Dynamic integration of ingestive behaviours and homeostasis by hypothalamo-neurohypophysial system glucagon like peptide 1 receptors

肥胖及其并发症，如糖尿病、高血压和COVID-19，会显著降低一个人的生活质量，并对医疗资源造成巨大压力。当我们吃饭时，我们的肠道和大脑会释放激素来控制我们摄入的食物和液体的量，以防止暴饮暴食。其中一种激素被称为胰高血糖素样肽1（GLP-1），并在食物摄入后从肠细胞释放，但也在大脑中产生和释放。GLP-1的药物类似物已经在临床上用于治疗糖尿病和肥胖症。这项工作计划的目的是获得有关大脑中肠肽信号传导的基础知识，以了解这些药物治疗如何影响大脑功能。为了了解GLP-1在大脑和外周中的作用，必须了解其受体（GLP-1 R）的位置及其功能。GLP-1 R在称为下丘脑的大脑部分中大量表达，特别是称为视上核（SON）的区域，其在局部和从垂体产生并分泌激素精氨酸加压素（AVP）和催产素（OXT）。AVP在外周中最被认可的作用是调节体液和心血管稳态，最近的证据表明其控制血糖。OXT因其在哺乳和分娩中的作用而闻名，在媒体中被称为“爱情荷尔蒙”。OXT还调节肾钠排泄、葡萄糖和胰岛素稳态、胃动力、进食行为、脂质代谢和骨形成，并且在脑内它促进饱腹感。我们发现，缺水和哺乳，刺激，促进AVP和OXT分泌到血液中，显着增加GLP-1受体在SON的表达。为了鉴定靶向SON中受体的GLP-1来源，我们将病毒注射到SON中表达荧光蛋白，以追踪与大脑其他区域的神经元连接。我们将使用荧光标记的探针来识别制造GLP-1并与SON连接的神经元。然后，我们将提供特定的病毒工具，关闭这些细胞，以改变到达SON的GLP-1的供应。在第二系列实验中，我们将减少SON神经元中GLP-1受体的数量，再次使用病毒传递遗传工具来减少SON神经元产生GLP-1受体。然后，我们将在一天中的特定时间给这些大鼠喂食（计划喂养），以研究喂养中的作用。在第三系列实验中，我们将使用最先进的生物传感器研究分离的SON和脑垂体的激素释放。在第四系列实验中，我们将使用一种名为利拉鲁肽的选择性受体激动剂研究GLP-1的药理作用，利拉鲁肽是一种获批用于治疗人类糖尿病和肥胖症的药物。为了填补我们关于利拉鲁肽对人体AVP和OXT释放影响的知识空白，我们旨在进行人体临床试验。在所有动物研究中，我们将测量食物和水的摄入量，激素释放和细胞功能的改变，以更好地了解该受体在SON中介导的与进食有关的生理和药理作用。了解GLP-1受体对于我们了解目前在人类中使用稳定肽类似物治疗糖尿病和肥胖症至关重要。我们的数据将提供有关SON GLP-1受体功能的建议，这些受体可能会影响有严重脱水风险的糖尿病患者的治疗方案。这对老年人来说是一个特别的问题。这些数据可能会告知GLP-1受体治疗的许多不良副作用中的一些，因此，这些发现可能有助于设计和开发新药，用于在特定部位激活受体的更具靶向的方法，从而影响当前的治疗策略。

Obesity and its co-morbidities, such as diabetes, hypertension and COVID-19, can significantly reduce a person's quality of life and place huge pressure on healthcare resources. When we eat a meal our gut and brain release hormones to control the amount of food and fluid we ingest to prevent overeating. One of these hormones is called glucagon-like peptide 1 (GLP-1) and is released from intestinal cells in response to food intake, but also produced and released in the brain. Drug analogues of GLP-1 are already in use in the clinic to treat both diabetes and obesity. The aim of this program of work is to obtain fundamental knowledge about gut peptide signalling in the brain to see how these drug treatments affect brain functions. To understand the actions of GLP-1 in the brain and periphery it is imperative to know where its receptor (GLP-1R) is located and how it functions. The GLP-1R is abundantly expressed in a part of the brain called the hypothalamus, specifically a region called the supraoptic nucleus (SON), which makes and secretes the hormones arginine vasopressin (AVP) and oxytocin (OXT) locally and from the pituitary gland. The most recognised roles of AVP in the periphery are the regulation body fluid and cardiovascular homeostasis and recent evidence suggests the control of blood glucose. OXT is best known for its roles in lactation and parturition and in the media it is known as the "love hormone". OXT also regulates renal sodium excretion, glucose and insulin homeostasis, gastric motility, eating behaviours, lipid metabolism, and bone formation, and within the brain it promotes satiety. We found that water deprivation and lactation, stimuli that that promote AVP and OXT secretion into the bloodstream, dramatically increase the expression of the GLP-1 receptor in the SON. To identify sources of GLP-1 that target receptors in the SON, we will inject viruses into the SON expressing fluorescent proteins to trace neuronal connections with other areas of the brain. We will use fluorescently labelled probes to identify neurones that make GLP-1 and connect with the SON. We will then deliver specific viral tools switch off these cells to alter the supply of GLP-1 reaching the SON. In a second series of experiments, we will reduce the number of GLP-1 receptors in neurones of the SON, again using viruses to deliver genetic tools to decrease production of GLP-1 receptors by SON neurones. We will then feed these rats meals at a specific time of day (schedule-feeding) to investigate roles in feeding. In a third series of experiments, we will investigate hormone release from isolated SONs and pituitary glands using state-of-the-art biosensors. In a fourth series of experiments, we will investigate the pharmacological actions of GLP-1 using a selective receptor agonist called liraglutide, a drug that is approved for diabetes and obesity treatment in humans. To fill a gap in our knowledge about the effect of liraglutide on AVP and OXT release in humans we aim to perform a human clinical trial. In all animal studies we will measure food and water intake, hormone release, and alterations to cell functions, to better understand the physiological and pharmacological roles mediated by this receptor in the SON in relation to feeding. Understanding GLP-1 receptors is essential for our knowledge of current treatments of diabetes and obesity that use stable peptide analogues in humans. Our data will advise about the functions of SON GLP-1 receptors which may influence treatment regimens for patients with diabetes who are at serious risk of dehydration. This is a particular problem for the elderly. This data may inform about some of the many undesired side effects of GLP-1 receptor treatments and as a result, these findings may help with design and development of new drugs for more targeted methods of activating receptors at specific sites, and thus influence current therapeutic strategies.