How the brain controls food intake: the emerging role of the brain GLP-1 system in energy balance and autonomic control

肥胖、糖尿病和高血压等并存疾病是患者的严重健康负担，也是公共资源的压力。可能对这些疾病的治疗有益的有希望的药物是胰高血糖素样肽1(GLP-1)类似物。GLP-1是一种餐后从肠道分泌的荷尔蒙。它也是在大脑中产生的。它的主要作用是促进糖的消化，并产生饱足感或饱足感。我们项目的目的是提高我们对大脑和肠道GLP-1信号在控制血糖和食物摄入量方面的相对重要性的认识，并澄清已经在临床使用的GLP-1类似物是否激活了大脑GLP-1系统。在脑干中已经发现了产生GLP-1的神经元。这些细胞将神经纤维网络发送到大脑的许多部分，包括下丘脑，这是一个与食欲调节有关的大脑区域。我们假设，正是这些脑干细胞释放的GLP-1介导了饱腹感效应，一些对血糖控制的有益效应，以及更多不太清楚的功能，如心血管控制，高血压，恶心和呕吐，以及学习和记忆。这项拟议的研究将阐明GLP-1神经元在这些效应中的确切作用，从而验证它们作为治疗代谢性疾病的药物靶点的重要性。我们将使用基因疗法的方法，将新基因输送到大脑特定区域的GLP-1细胞。这些基因将产生蛋白质，从而以前所未有的时间和空间分辨率对GLP-1细胞的活性进行细胞特异性抑制(或增强)。通过测量抑制或增加表达GLP-1的特定细胞的活性对血糖控制、食物摄取和行为的影响，我们将能够梳理出表达GLP-1的中枢神经元所发挥的确切生理功能。我们项目的主要目的是提高对外周和中枢GLP-1受体激活之间相互作用的认识。从这项工作中，我们将了解干扰大脑GLP-1的释放是否是治疗肥胖、糖尿病和合并症的重要靶点。这些数据将进一步洞察基于GLP-1的治疗的临床益处，可能不仅适用于糖尿病患者，而且更广泛地适用于代谢性疾病。此外，它将提供有关恶心等不良副作用的原因的信息。由于GLP-1类似物已经上市用于治疗超重患者的2型糖尿病，我们预计该项目的知识将用于药物开发和配方，因此有望在10年内对治疗产生影响。

Obesity, diabetes and co-morbidities, such as hypertension, are a serious health burden for the patient and a strain on public resources. Promising drugs that might be beneficial for the treatment of these conditions are glucagon-like peptide 1 (GLP-1) analogues. GLP-1 is a hormone that is secreted from the gut after a meal. It is also produced in the brain. Its principal role is to improve the digestion of sugars, and to generate the sensation of fullness, or satiety. The aim of our project is to improve our knowledge of the relative importance of the brain and gut GLP-1 signalling in the control of blood sugar and food intake, and to clarify whether GLP-1 analogues, which are already in clinical use, activate the brain GLP-1 system. Neurons that produce GLP-1 have been found in the brainstem. These cells send a network of nerve fibres to many parts of the brain, including the hypothalamus, a brain region implicated in the regulation of appetite. We hypothesise that it is GLP-1 released from these brainstem cells that mediates the satiety effects, some of the beneficial effects on blood glucose control, and further functions that are less well understood, such as in cardiovascular control, developing of hypertension, nausea and vomiting, and learning and memory. The proposed research will clarify the exact role of GLP-1 neurons in these effects and thus validate their importance as a drug target for treatment of metabolic disease.We will use a gene therapy approach where new genes are delivered to GLP-1 cells in specific areas of the brain. These genes will produce proteins allowing cell-specific suppression (or alternatively increases) of the activity of GLP-1 cells with unprecendented temporal and spatial resolution. By measuring the effects of inhibiting or increasing activity of specific GLP-1-expressing cells on blood glucose control, food intake and behaviour, we will be able to tease out the exact physiological function played by GLP-1-expressing central neurons. The primary aim of our project is to improve knowledge on the interaction between peripheral and central GLP-1 receptor activation. From this work we will learn whether interference with brain GLP-1 release is an important target for the treatment of obesity, diabetes and co-morbidities. These data will provide further insight into the clinical benefit of GLP-1-based treatments, possibly not only for patients with diabetes, but more generally in metabolic disease. Furthermore, it will provide information on the cause of undesired side effects such as nausea. Since GLP-1 analogues are already on the market for the treatment of type 2 diabetes in overweight patients, we expect that the knowledge from this project will feed into drug development and formulation, and thus an influence on therapy could be hoped for within 10 years.