HT and stimulates its release. In the mid-1990's, d-Fen was prescribed to millions of people in the United States for weight loss, frequently in combination with the sympathomimetic phentermine, but was withdrawn from clinical use in 1997 by the Food and Drug Administration due to reports of adverse cardiopulmonary events. The purpose of this proposal is to delineate the central nervous system (CNS) pathways through which drugs such as d-Fen selectively mediate their effects on food intake. We have strong preliminary data indicating that these drugs exert their effect on energy homeostasis by engaging melanocortin pathways. These central melanocortin pathways, through the melanocortin-4 receptors (MC4-Rs), have potent effects on metabolic-hormonal, neuroendocrine, and behavioral parameters associated with energy balance. In this proposal, we will assess whether 5-HT drugs selectively affect energy homeostasis through a necessary downstream activation of MC4-Rs. We propose a model of the mechanism of serotonergic drug action in which activation of specific serotonergic receptors increases the release of the endogenous MC4-R agonist alpha-melanocyte stimulating hormone (alpha-MSH) and inhibits the release of the endogenous antagonist agouti related peptide (AgRP). We will determine whether serotonergic diet drugs require functional downstream MC4-Rs to exert their effect. We offer a series of behavioral, physiological, genetic, and electrophysiological experiments to test components of our model. Data generated from this proposal have the potential to not only delineate the interaction between two key pathways regulating energy homeostasis, but to also identify a promising and very selective target for the prevention and treatment of obesity and type II diabetes.

描述（由申请人提供）：阐明能量稳态的基本神经生物学对预防和治疗肥胖和II型糖尿病至关重要。提高中枢血清素（5-羟色胺，5-HT）活性的药物已被广泛用作食欲抑制剂。然而，这些药物通常会引起不必要的副作用，因为它们针对多种5-羟色胺途径和受体。一个显著的例子是d-芬氟拉明（d-Fen），一种阻断5-羟色胺再吸收并刺激其释放的药物。在20世纪90年代中期，d-Fen在美国被开给数百万人用于减肥，经常与拟交感神经药物芬特明联合使用，但由于不良心肺事件的报道，1997年美国食品和药物管理局（Food and Drug Administration）停止了临床使用。这项提议的目的是描绘中枢神经系统（CNS）的途径，通过药物，如d-Fen选择性调节其对食物摄入的影响。我们有强有力的初步数据表明，这些药物通过参与黑素皮质素途径发挥其对能量稳态的影响。这些黑素皮质素中枢通路通过黑素皮质素-4受体（MC4-Rs），对代谢激素、神经内分泌和与能量平衡相关的行为参数有强有力的影响。在本提案中，我们将评估5-HT药物是否通过必要的MC4-Rs下游激活选择性地影响能量稳态。我们提出了一个5 -羟色胺能药物作用机制的模型，其中特定5 -羟色胺能受体的激活增加内源性MC4-R激动剂α -黑素细胞刺激激素（α - msh）的释放，并抑制内源性拮抗剂agouti相关肽（AgRP）的释放。我们将确定血清素能减肥药是否需要功能性下游MC4-Rs来发挥其作用。我们提供了一系列的行为、生理、遗传和电生理实验来测试我们模型的组成部分。该提案产生的数据不仅有可能描述调节能量稳态的两个关键途径之间的相互作用，而且还可能确定预防和治疗肥胖和II型糖尿病的有前途的和非常有选择性的靶点。