Neural mechanism of glucagon-like-peptide-1 receptor-mediated nausea /malaise

描述(申请人提供)：建议的研究重点是神经肽类胰高血糖素-1(GLP-1)及其在控制食物摄入量和体重方面的作用。FDA批准的GLP-1受体(GLP-1R)激动剂用于治疗II型糖尿病(T2 DM)可以改善血糖调节，此外，在人类和动物模型中都能显著减少食物摄入量和体重。因此，长效GLP-1R激动剂作为一种潜在的治疗肥胖症的药物最近受到了关注。然而，值得注意的是，虽然恶心和/或呕吐是报告的主要不良事件(即副作用)，约20%-50%的T2 DM患者服用GLP-1R激动剂，但对介导恶心/恶心的机制的研究很少，而且几乎不了解恶心/恶心与GLP-1R介导的食物摄入抑制有关的重要性。在这项提议中的实验将通过检查：[1)迷走神经传入和中枢神经系统神经元上表达的GLP-1RS在介导GLP-1R激动剂的恶心/不适和食物摄入抑制中的作用，来研究GLP-1R激动剂激活后介导恶心/不适的潜在机制和胃肠和中枢神经系统(CNS)结构；[2]介导GLP-1R激动剂的恶心/不适反应的胃肠机制。拟议的整体研究将为开发GLP-1R介导的治疗方法提供一个框架，减少恶心/呕吐的发生率，可供更多的肥胖者使用。此外，结果可能有助于确定联合药物治疗的潜在靶点，以缓解目前FDA批准的GLP-1R配体的不适副作用。 与公共健康相关：基础科学发现已经确定了特定的大脑化学系统，这些系统可以在受到刺激时减少食物的摄入。虽然目前还没有针对肥胖的药物治疗，但针对激素胰高血糖素样肽-1(GLP-1)的药物很有希望，因为它们服用后食物摄入量受到抑制。不幸的是，恶心和/或呕吐是这些GLP-1药物的主要副作用，因此本提案旨在确定这些药物调节恶心的潜在机制以及胃肠道和脑结构，为开发减少恶心/呕吐发生率的GLP-1肥胖症治疗提供必要的研究。

DESCRIPTION (provided by applicant): The proposed research focuses on the neuropeptide glucagon-like-peptide-1 (GLP-1) and its role in controlling for food intake and body weight. FDA-approved GLP-1 receptor (GLP-1R) agonists for the treatment of Type II Diabetes Mellitus (T2DM) produce improvements in blood glucose regulation and, in addition, produce meaningful reductions in food intake and body weight in both humans and animal models. Therefore, recent attention has been given to long-acting GLP-1R agonists as a potential treatment for obesity. It is remarkable to note, however, while nausea and/or vomiting are the major adverse events (i.e. side effect) reported in ~20-50% of T2DM patients prescribed GLP-1R agonists there is very little investigation of the mechanisms mediating the nausea/malaise and virtually no understanding of the significance of nausea/malaise in relation to GLP-1R- mediated suppression of food intake. Experiments in this proposal will examine the potential mechanisms and gastrointestinal and central nervous system (CNS) structures mediating the nausea/malaise following GLP-1R activation by examining: [1] the role of GLP-1Rs expressed on vagal afferent and CNS neurons in mediating the nausea/malaise and food intake suppression of GLP-1R agonists; [2] gastrointestinal mechanisms mediating the nausea/malaise response of GLP-1R agonists. The overall research proposed will provide a framework for development of GLP-1R-mediated treatments with reduced incidence of nausea/vomiting that can be used by a greater population of obese individuals. In addition, results may help identify potential targets for combination drug therapy to ameliorate the malaise side effects of current FDA-approved GLP-1R ligands. PUBLIC HEALTH RELEVANCE: Basic science discoveries have identified specific brain chemical systems that can reduce food intake when stimulated. While currently no pharmaceutical treatment for obesity exists, drugs targeting the hormone glucagon-like-peptide-1 (GLP-1) hold promise as food intake is suppressed following their administration. Unfortunately, nausea and/or vomiting are the major side effects of these GLP-1 drugs and therefore this proposal aims to identify the potential mechanisms and gastrointestinal and brain structures mediating the nausea of these drugs, providing necessary research for development of GLP-1 treatments for obesity with reduced incidence of nausea/vomiting.