CSF Neuropeptide, Hormonal and Metabolomic Analysis in Human Energy

项目摘要/摘要 这项建议的核心是饮食和药物诱导的人类受试者减肥。节食的成功可能是 通过药物治疗增强，但有相当大的个体差异，没有办法预测 谁会对特定的药物有良好的反应。该提案的总体目标是验证符合以下条件的生物标志物 可以用来预测对给定减肥药的反应，并表征反调节 对可能限制疗效的药物治疗的反应。研究将集中在减肥药氯卡瑟林和 下丘脑黑素皮质素(MC)系统，包括前阿片黑素皮质素(POMC)来源的MSH多肽， MSH拮抗剂、刺鼠相关蛋白(AgRP)和脑MC-R是中枢神经系统的关键介质。 对减肥的反应。氯酪蛋白是一种5-羟色胺(5HT2cR)激动剂，主要通过激活POMC起作用 神经元和黑素皮质素信号。在前一个资助期内，我们发现 脑脊液中POMC前激素可作为中枢性POMC活性的标志物； 血浆AgRP测定也已成为脑内AgRP活性的潜在生物标志物。海流 提案将研究氯酪蛋白和安慰剂对这些生物标记物和喂养的急性(1周)影响。 对实验室测试餐的反应，作为对氯酪蛋白的长期(24周)反应的预测因子。 可能限制氯卡韦林治疗有效性的反监管机制也将是 特点是集中在下丘脑-垂体-肾上腺(HPA)轴和AgRP水平的变化。这个 5HT2cR在CRH神经元上表达，可介导氯酪蛋白对HPA轴的刺激作用； 皮质醇的增加可以减轻氯酪蛋白诱导的体重减轻。HPA活动将使用以下方法进行评估 测定血浆、唾液、尿液和脑脊液。最终目标将描述HPA之间的相互作用 Axis和AgRP神经元(表达糖皮质激素受体)，并将检验AgRP的假设 调节糖皮质激素对体重和新陈代谢的一些影响。将进行研究 短期(1wk)使用氢化可的松。试餐期间食物摄入量的变化将是 根据皮质醇和AgRP的变化进行评估。脑脊液中皮质醇与AgRP的关系及临床意义 还将研究血浆及其昼夜节律。生化标记物(脑脊液和血浆)的验证 神经肽)和行为标记物(摄食反应)可以预测药物疗效 开始治疗时的药物选择。此外，了解反监管反应 发展对减肥和药物治疗的反应可能导致提高药物疗效的干预措施。

Project Summary/Abstract This proposal centers on diet and drug induced weight loss in human subjects. The success of dieting can be enhanced by pharmacotherapy but there is considerable individual variability and there is no way to predict who will respond well to a particular drug. The overall objectives of this proposal are to validate biomarkers that can be used to predict responses to a given weight loss medication and to characterize counterregulatory responses to drug therapy that may limit efficacy. Studies will focus on the weight loss drug, lorcaserin, and the hypothalamic melanocortin (MC) system, including the proopiomelanocortin (POMC)-derived MSH peptides, the MSH antagonist, agouti related protein (AgRP) and brain MC-Rs, which are key mediators of the central response to weight loss. Lorcaserin is a serotonin (5HT2cR) agonist that works primarily by activation of POMC neurons and melanocortin signaling. During the previous funding period we have found that measurements of the POMC prohormone in cerebrospinal fluid (CSF) can serve as a marker of central POMC activity in humans; plasma AgRP measurements have also emerged as a potential biomarker of brain AgRP activity. The current proposal will study the acute (1 wk) effects of lorcaserin vs placebo on these biomarkers and on feeding behavior, in response to a laboratory test meal, as predictors of the longer-term (24-wk) response to lorcaserin. Counterregulatory mechanisms that may limit the effectiveness of lorcaserin treatment will also be characterized with a focus on the hypothalamic-pituitary-adrenal (HPA) axis and changes in AgRP levels. The 5HT2cR is expressed on CRH neurons and can mediate stimulatory effects of lorcaserin on the HPA axis; increases in cortisol could attenuate lorcaserin-induced weight loss. HPA activity will be assessed using plasma, salivary, urine and CSF measurements. The final Aim will characterize interactions between the HPA axis and AgRP neurons (which express glucocorticoid receptors) and will test the hypothesis that AgRP mediates some of the effects of glucocorticoids on body weight and metabolism. Studies will be performed during short-term (1 wk) administration of hydrocortisone. Changes in food intake during a test meal will be assessed in relation to changes in cortisol and AgRP. The relationship between cortisol and AgRP in CSF and plasma and their diurnal rhythms will also be studied. The validation of biochemical markers (CSF and plasma neuropeptides) and behavioral markers (feeding response) that are predictive of drug efficacy would facilitate the choice of drug when initiating therapy. Furthermore understanding the counterregulatory responses that develop in response to weight loss and drug therapy could lead to interventions that improve drug efficacy.