CSF Neuropeptide, Hormonal and Metabolomic Analysis in Human Energy Balance

描述（由申请人提供）：本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素）如何与脑神经肽相互作用以维持人体能量平衡。该目标集中于大脑黑皮质素系统，该系统在维持能量平衡中起关键作用，并受瘦素、胰岛素和营养素调节。该系统由阿黑皮素原（POMC）衍生的MSH肽、MSH拮抗剂、聚集蛋白相关蛋白（AgRP）和脑黑皮质素受体组成，在啮齿类动物中进行了充分的研究，但除非能找到脑POMC和AgRP活性的可靠标志物，否则在人类中进行此类研究是不可能的。POMC和AgRP测量作为下丘脑黑皮质素活性的替代，与CSF瘦素、胰岛素和营养水平相关。最近在啮齿类动物中的研究表明，CSF中完整的POMC激素原水平反映了下丘脑POMC活性。我们已经证实POMC激素原是人CSF中主要的POMC肽，并提供了CSF POMC与BMI和肥胖相关的初步数据。我们的数据支持POMC在调节体重中的假设主要作用。将在健康瘦型和肥胖型人类受试者中测量基线时以及响应于禁食和再喂养以及饮食诱导的体重减轻的CSF POMC、POMC衍生肽和AgRP水平。POMC和AgRP肽加工将平行表征，因为加工可以通过进食来调节。将研究血浆瘦素和向CSF中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;将平行研究CSF胰岛素，并确定CSF POMC和AgRP与血浆和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，CSF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，安非他酮加纳洛酮的新减肥药物组合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CSF中的影响。这将是第一个研究CSF瘦素，胰岛素和营养水平与BMI和适当的目标神经肽的关系，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CSF中的生物标志物，这些生物标志物可以预测针对黑皮质素系统的节食和肥胖药物治疗的反应。 公共卫生相关性：该项目的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，以控制食欲和维持人体体重。该提案将重点关注脑脊液（CSF）神经肽测量作为脑神经肽活性的替代品，以及已知调节动物脑神经肽活性的激素（瘦素和胰岛素）和营养素的CSF水平。这将是第一项研究，以检查CSF激素和营养水平与体重和肥胖症和适当的目标神经肽，并应提供有关人类能量平衡的调节的独特数据，并可以确定CSF中的生物标志物，可用于预测对节食和肥胖药物治疗的反应。

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. PUBLIC HEALTH RELEVANCE: The goal of this project is to understand how peripheral metabolic signals, including leptin, insulin and ingested nutrients, interact with brain neuropeptides to control appetite and maintain body weight in the human. This proposal will focus on cerebrospinal fluid (CSF) neuropeptide measurements as a surrogate for brain neuropeptide activity and on CSF levels of hormones (leptin and insulin) and nutrients that are known to regulate brain neuropeptide activity in animals. This would be the first study to examine CSF hormone and nutrient levels in relation to body weight and adiposity and appropriate target neuropeptides and should provide unique data about the regulation of human energy balance and could identify biomarkers in CSF that are useful in predicting responses to dieting and to pharmacotherapy for obesity.