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的能量平衡。Aims重点关注大脑黑素皮质素系统，该系统在维持能量平衡方面起着关键作用，并受瘦素、胰岛素和营养物质的调节。该系统的生理学，包括proopiomelanocortin （POMC）衍生的MSH肽，MSH拮抗剂，agouti相关蛋白（AgRP）和脑黑素皮质素受体，已经在啮齿动物中得到了很好的研究，但除非能找到可靠的脑POMC和AgRP活性标记，否则不可能在人类中进行此类研究。该提案将侧重于脑脊液（CSF） POMC和AgRP测量作为下丘脑黑素皮质素活性的替代品，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，脑脊液中完整的POMC原激素水平反映下丘脑POMC活性。我们已经证实，POMC原激素是人类脑脊液中主要的POMC肽，并提供了脑脊液POMC与BMI和肥胖有关的初步数据。我们的数据支持POMC在调节体重中起主要作用的假设。将在健康的瘦肉和肥胖受试者中测量脑脊液POMC、POMC衍生肽和AgRP水平，这些受试者在基线时以及在禁食、再喂养和饮食引起的体重减轻时进行测量。POMC和AgRP肽的加工将是平行的，因为加工可以通过饲喂来调节。将研究血浆瘦素和转运到脑脊液中与可溶性瘦素受体水平的关系以及作为肥胖和喂养的功能；将并行研究脑脊液胰岛素，并测定脑脊液POMC和AgRP与血浆和脑脊液瘦素和胰岛素的相关性。由于营养物质本身与黑素皮质素神经元相互作用，因此脑脊液代谢组学分析将重点放在氨基酸和脂质种类上。最后，有证据表明，新的减肥药安非他酮加纳曲酮的组合刺激动物的黑素皮质素途径。因此，这些药物对黑素皮质素肽释放到人脑脊液的影响将被研究。这将是首次研究脑脊液瘦素、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脑脊液中的生物标志物，这些生物标志物可以预测针对黑素皮质素系统的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.