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

肥胖、糖尿病和高血压等合并症给患者带来了严重的健康负担，并给公共资源带来了压力。可能有益于治疗这些疾病的有前途的药物是胰高血糖素样肽1（GLP-1）类似物。GLP-1是一种在饭后从肠道分泌的激素。它也在大脑中产生。它的主要作用是改善糖的消化，并产生饱腹感或饱腹感。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类似物是否激活大脑GLP-1系统。在脑干中发现了产生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，从这些脑干细胞释放的GLP-1介导饱腹感效应，对血糖控制的一些有益作用，以及尚不清楚的其他功能，如心血管控制，高血压的发展，恶心和呕吐，以及学习和记忆。该研究将阐明GLP-1神经元在这些效应中的确切作用，从而验证其作为治疗代谢性疾病的药物靶点的重要性。我们将使用基因治疗方法，将新基因递送到大脑特定区域的GLP-1细胞。这些基因将产生允许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（或增加）的蛋白质。通过测量抑制或增加特定GLP-1表达细胞的活性对血糖控制、食物摄入和行为的影响，我们将能够梳理出GLP-1表达中枢神经元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。这些数据将进一步深入了解基于GLP-1的治疗的临床益处，可能不仅适用于糖尿病患者，而且更普遍地适用于代谢疾病。此外，它还将提供有关不良副作用（如恶心）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制剂，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.