Changes in CSF Biomarkers after Bariatric Surgery

项目概要/摘要 该提案的长期目标是了解为什么减肥手术是一种如此有效的治疗方法 肥胖及其相关的代谢并发症。外周代谢信号传达能量水平 储存到大脑并引发一系列维持能量平衡的神经元反应；这样的监管 机制使得饮食引起的减肥难以维持。目标是了解这些中心是如何 肠道手术改变后，调节机制被规避。人类研究已经 由于缺乏严格的饮食引起的体重减轻控制以及缺乏反映的生化测量结果而受到限制 中枢脑通路。该提案将重点关注假设介导的影响的关键大脑通路 能量平衡手术以及在 Roux-en-Y 胃绕道手术后确定受试者的新途径 （RYGB）和垂直袖状胃切除术（SG）与仔细匹配的饮食诱导减肥对照进行比较。 该创新在于使用脑脊液 (CSF) 神经肽、激素和蛋白质测量作为 大脑活动变化的替代品。除了研究神经肽（黑皮质素、阿片类药物）外，激素 （瘦素和肠道激素）和神经递质（多巴胺和血清素）与此有关 在此过程中，蛋白质组分析将用于发现手术减肥所特有的新生物标志物。我们的 初步的蛋白质组学数据已经确定了饮食引起的减肥后脑脊液发生的变化模式 并构成确定手术后如何改变这种模式的基础。一个重要的重点将是 黑皮质素系统由阿片黑皮质素原 (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发挥关键作用 减肥，并受到瘦素和肠道激素的影响。 CSF 中 POMC 激素原的水平可作为 中枢 POMC 活动的标志物，我们已经表明 CSF POMC 与 BMI 和瘦素具有显着的相关性。 饮食引起的体重减轻后，CSF POMC 和 AgRP 水平分别降低和升高；等离子 AgRP 也会增加。鉴于 RYGB 和 SG 对肠道激素水平的影响，我们将测量 ghrelin、GLP- 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 还将测量受体以评估对瘦素转运到大脑的影响。另一个焦点将是 HPA 与大脑黑皮质素系统具有双向相互作用的轴。我们的数据显示脑脊液皮质醇 减肥后增加。我们的假设是饮食后脑脊液中会发生明显的生化变化 引起体重减轻，这种模式在 RYBG 和 SG 后会改变； 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导致戏剧性变化的新途径 减肥手术的影响。了解手术产生长期体重的机制 损失非常重大，对于开发新的药物靶点和填补治疗空白至关重要 治疗肥胖。

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.