Central Serotonergic Pathways Regulating Energy Balance

描述（由申请人提供）：阐明能量稳态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-hydroxytryptamine，5-HT）活性的药物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，因为它们靶向多种5-HT途径和受体。一个值得注意的例子是d-芬氟拉明（d-Fen），一种阻止5-HT再摄取并刺激其释放的药物。在20世纪90年代中期，在美国，d-芬被处方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年被食品和药物管理局从临床使用中撤回。本提案的目的是描述中枢神经系统（CNS）途径，通过这些途径，药物如d-Fen选择性地介导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皮质素途径对能量稳态发挥作用。这些通过黑皮质素-4受体（MC 4-Rs）的中枢黑皮质素途径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强效作用。在这个提议中，我们将评估5-HT药物是否通过必要的下游激活MC 4-Rs选择性地影响能量稳态。我们提出了一个模型的肾上腺素能药物的作用机制，其中特定的肾上腺素能受体的激活增加释放的内源性MC 4-R激动剂α-黑素细胞刺激激素（α-MSH），并抑制释放的内源性拮抗剂肾上腺素相关肽（AgRP）。我们将确定血清素饮食药物是否需要功能性下游MC 4-R才能发挥其作用。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的模型组件。从这一建议产生的数据不仅有可能描绘两个关键途径之间的相互作用调节能量稳态，但也确定了一个有前途的和非常有选择性的目标，预防和治疗肥胖症和II型糖尿病。

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people in the United States for weight loss, frequently in combination with the sympathomimetic phentermine, but was withdrawn from clinical use in 1997 by the Food and Drug Administration due to reports of adverse cardiopulmonary events.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