CSF Neuropeptide, Hormonal and Metabolomic Analysis in Human Energy Balance

脑脊液神经肽、人体能量平衡中的激素和代谢组学分析

• 批准号: 8335397
• 负责人: Sharon L. Wardlaw
• 金额: $ 34.8万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8335397
• 关键词: ART protein; Acute; Alzheimer' s Disease; Amino Acids; Animals; Biological Assay; Biological Markers; Blood; Body Weight; Body Weight decreased; Brain; Brain region; Bupropion; Catheters; Cerebrospinal Fluid; Corticotropin; Data; Desire for food; Diet; Drug Combinations; Endorphins; Fasting; Fatty Acids; Female; Goals; Hormonal; Hormones; Human; Hypothalamic structure; Individual; Insulin; Leptin; Leptin resistance; Lipids; Measurement; Measures; Metabolic; Methods; Naltrexone; Neurons; Neuropeptides; Nutrient; Obesity; Overweight; Pathway interactions; Pattern; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Physiology; Plasma; Play; Pro-Opiomelanocortin; Process; Regulation; Rodent; Role; Sampling; Signal Transduction; System; Testing; Weight; Weight-Loss Drugs; energy balance; feeding; human subject; leptin receptor; male; melanocortin receptor; metabolomics; prohormone; response

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand how peripheral metabolic signals, including leptin, insulin and ingested nutrients, interact with brain neuropeptides to maintain energy balance in the human. The Aims focus on the brain melanocortin system which plays a critical role in maintaining energy balance and is regulated by leptin, insulin and nutrients. The physiology of this system, consisting of the proopiomelanocortin (POMC)-derived MSH peptides, the MSH antagonist, agouti related protein (AgRP) and the brain melanocortin receptors, has been well studied in rodents but such studies are not possible in humans unless reliable markers of brain POMC and AgRP activity can be found. This proposal will focus on cerebrospinal fluid (CSF) POMC and AgRP measurements as a surrogate for hypothalamic melanocortin activity, as related to CSF leptin, insulin and nutrient levels. Recent studies in the rodent show that levels of the intact POMC prohormone in CSF reflect hypothalamic POMC activity. We have confirmed that the POMC prohormone is the predominant POMC peptide in human CSF and present preliminary data relating CSF POMC to BMI and adiposity. Our data support a hypothesized primary role for POMC in regulating body weight. CSF POMC, POMC-derived peptides and AgRP levels will be measured in healthy lean and obese human subjects at baseline and in response to fasting and re-feeding and diet-induced weight loss. POMC and AgRP peptide processing will be characterized in parallel, as processing can be regulated by feeding. Plasma leptin and transport into CSF will be studied in relation to soluble leptin receptor levels and as a function of adiposity and feeding; CSF insulin will be studied in parallel and correlations of CSF POMC and AgRP with plasma and CSF leptin and insulin will be determined. Since nutrients themselves interact with melanocortin neurons, CSF metabolomic analysis will be performed with an emphasis on amino acid and lipid species. Finally, there is evidence that the new weight loss drug combination of bupropion plus naltrexone stimulates the melanocortin pathway in animals. Effects of these drugs on melanocortin peptide release into human CSF will therefore be studied. This would be the first study to examine CSF leptin, insulin and nutrient levels in relation to BMI and appropriate target neuropeptides and should provide unique data about the regulation of human energy balance. An important goal is to identify biomarkers in CSF that could predict responses to dieting and to pharmacotherapy for obesity that target the melanocortin system.

描述（由申请人提供）：该提案的长期目标是了解外周代谢信号（包括瘦素、胰岛素和摄入的营养物质）如何与大脑神经肽相互作用以维持人体能量平衡。目标集中于大脑黑皮质素系统，该系统在维持能量平衡中发挥着关键作用，并受到瘦素、胰岛素和营养素的调节。该系统由阿片黑皮质素原 (POMC) 衍生的 MSH 肽、MSH 拮抗剂、刺豚鼠相关蛋白 (AgRP) 和大脑黑皮质素受体组成，其生理学已在啮齿类动物中进行了充分研究，但除非可靠，否则此类研究不可能在人类中进行。可以找到大脑 POMC 和 AgRP 活性的标记。该提案将重点关注脑脊液 (CSF) POMC 和 AgRP 测量，作为下丘脑黑皮质素活性的替代指标，与 CSF 瘦素、胰岛素和营养水平相关。最近对啮齿动物的研究表明，脑脊液中完整 POMC 激素原的水平反映了下丘脑 POMC 活性。我们已经证实 POMC 激素原是人脑脊液中主要的 POMC 肽，并提供了将 CSF POMC 与 BMI 和肥胖相关的初步数据。我们的数据支持假设的 POMC 在调节体重方面的主要作用。将测量健康瘦和肥胖人类受试者的基线 CSF POMC、POMC 衍生肽和 AgRP 水平，以及对禁食和重新喂养以及饮食引起的体重减轻的反应。 POMC 和 AgRP 肽加工将并行进行表征，因为加工可以通过补料进行调节。将研究血浆瘦素及其向脑脊液的转运与可溶性瘦素受体水平的关系以及肥胖和进食的函数；将同时研究 CSF 胰岛素，并确定 CSF POMC 和 AgRP 与血浆、CSF 瘦素和胰岛素的相关性。由于营养物质本身与黑皮质素神经元相互作用，因此脑脊液代谢组学分析将重点关注氨基酸和脂质种类。最后，有证据表明安非他酮和纳曲酮的新型减肥药物组合可以刺激动物的黑皮质素途径。因此，将研究这些药物对黑皮质素肽释放到人脑脊液中的影响。这将是第一项检查脑脊液瘦素、胰岛素和营养水平与 BMI 和适当目标神经肽相关的研究，并应提供有关人体能量平衡调节的独特数据。一个重要的目标是确定脑脊液中的生物标志物，这些生物标志物可以预测对针对黑皮质素系统的节食和肥胖药物治疗的反应。