CSF Neuropeptide, Hormonal and Metabolomic Analysis in Human Energy Balance

描述(申请人提供)：这项建议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，如何与脑神经肽相互作用，以维持人类的能量平衡。目的是研究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。这一系统由前阿片黑素皮质素(POMC)衍生的MSH多肽、MSH拮抗剂、刺鼠相关蛋白(AgRP)和脑黑素皮质素受体组成，在啮齿类动物中已经得到了很好的研究，但在人类中，除非找到可靠的脑POMC和AgRP活性的标记物，否则这类研究是不可能的。这项建议将侧重于脑脊液POMC和AgRP的测量，作为下丘脑黑素皮质素活性的替代指标，与脑脊液瘦素、胰岛素和营养水平有关。最近对啮齿动物的研究表明，脑脊液中完整的POMC前激素水平反映了下丘脑POMC的活性。我们已经证实POMC前激素是人脑脊液中主要的POMC多肽，并提供了脑脊液POMC与体重指数和肥胖相关的初步数据。我们的数据支持假设POMC在调节体重中的主要作用。在健康、瘦和肥胖的受试者中，将测量脑脊液POMC、POMC衍生的多肽和AgRP水平，以应对禁食、再喂养和饮食诱导的体重减轻。POMC和AgRP多肽的加工将是平行的，因为加工可以通过进料进行调节。将研究血浆瘦素和脑脊液转运与可溶性瘦素受体水平的关系，以及作为肥胖和喂养的函数；将并行研究脑脊液胰岛素，并确定脑脊液POMC和AgRP与血浆和脑脊液瘦素和胰岛素的相关性。由于营养素本身与黑素皮质素神经元相互作用，因此将进行脑脊液代谢分析，重点放在氨基酸和脂肪种类上。最后，有证据表明，安非他酮和纳曲酮的新减肥药组合可以刺激动物体内的黑素皮质素途径。因此，我们将研究这些药物对黑素皮质素释放到人脑脊液中的影响。这将是第一次研究脑脊液瘦素、胰岛素和营养水平与体重指数和适当的靶神经肽的关系，并将提供关于调节人类能量平衡的独特数据。一个重要的目标是识别脑脊液中的生物标记物，这些生物标记物可以预测对节食和针对黑素皮质素系统的肥胖症药物治疗的反应。 与公共健康相关：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，控制人类的食欲和保持体重。这项建议将重点放在脑脊液(CSF)神经肽的测量上，作为脑神经肽活性的替代指标，以及脑脊液激素(瘦素和胰岛素)和营养物质的水平，这些激素和营养素已知可以调节动物的脑神经肽活动。这将是第一次研究脑脊液激素和营养水平与体重和肥胖的关系，以及适当的靶神经肽，并应该提供关于人类能量平衡调节的独特数据，并可以确定脑脊液中有助于预测对节食和肥胖症药物治疗反应的生物标记物。

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.