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: 8505010
• 负责人: Sharon L. Wardlaw
• 金额: $ 33.58万
• 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/8505010
• 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，胰岛素和摄取的营养素）如何与脑神经肽相互作用以维持人的能量平衡。该目的集中于脑黑素皮质系统，该系统在维持能量平衡中起着至关重要的作用，并受瘦素，胰岛素和营养的调节。该系统的生理学由proOpiomelanocortin（POMC）衍生的MSH肽，MSH拮抗剂，AGOUTI相关蛋白（AGRP）和脑黑素性素受体组成，在啮齿动物中已经很好地研究了啮齿动物，但是除非人类的可靠标记脑POMC和AGRP活动，否则无法进行此类研究。该提案将集中于脑脊液（CSF）POMC和AGRP测量，作为下丘脑黑色素性活性的替代物，与CSF瘦素，胰岛素和营养水平有关。啮齿动物的最新研究表明，CSF中完整的POMC激素水平反映了下丘脑POMC活性。我们已经证实，POMC激素是人CSF中主要的POMC肽，并呈现有关CSF POMC与BMI和肥胖的初步数据。我们的数据支持POMC在调节体重中的假设主要作用。 CSF POMC，POMC衍生的肽和AGRP水平将在基线时健康和肥胖的人类受试者中进行测量，并响应禁食，重新喂养以及饮食引起的体重减轻。 POMC和AGRP肽加工将平行表征，因为可以通过进食来调节加工。血浆瘦素和转运为CSF，将与可溶性瘦素受体水平以及肥胖和喂养有关。 CSF胰岛素将与CSF POMC和AGRP与等离子体和CSF瘦素和胰岛素的平行研究。由于营养素本身与黑素性神经元相互作用，因此将对氨基酸和脂质物种进行CSF代谢组分分析。最后，有证据表明，安非他酮和纳曲酮的新型体重药物组合刺激了动物中黑色皮质素的途径。因此，将研究这些药物对黑色皮质素肽释放到人CSF中的影响。这将是第一个研究与BMI和适当靶神经肽有关的CSF瘦素，胰岛素和营养水平的研究，并应提供有关调节人类能量平衡的独特数据。一个重要的目标是鉴定CSF中的生物标志物，这些生物标志物可以预测对靶向黑素皮质素系统的肥胖症对饮食和药物治疗的反应。