Regulation of gastrointestinal hormone signaling and metabolism by Neuromedin U

摘要 在肥胖症和2型糖尿病（T2 D）中，多激素失调可导致相对的 胰岛素缺乏状态。间接证据最近积累了肠道激素（称为decretin） 抑制胰岛素并增强胰高血糖素输出以促进T2 D。这是该领域的一个根本性进步 将鉴定正常调节胰岛素和胰高血糖素产生的天然激素， 由胰岛细胞分泌。我们最近发现了一种肠内分泌decretin信号通路， 果蝇Drosophila melanogaster受营养物质利用率调节，对脂质、葡萄糖和胰岛素至关重要 平衡我们从体外研究中证明，哺乳动物肽激素神经介肽U（Nmu） 与其同源的G蛋白偶联受体Nmu受体1（NmuR 1）具有相似的功能。恩穆群岛 产生于肠内分泌细胞，集中在胃、十二指肠和回肠。在本提案中，我们 概述了几种新颖的方法来研究配体-受体对Nmu/NmuR 1如何调节 胃肠激素分泌 为了在小鼠和人类中解决这些基本问题，我们提出了具体目标：1。 评估小鼠代谢稳态对肠Nmu的需求。2.解码Nmu信号转导 胰岛中G蛋白和NmuR 1的作用机制。3.确定调节NMU信号传导的机制 人胰岛中 这项建议也是值得注意的技术创新，在每个目标，包括建设多个新的 小鼠品系，以及使用新的ELISA来研究小鼠和人类中的Nmu调节。总的来说，这些 最先进的方法将产生对细胞和分子机制的重大新见解 在生理环境中控制代谢的肠内分泌调节。从根本上说，我们的工作 应该建立相互联系的代谢信号和关键的调控模式， 胃肠激素因此，我们的工作应该有广泛的影响，建议战略诊断， 分层风险，并治疗糖尿病或重要糖尿病前期疾病（如肥胖症）患者亚群 和葡萄糖耐量受损。

ABSTRACT In obesity and type 2 diabetes mellitus (T2D), polyhormonal dysregulation can culminate in a relative insulin-deficient state. Indirect evidence has recently accumulated for an enteric hormone (called a decretin) that suppresses insulin and enhances glucagon output to promote T2D. A fundamental advance for the field would be the identification of native hormones that normally regulate insulin and glucagon production and secretion by pancreatic islet cells. We recently identified an enteroendocrine decretin signaling pathway in the fruit fly Drosophila melanogaster regulated by nutrient availability, and essential for lipid, glucose and insulin balance. We demonstrated from in vitro studies that the mammalian peptide hormone Neuromedin U (Nmu) and its cognate G protein-coupled receptor, Nmu Receptor 1 (NmuR1) have similar functions. Nmu is produced in enteroendocrine cells concentrated in the stomach, duodenum and ileum. In this proposal we outline several original and novel approaches to investigate how the ligand-receptor pair Nmu/NmuR1 regulate gastrointestinal hormone output. To address these fundamental questions in both in mice and humans, we propose Specific Aims to: 1. Assess the requirement for enteric Nmu in mouse metabolic homeostasis. 2. Decode Nmu signal transduction mechanisms by G proteins and NmuR1 in pancreatic islets. 3. Identify mechanisms regulating NMU signaling in human islets This proposal is also notable for technical innovations in each Aim, including construction of multiple novel mouse strains, and use of new ELISAs to investigate Nmu regulation in mice and humans. Collectively, these state-of-the-art approaches will generate major new insights into the cellular and molecular mechanisms controlling enteroendocrine regulation of metabolism in physiological settings. At a fundamental level, our work should establish regulatory paradigms that interconnect metabolic signaling and regulation of crucial gastrointestinal hormones. Thus, our work should have broad impact by suggesting strategies to diagnose, stratify risk, and treat subsets of humans with diabetes mellitus or important pre-diabetic conditions like obesity and impaired glucose tolerance.