Investigation of the role of hypothalamic Y1 receptors in obesity

肥胖在世界范围内的患病率令人担忧，并且是2型糖尿病等疾病的主要危险因素。虽然体重超重的人减肥的好处是无可争议的，但目前还没有有效的长期治疗肥胖的方法。因此，对肥胖的药物干预可以显著减轻这种疾病的负担。人们对肥胖治疗方法的发展非常感兴趣，这种治疗方法可以阻止大脑中被认为会导致食物摄入增加和身体脂肪增加的蛋白质的活动，比如神经肽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身体脂肪的区域。然而，Y1受体在调节下丘脑体重中的真正作用目前尚不清楚，因为没有已知的药理学工具可以特异性地阻断或激活该受体以证明其功能。为了解决这个问题，我们开发了转基因小鼠，使我们能够从成年小鼠的下丘脑特异性地删除Y1受体，从而确定其在调节体重中的作用。该项目将证明下丘脑Y1受体缺失是否可以长期减少小鼠的食物摄入量和体脂，以及是否可以引起其他可能有助于降低体脂的代谢变化。我们还将证明，小鼠中由高脂肪饮食、应激激素皮质酮过量或基因突变引起的肥胖，是否可以通过删除下丘脑Y1受体来预防或逆转。这一结果将有助于决定开发专门阻断下丘脑Y1受体的药物是否对人类肥胖的长期治疗有重大益处。肥胖是由多种遗传和环境因素引起的。

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.