Changes in CSF Biomarkers after Bariatric Surgery

项目概要/摘要 这项建议的长期目标是了解为什么减肥手术是一种有效的治疗方法， 肥胖及其相关的代谢并发症。外周代谢信号传达能量水平 储存到大脑并引起维持能量平衡的许多神经元反应;这种调节性的反应是神经元反应。 这些机制使得难以维持饮食诱导的体重减轻。我们的目标是了解这些中央 肠道的外科手术改变后，调节机制被规避。人体研究 由于缺乏严格的饮食引起的体重减轻控制和缺乏反映 中枢脑通路这项建议将集中在假设的关键大脑通路，以介导的影响， Roux-en-Y胃旁路术后受试者的能量平衡以及识别新途径的手术 （RYGB）和垂直袖状胃切除术（SG）与仔细匹配的饮食诱导的体重减轻对照进行比较。 创新之处在于使用脑脊液（CSF）神经肽、激素和蛋白质测量， 大脑活动变化的替代品除了研究神经肽（黑皮质素，阿片类），激素 （瘦素和肠道激素）和神经递质（多巴胺和血清素）， 在这一过程中，蛋白质组学分析将用于发现手术减肥所特有的新生物标志物。我们 初步的蛋白质组学数据已经确定了饮食诱导的体重减轻后发生的CSF变化模式 并形成了确定这种模式在手术后如何改变的基础。一个重要的重点将是 由阿黑皮素原（POMC）衍生的MSH肽和MSH肽组成的黑皮质素系统 拮抗剂，agglutinase相关蛋白（AgRP），在调节能量平衡和响应 体重减轻，并受到瘦素和肠道激素的影响。CSF中POMC激素原的水平可以作为 中枢POMC活性的标志物，并且我们已经显示CSF POMC与BMI和瘦素的显著相关性。 CSF POMC和AgRP水平在饮食诱导的体重减轻后分别降低和升高;血浆 AgRP也在增加。考虑到RYGB和SG对肠道激素水平的影响，我们将测量胃饥饿素、GLP-1和GSH-I。 1、PYY和FGF19，因为它们都可以影响黑皮质素活性和代谢。脑脊液瘦素和可溶性瘦素 还将测量瘦素受体以评估对瘦素转运入脑的影响。另一个重点将是自置居所津贴 与大脑黑皮质素系统双向相互作用的轴。我们的数据显示脑脊液皮质醇 体重减轻后增加。我们的假设是，饮食后CSF会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后改变; CSF蛋白质组学分析将验证 预期在已知途径中发生的变化，以及确定新的途径， 减肥手术的效果。了解手术产生长期体重的机制 损失对于开发新的药物靶点和填补治疗空白是非常重要的。 治疗肥胖症。

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.