Central Serotonergic Pathways Regulating Energy Balance

调节能量平衡的中枢血清素通路

• 批准号: 7031554
• 负责人: Lora K Heisler
• 金额: $ 17.41万
• 依托单位: UNIVERSITY OF CAMBRIDGE
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7031554
• 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of people in the United States for weight loss, frequently in combination with the sympathomimetic phentermine, but was withdrawn from clinical use in 1997 by the Food and Drug Administration due to reports of adverse cardiopulmonary events.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于预防和治疗肥胖和II型糖尿病至关重要。增加了中央5-羟色胺活性（5-羟基丙胺，5-HT）活性的药物已被广泛用作食欲抑制剂。但是，这些药物通常会引起不必要的副作用，因为它们瞄准了多个5-HT途径和受体。一个值得注意的例子是D-fenfluramine（D-fen），一种阻断5-HT并刺激其释放的药物。在1990年代中期，D-Fen在美国的数百万人中开了数百万人，以减轻体重，通常与交感神经芬特明相结合，但由于据报道，食品和药物管理局在1997年被撤回了临床用途。该提案的目的是描述中枢神经系统（CNS）途径，通过这些途径，诸如D-FEN等药物有选择地介导了其对食物摄入的影响。我们有强大的初步数据，表明这些药物通过参与黑色素皮质素途径对能量稳态产生影响。这些中央黑色皮质素途径通过黑色素皮质素-4受体（MC4-RS）对与能量平衡相关的代谢激素，神经内分泌和行为参数具有有效的影响。在此提案中，我们将通过必要的下游激活MC4-RS评估5-HT药物是否有选择地影响能量稳态。我们提出了一种血清素能药物作用机制的模型，其中特定的血清素能受体的激活增加了内源性MC4-R激动剂α-甲状腺细胞刺激激素（Alpha-MSH）的释放，并抑制内源性拮抗剂Agoti相关肽（Agrp）的释放。我们将确定5-羟色胺饮食药物是否需要下游MC4-RS发挥作用。我们提供一系列的行为，生理，遗传和电生理实验，以测试模型的组成部分。该提案产生的数据不仅有可能描述调节能量稳态的两种关键途径之间的相互作用，而且还可以确定一个有希望的且非常有选择性的目标，以预防和治疗肥胖症和II型糖尿病。