Mechanisms of Bile Acid Signaling and Metabolism following Gastric Bypass

描述(申请人提供)：肥胖和糖尿病被认为是新的世界性流行病。众所周知，Roux-en-Y胃旁路手术(RYGB)是治疗肥胖症及其相关的2型糖尿病最有效的方法。有趣的是，RYGB的改善在减肥之前就开始了，这些影响的机制尚不清楚。我们实验室最近的研究发现，胆汁酸是代谢改善的重要原因。我们的实验室已经成功地建立了与人类相似的RYGB小鼠模型。为了了解胆汁酸在RYGB新陈代谢改善中的潜在作用，我们创建了一个新的小鼠模型，使胆汁酸能够在不改变胃的解剖结构的情况下转移到小肠的不同部分。我们的初步研究表明，胆汁回肠分流比RYGB能更好地减肥和防止高脂饮食引起的肥胖。这些发现表明，胆汁酸可能是RYGB治疗后改善肥胖和治愈糖尿病的主要信号。这项建议将研究胆汁分流如何改变胆汁酸代谢/动力学和信号的分子机制，以产生比RYGB更有效和更持久的体重减轻和对饮食诱导的肥胖的抵抗。这项工作可能会确定新的抗糖尿病和抗肥胖药物靶点，但更重要的是可以确定更简单但更有效的肥胖和糖尿病手术治疗方法。

DESCRIPTION (provided by applicant): Obesity and diabetes are considered the new worldwide epidemics. It is well accepted that Roux-en-Y gastric bypass (RYGB) surgery is the most effective treatment for obesity and the associated type 2 diabetes. Interestingly, the improvements following RYGB start occurring before weight loss, and the mechanism for these effects is unknown. Recent findings in our laboratory have identified bile acids to be responsible for a significant portion of such metabolic improvements. Our laboratory has been successful in establishing mouse models of RYGB similar to those performed in humans. In an attempt to understand the potential role of bile acids in the metabolic improvements seen with RYGB, we have created a new mouse model that enables diversion of bile acids to various segments of the small intestine without altering the anatomy of the stomach. Our preliminary studies show that biliary diversion to the ileum produces better weight loss and protection from high fat diet-induced obesity than RYGB. These findings suggest that bile acids may be a major signal leading to amelioration of obesity and cure of diabetes after RYGB. This proposal will examine the molecular mechanisms of how bile acid metabolism/kinetics and signaling are altered by biliary diversion to produce more effective and sustained weight loss and resistance to diet- induced obesity compared to RYGB. This work may identify new anti-diabetes and anti-obesity drug targets, but more importantly could identify simpler but more effective surgical treatments for obesity and diabetes.