Changes in CSF Biomarkers after Bariatric Surgery

减肥手术后脑脊液生物标志物的变化

• 批准号: 10460460
• 负责人: Judith Korner
• 金额: $ 49.8万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10460460
• 关键词: ART protein; Address; Affect; Biochemical; Biological Markers; Body Weight decreased; Body mass index; Brain; Cerebrospinal Fluid; Cortisone; Data; Development; Diet; Dopamine; FGF19 gene; Gastrectomy; Gastric Bypass; Goals; Hormonal; Hormones; Human; Hydrocortisone; Intervention; Lead; Leptin; Liquid substance; Measurement; Measures; Mediating; Metabolic; Metabolism; Methods; Neuraxis; Neurons; Neuropeptides; Neurotransmitters; Obesity; Operative Surgical Procedures; Opioid; Pathway interactions; Pattern; Peptides; Peripheral; Plasma; Play; Pro-Opiomelanocortin; Process; Proteins; Proteomics; Rewards; Role; Serotonin; Signal Transduction; System; Testing; Therapeutic; antagonist; bariatric surgery; beta-Endorphin; brain pathway; effective therapy; energy balance; feeding; ghrelin; glucagon-like peptide 1; hormonal signals; hypothalamic-pituitary-adrenal axis; innovation; leptin receptor; monoamine; mu opioid receptors; neurotransmission; new therapeutic target; novel; obese person; obesity treatment; prohormone; response

Project Summary/Abstract The long-term objective of this proposal is to understand why bariatric surgery is such an effective treatment for obesity and its associated metabolic complications. Peripheral metabolic signals communicate levels of energy stores to the brain and elicit a host of neuronal responses that maintain energy balance; such regulatory mechanisms make it difficult to maintain diet-induced weight loss. The goal is to understand how these central regulatory mechanisms are circumvented following surgical alterations in the gut. Human studies have been limited by the lack of rigorous diet-induced weight loss controls and lack of biochemical measurements reflecting central brain pathways. This proposal will focus on key brain pathways hypothesized to mediate the effects of surgery on energy balance as well on identifying new pathways in subjects after Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (SG) compared to carefully matched dietinduced weight loss controls. The innovation is in the use of cerebrospinal fluid (CSF) neuropeptide, hormone and protein measurements as a surrogate for changes in brain activity. In addition to studying neuropeptides (melanocortin, opioid), hormones (leptin and gut hormones) and neurotransmitters (dopamine and serotonin) that have been implicated in this process, proteomic analysis will be used to uncover new biomarkers that are unique to surgical weight loss. Our preliminary proteomic data have identified a pattern of changes in CSF that occurs after diet-induced weight loss and forms the basis for determining how this pattern is altered after surgery. An important focus will be on the melanocortin system consisting of the proopiomelanocortin (POMC)derived MSH peptides and the MSH antagonist, agouti related protein (AgRP), that plays a critical role in regulating energy balance and in responding to weight loss and is impacted by leptin and gut hormones. CSF levels of the POMC prohormone can serve as a marker of central POMC activity and we have shown striking correlations of CSF POMC with BMI and leptin. CSF POMC and AgRP levels decrease and increase respectively following diet-induced weight loss; plasma AgRP also increases. Given the effects of RYGB and SG on gut hormone levels, we will measure ghrelin, GLP- 1, PYY and FGF19, as they can all affect melanocortin activity and metabolism. CSF leptin and soluble leptin receptor will also be measured to assess effects on leptin transport into brain. Another focus will be on the HPA axis which has bidirectional interactions with the brain melanocortin system. Our data show that CSF cortisol increases after weight loss. Our hypothesis is that distinct biochemical changes will occur in CSF after diet- induced weight loss and this pattern will be altered after RYBG and SG; CSF proteomic analysis will validate changes expected to occur in known pathways as well as identify new pathways responsible for the dramatic effects of bariatric surgery. Understanding the mechanisms through which surgery produces long-term weight loss is highly significant and paramount to developing new drug targets and filling the therapeutic void in the treatment of obesity.

项目摘要/摘要 该提议的长期目标是了解为什么减肥手术是如此有效的治疗方法 肥胖及其相关的代谢并发症。外围代谢信号传达能量水平 将大脑存储并引起一系列维持能量平衡的神经元反应；这样的监管 机制使保持饮食引起的体重减轻变得困难。目标是了解这些中心 肠道手术改变后，调节机制是规避的。人类研究已经 由于缺乏严格饮食引起的减肥控制和缺乏反映生化测量的限制 中央大脑通路。该建议将着重于假设的关键大脑通道，以调解 能量平衡手术以及识别roux-en-y胃旁路后受试者的新途径 （RYGB）和垂直套筒胃切除术（SG）与精心匹配的饮食诱导的减肥控制相比。 创新是在使用脑脊液（CSF）神经肽，激素和蛋白质测量 大脑活动变化的替代物。除了研究神经肽（黑色素皮质，阿片类药物），激素外 （瘦素和肠激素）和神经递质（多巴胺和5-羟色胺）与此有关 过程，蛋白质组学分析将用于揭示手术体重减轻独有的新生物标志物。我们的 初步的蛋白质组学数据已经确定了CSF的变化模式，该模式发生在饮食引起的体重减轻后发生 并构成了确定手术后如何改变这种模式的基础。一个重要的重点将放在 黑色皮质素系统由proOpiomelanocortin（POMC）衍生的MSH肽和MSH组成 拮抗剂，Agouti相关蛋白（AGRP），在调节能量平衡和响应中起着至关重要的作用 减肥，并受到瘦素和肠激素的影响。 POMC激素的CSF水平可以用作 中央POMC活性的标志物，我们显示了CSF POMC与BMI和瘦素的惊人相关性。 饮食引起的体重减轻后，CSF POMC和AGRP水平分别降低和增加；等离子体 AGRP也增加。鉴于RYGB和SG对肠道激素水平的影响，我们将测量GLP- 1，PYY和FGF19，因为它们都会影响黑色素质素的活性和代谢。 CSF瘦素和可溶性瘦素 还将测量受体以评估对瘦素转运到大脑的影响。另一个重点将放在HPA上 轴与脑黑素皮质系统有双向相互作用。我们的数据表明CSF皮质醇 减肥后增加。我们的假设是，饮食后CSF中将发生明显的生化变化。 诱导的体重减轻，这种模式将在RYBG和SG之后改变； CSF蛋白质组学分析将验证 预期发生的变化将发生在已知的途径中，并确定负责戏剧性的新途径 减肥手术的影响。了解手术产生长期体重的机制 损失非常重要，对于开发新药物靶标和填充治疗空隙至关重要 肥胖的治疗。