GLP-1 Effects in Water and Salt Intake

项目概述：糖尿病在美国是一种日益严重的流行病。针对胰高血糖素的药物- 如肽-1（GLP-1）或其受体（GLP-1 R）用于治疗2型糖尿病。此外 GLP-1类似物降低了食物摄入，这与已证实的糖尿病治疗效果不同。效果 由于糖尿病和肥胖之间存在明确的联系，因此对食物摄入量的影响是有希望的。更 然而，最近的研究表明GLP-1 R激动剂也会减少水的摄入。这是特别 与某些糖尿病和脱水高风险患者人群相关。在 例如，老年人糖尿病的发病率是老年人的两倍多。 脱水是常见的，在老年人中尤其成问题。因此，在本发明中， 了解GLP-1如何影响液体摄入对于指导治疗决策并帮助导致 治疗糖尿病和减轻体重的未来疗法，同时预防任何并发症 与液体摄入量减少有关我们实验室的研究表明，GLP-1可以在大脑中起作用， 抑制液体摄入，但仍不清楚内源性GLP-1是否正常参与了 调节液体摄入量。本提案中的研究旨在测试工作模型， GLP-1确实在控制液体摄入方面发挥作用，更具体地说，是通过作用于 作为一个饱足的信号。该提案描述了测试以下具体目标的实验：1） GLP-1或GLP-1 R的敲低增加饮酒行为，这种作用在男性和女性中是否相同？ 雌鼠？2)体液稳态的挑战对GLP-1表达细胞有什么影响？ 中枢神经系统，特别是孤束核（NTS）？3)挑战的影响是什么？ 对NTS投射目标的体液稳态？这些实验使用多种方法 包括病毒介导的敲除、基因表达的测量、体内微透析 光遗传学和精细的行为分析，以测试液体摄入量，神经活动，基因 GLP-1的表达和释放。这些研究将提高我们对控制 液体摄入量，并可能通过提高我们对肽的理解， 发散动作（例如，用作激素和神经调节剂）。从翻译的角度来看， 实验将为糖尿病患者提供更深入的治疗选择， 可以揭示关于与能量平衡有关的共病障碍之间的联系的信息（例如， 肥胖）和与体液平衡有关的疾病（例如，高血压）。

Project Summary: Diabetes is a growing epidemic in the United States. Drugs that target glucagon- like peptide-1 (GLP-1) or its receptor (GLP-1R) are used to treat type 2 diabetes mellitus. In addition to the demonstrated therapeutic efficacy for diabetes, GLP-1 analogs decrease food intake. The effect on food intake is promising because of the clear association between diabetes and obesity. More recent studies, however, show that GLP-1R agonists also decrease water intake. This is particularly relevant for certain patient populations that are at high risk for both diabetes and dehydration. In older adults, for example, the incidence of diabetes is more than two times greater than it is in younger adults and dehydration is common and particularly problematic in the elderly. As such, knowing how GLP-1 affects fluid intake is essential to inform treatment decisions and help lead to future therapies that treat diabetes and reduce body weight, while preventing any complications related to decreased fluid intake. Studies from our laboratory suggest that GLP-1 can act in the brain to suppress fluid intake, but it remains unknown if endogenous GLP-1 is normally involved in the regulation of fluid intake. The studies in this proposal are designed to test the working model that GLP-1 does, indeed, play a role in the control of fluid intake and, more specifically, does so by acting as a satiety signal. The proposal describes experiments that test the following Specific Aims: 1) Does knockdown of GLP-1 or GLP-1R increase drinking behavior and is this effect the same in male and female rats? 2) What effect do challenges to body fluid homeostasis have on GLP-1-expressing cells in the CNS, particularly in the nucleus of the solitary tract (NTS)? 3) What is the effect of challenges to body fluid homeostasis on targets of NTS projections? These experiments use multiple approaches including viral-mediated knockdown, measures of gene expression, in vivo microdialysis, optogenetics, and refined analysis of behavior to test for changes in fluid intake, neural activity, gene expression, and release of GLP-1. These studies will improve our understanding of the control of fluid intake and could have a broader impact by improving our understanding of peptides that have divergent actions (e.g., used as hormone and neuromodulator). From a translational perspective, the experiments will provide greater insight regarding treatment options for patients with diabetes and could reveal information about the link between co-morbid disorders related to energy balance (e.g., obesity) and disorders related to fluid balance (e.g., hypertension).