CSF Neuropeptide, Hormonal and Metabolomic Analysis in Human Energy

脑脊液神经肽、人体能量中的激素和代谢组学分析

• 批准号: 9514976
• 负责人: Sharon L. Wardlaw
• 金额: $ 54.47万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9514976
• 关键词: ART protein; Acute; Adrenal Glands; Agonist; Attenuated; Behavioral; Biochemical; Biochemical Markers; Biological Markers; Body Weight; Body Weight decreased; Brain; Brain region; CRH gene; Catheters; Cerebrospinal Fluid; Chronic; Circadian Rhythms; Collaborations; Cortisone; Desire for food; Diet; Eating; Effectiveness; Feeding behaviors; Funding; Glucocorticoid Receptor; Glucocorticoids; Goals; Hormonal; Hormones; Human; Hydrocortisone; Hypothalamic structure; Insulin; Intervention; Laboratories; Lead; Leptin; Long-Term Effects; Measurement; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolism; Neurons; Neuropeptides; Neurosecretory Systems; Obesity; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Physiological; Pituitary Gland; Placebos; Plasma; Play; Prevalence; Pro-Opiomelanocortin; Role; Salivary; Serotonin; Signal Transduction; Sleep; System; Testing; Thinness; Urine; Validation; Weight-Loss Drugs; Work; beta-Endorphin; drug efficacy; energy balance; feeding; glucose tolerance; human subject; hypothalamic-pituitary-adrenal axis; improved; individual patient; individual variation; insulin tolerance; melanocortin receptor; metabolomics; neuronal circuitry; potential biomarker; predicting response; prohormone; receptor; response; success

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.

项目摘要/摘要 该提案以饮食和药物为中心，引起人类受试者的体重减轻。节食的成功可能是 通过药物治疗增强 谁会对特定药物做出良好的反应。该提案的总体目标是验证生物标志物 可用于预测对给定减肥药物的反应，并表征反调节性的反应 对可能限制功效的药物治疗的反应。研究将侧重于减肥药，劳卡森和 下丘脑黑色皮质素（MC）系统，包括proOpiomelanocortin（POMC）衍生的MSH肽， MSH拮抗剂，Agouti相关蛋白（AGRP）和脑MC-RS，它们是中央的关键介体 对减肥的反应。劳卡森是一种5-羟色胺（5HT2CR）激动剂，主要通过POMC的激活作用 神经元和黑色皮质素信号传导。在上一个资金期间，我们发现 脑脊液（CSF）中的POMC激素可以用作人类中央POMC活性的标志。 血浆AGRP测量也已成为脑AGRP活性的潜在生物标志物。电流 提案将研究Lorcaserin vs安慰剂对这些生物标志物和喂养的急性（1周）影响 行为是针对实验室测试粉的响应，作为对劳卡林的长期（24周）反应的预测指标。 可能限制Lorcaserin治疗有效性的反调节机制也将是 以下丘脑 - 垂体 - 肾上腺（HPA）轴和AGRP水平变化为特征。这 5HT2CR在CRH神经元上表达，可以介导Lorcaserin对HPA轴的刺激作用。 皮质醇的增加可能会衰减Lorcaserin诱导的体重减轻。 HPA活动将使用 血浆，唾液，尿液和CSF测量。最终目标将表征HPA之间的相互作用 轴和AGRP神经元（表达糖皮质激素受体），将检验AGRP的假设 介导糖皮质激素对体重和代谢的某些影响。将进行研究 在短期（1周）给药氢化可的松。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。 CSF和CSF中的皮质醇与AGRP之间的关系 还将研究血浆及其昼夜节奏。生化标记的验证（CSF和血浆 神经肽）和行为标记（进食反应）可预测药物疗效 启动治疗时的药物选择。此外，了解反对的反应 响应体重减轻和药物治疗可能会导致提高药物疗效的干预措施。