Changes in CSF Biomarkers after Bariatric Surgery

项目摘要/摘要 这项建议的长期目标是了解为什么减肥手术是一种如此有效的治疗 肥胖及其相关的代谢并发症。外周代谢信号传递能量水平 储存到大脑，并引发一系列神经元反应，维持能量平衡；这种调节 这种机制使得维持饮食诱导的减肥变得困难。我们的目标是了解这些中心 在肠道手术改变后，调节机制被绕过。人类研究一直是 受限于缺乏严格的饮食诱导的减肥控制，以及缺乏反映 中枢大脑通路。这项提议将重点放在关键的大脑通路上，这些通路被假设为调节 能量平衡手术在Roux-en-Y胃旁路术后发现新通路中的作用 (RYGB)和垂直袖状胃切除术(SG)与精心匹配的饮食诱导减肥对照组进行比较。 创新之处在于使用脑脊液神经肽、激素和蛋白质的测量作为 大脑活动变化的替代者。除了研究神经肽(黑素皮质素、阿片类药物)、激素 (瘦素和胃肠激素)和神经递质(多巴胺和5-羟色胺)与此有关 在这个过程中，蛋白质组学分析将被用来发现手术减肥独有的新生物标记物。我们的 初步的蛋白质组学数据已经确定了饮食诱导减肥后脑脊液的一种变化模式 并形成了确定手术后这种模式如何改变的基础。一个重要的焦点将是 由前阿片黑素皮质素(POMC)衍生的MSH多肽和MSH组成的黑素皮质素系统 拮抗剂，刺鼠相关蛋白(AgRP)，在调节能量平衡和反应中发挥关键作用 瘦素和胃肠激素的影响。脑脊液中POMC前激素水平可以作为 脑脊液POMC与BMI、Leptin呈显著正相关。 饮食减肥后脑脊液POMC和AgRP水平分别降低和升高；血浆 AgRP也增加。鉴于RYGB和SG对胃肠激素水平的影响，我们将测定Ghrelin、GLP- 1、PYY和FGF19，因为它们都能影响黑素皮质素的活性和代谢。脑脊液瘦素与可溶性瘦素 还将测量受体以评估对瘦素进入大脑的影响。另一个重点将是HPA 与大脑黑素皮质素系统有双向相互作用的轴。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，饮食后脑脊液会发生明显的生化变化- 诱导体重减轻，这种模式将在RYBG和SG后改变；脑脊液蛋白质组分析将验证 预计将在已知途径中发生变化，并确定导致戏剧性变化的新途径 减肥手术的效果。了解手术产生长期体重的机制 损失是非常重要的，对于开发新的药物靶点和填补治疗空白至关重要 肥胖的治疗。

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.