AC5 Inhibitor for Obesity

描述(申请人提供)：这项提案的目标是开发一种治疗肥胖症和糖尿病并提高运动耐量的药物。肥胖、糖尿病和运动有着千丝万缕的联系，因此，一种可以提高运动耐量、预防肥胖或糖尿病发展的药物很可能在这三种情况下都起到治疗作用。肥胖是一种全球流行病，它会促进糖尿病，是一个主要的心血管风险因素，导致预期寿命减少。肥胖和糖尿病可由饮食、行为和遗传因素引起。这两种疾病都是一个公共卫生问题，找到一种新的治疗方法将是一大进步。最近，我们报道了一种新的基因工程小鼠模型，其中腺酰环化酶(AC)5型亚型被敲除(AC5KO)。AC5失活导致寿命延长，并对应激具有保护作用。此外，AC5KO小鼠比WT小鼠吃得更多，但体重更轻，这表明抑制AC5可能是一种新的减肥方法。AC5 KO小鼠也表现出更强的运动耐力。与此同时，我们已经开发出一种药理上的AC5抑制剂，它也可以预防心血管应激。这个试点项目的主要假设是，抑制小鼠的AC5可以防止肥胖。我们的三个工作假设是：A.抑制AC5将减少高脂饮食小鼠的肥胖，B.抑制AC5将防止胰岛素抵抗和糖尿病的发展，以及C.抑制AC5将改善这些小鼠的运动耐量。鉴于肥胖和糖尿病在美国人口中的重要性，这个项目对健康有很大的好处。 公共卫生相关性：肥胖是一种全球流行病，它会促进糖尿病，是一个主要的心血管风险因素，导致预期寿命减少。肥胖和糖尿病可由饮食、行为和遗传因素引起；已确定有几个基因与肥胖的发展有关。这两种疾病都是一个公共卫生问题，找到一种新的治疗方法将是一大进步。

DESCRIPTION (provided by applicant): The goal of this proposal is to develop a drug that will be therapeutic for obesity and diabetes and improve exercise tolerance. Obesity, diabetes and exercise are inextricably linked such that an agent that improves exercise tolerance or prevents obesity or the development of diabetes will likely have a therapeutic role in all three conditions. Obesity is a global epidemic, which promotes diabetes and is a major cardiovascular risk factor, resulting in reduced life expectancy. Obesity and diabetes can be caused by dietary, behavioral and genetic factors. Both diseases are a public health problem and finding a novel therapeutic approach would be a major advance. Recently, we reported a novel, genetically engineered mouse model, where the adenylyl cyclase (AC) type 5 isoform is knocked out (AC5 KO). AC5 inactivation resulted in increased longevity and was protective against stress. Furthermore, the AC5 KO mice ate more than WT mice, but weighed less, suggesting that AC5 inhibition could be a novel approach to weight loss. The AC5 KO mouse also demonstrates enhanced exercise tolerance. Concurrently, we have developed a pharmacological AC5 inhibitor which also protects against cardiovascular stress. The main hypothesis of this pilot project is that inhibition of AC5 in mice protects against obesity. Our three working hypotheses are: A. Inhibition of AC5 will reduce obesity in mice fed a high fat diet, and B. Inhibition of AC5 will protect against the development of insulin resistance and diabetes, and C. Inhibition of AC5 will improve exercise tolerance in those mice. In view of the significance of obesity and diabetes in the US population, there is a major health benefit to this project. PUBLIC HEALTH RELEVANCE: Obesity is a global epidemic, which promotes diabetes and is a major cardiovascular risk factor, resulting in reduced life expectancy. Obesity and diabetes can be caused by dietary, behavioral and genetic factors; several genes have been identified to be involved in the development of obesity. Both diseases are a public health problem and finding a novel therapeutic approach would be a major advance.