Investigation of the role of hypothalamic Y1 receptors in obesity

肥胖在世界范围内的流行令人震惊，是2型糖尿病等疾病的主要危险因素。尽管超重受试者减肥的好处是毋庸置疑的，但目前还没有有效的长期治疗肥胖症的方法。因此，对肥胖的药物干预可以极大地减轻这种疾病的负担。人们对开发肥胖治疗方法非常感兴趣，以防止大脑中被认为会导致食物摄入量增加和体脂增加的蛋白质的作用，例如神经肽Y及其受体Y1，这两种蛋白质都存在于下丘脑中已知的调节体脂的区域。然而，Y1受体在下丘脑中调节体重的真正作用目前尚不清楚，因为目前还没有已知的药理工具可以特异性地阻断或激活这一受体，以证明其功能。为了绕过这个问题，我们开发了转基因小鼠，使我们能够特异性地从成年小鼠的下丘脑中删除Y1受体，从而确定其在调节体重中的作用。该项目将展示从长远来看，下丘脑Y1受体缺失是否可以减少小鼠的食物摄入量和体脂，以及它是否可以导致其他可能有助于减少体脂的新陈代谢变化。我们还将展示是否可以通过缺失下丘脑Y1受体来预防或逆转由高脂肪饮食、压力荷尔蒙皮质酮过量或小鼠基因突变引起的肥胖。这些结果将有助于决定开发专门阻断下丘脑Y1受体的药物是否对长期治疗由多种遗传和环境因素引起的人类肥胖症有重大好处。

The worldwide prevalence of obesity alarming, and is a major risk factor for diseases such as type 2 diabetes. Although the benefits of weight loss in overweight subjects are undisputed, there currently exists no effective long-term treatment for obesity. Therefore pharmacological interventions for obesity could dramatically reduce the burden of this disease. There is much interest in the development of treatments for obesity that prevent the action of proteins in the brain that are thought to lead to increased food intake and gain of body fat, such as neuropeptide Y and its receptor Y1, both of which are found in the hypothalamus in regions known to regulate body fat. However, the true role of Y1 receptors in regulating body weight in the hypothalamus is currently unclear, since there are no known pharmacological tools that can specifically block or activate this receptor in order to demonstrate its function. To circumvent this problem we have developed genetically modified mice that enable us to specifically delete the Y1 receptor from the hypothalamus of adult mice, and therefore determine its role in regulating body weight. This project will demonstrate whether hypothalamic Y1 receptor deletion can reduce food intake and body fat in mice in the long-term, and whether it can cause other changes in metabolism that might also contribute to reducing body fat. We will also show whether the obesity that results from either a high-fat diet, from an excess of the stress hormone corticosterone, or from genetic mutation in mice, can be prevented or reversed by deletion of hypothalamic Y1 receptors. The results will be instrumental in deciding whether developing medicines that specifically block Y1 receptors in the hypothalamus will be of significant benefit for the long-term treatment of human obesity, which is caused by multiple genetic and environmental factors.