Central Serotonergic Pathways Regulating Energy Balance

描述(由申请人提供)：阐明能量平衡的基本神经生物学在预防和治疗肥胖症和II型糖尿病中至关重要。增加中枢5-羟色胺(5-羟色胺，5-羟色胺)活性的药物已被广泛用作食欲抑制药。然而，这些药物往往会引起不想要的副作用，因为它们针对多个5-羟色胺途径和受体。一个值得注意的例子是d-芬氟拉明(d-Fen)，这是一种阻止5-羟色胺再摄取并刺激其释放的药物。20世纪90年代中期，S在美国给数以百万计的人开了d-Fen用于减肥，经常与交感神经类似物联合使用，但由于不良心肺事件的报告，美国食品和药物管理局于1997年停止临床使用。这项建议的目的是描绘中枢神经系统(CNS)途径，通过这些途径，d-Fen等药物选择性地调节其对食物摄入量的影响。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来发挥其对能量稳态的影响。这些中枢黑素皮质素途径，通过黑素皮质素-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产生强有力的影响。在这项提案中，我们将评估5-羟色胺药物是否通过必要的下游激活MC4-Rs来选择性地影响能量平衡。我们提出了一个5-羟色胺能药物作用机制的模型，在这个模型中，特定的5-羟色胺能受体的激活增加了内源性MC4-R激动剂α-黑素细胞刺激素(α-MSH)的释放，并抑制了内源性拮抗剂刺鼠相关肽(AgRP)的释放。我们将确定5-羟色胺能减肥药是否需要功能下游的MC4-R才能发挥作用。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件。这一提议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，而且还有可能确定一个有希望的、非常有选择性的预防和治疗肥胖症和II型糖尿病的目标。

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of people in the United States for weight loss, frequently in combination with the sympathomimetic phentermine, but was withdrawn from clinical use in 1997 by the Food and Drug Administration due to reports of adverse cardiopulmonary events.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.