AC5 Inhibitor for Obesity

描述（由申请人提供）：本提案的目标是开发一种治疗肥胖和糖尿病并改善运动耐量的药物。肥胖症、糖尿病和运动密不可分，使得改善运动耐量或预防肥胖症或糖尿病发展的药剂可能在所有三种病症中具有治疗作用。肥胖是一种全球性流行病，它促进糖尿病，是一个主要的心血管危险因素，导致预期寿命缩短。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个重大进展。最近，我们报道了一种新的基因工程小鼠模型，其中腺苷酸环化酶（AC）5型同种型被敲除（AC 5 KO）。AC 5失活导致寿命延长，并对应激具有保护作用。此外，AC 5 KO小鼠比WT小鼠吃得更多，但体重更轻，这表明AC 5抑制可能是一种新的减肥方法。AC 5 KO小鼠还显示出增强的运动耐量。同时，我们开发了一种药理学AC 5抑制剂，也可以防止心血管应激。该试验项目的主要假设是，抑制小鼠中的AC 5可以防止肥胖。我们的三个工作假设是：A。AC 5的抑制将减少喂食高脂肪饮食的小鼠的肥胖，而B. AC 5的抑制将防止胰岛素抵抗和糖尿病的发展，并且C. AC 5的抑制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，该项目具有重大的健康益处。 公共卫生相关性：肥胖是一种全球性流行病，它促进糖尿病，是一个主要的心血管危险因素，导致预期寿命缩短。肥胖和糖尿病可由饮食、行为和遗传因素引起;已确定几个基因参与肥胖的发展。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个重大进展。

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.