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

描述（由申请人提供）：拟研究的重点是神经肽胰高血糖素样肽-1 （GLP-1）及其在控制食物摄入和体重中的作用。fda批准用于治疗II型糖尿病（T2DM）的GLP-1受体（GLP-1R）激动剂可改善血糖调节，此外，在人类和动物模型中均可显著减少食物摄入量和体重。因此，最近人们开始关注长效GLP-1R激动剂作为肥胖的潜在治疗方法。然而，值得注意的是，虽然恶心和/或呕吐是约20-50%的服用GLP-1R激动剂的T2DM患者的主要不良事件（即副作用），但对恶心/不适的机制的研究很少，而且几乎没有人了解恶心/不适与GLP-1R介导的食物摄入抑制的关系。本研究将探讨GLP-1R激活后胃肠道和中枢神经系统（CNS）结构介导恶心/不适的潜在机制，包括：b[1]迷走神经传入和中枢神经系统神经元表达的GLP-1Rs在GLP-1R激动剂介导恶心/不适和食物摄入抑制中的作用；胃肠道机制介导GLP-1R激动剂的恶心/不适反应。提出的整体研究将为开发glp - 1r介导的治疗方法提供框架，减少恶心/呕吐的发生率，可用于更多的肥胖人群。此外，结果可能有助于确定联合药物治疗的潜在靶点，以改善目前fda批准的GLP-1R配体的不适副作用。

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.