Mechanisms of Bile Acid Signaling and Metabolism following Gastric Bypass

描述（由申请人提供）：肥胖和糖尿病被认为是新的全球流行病。众所周知，Roux-en-Y胃旁路术（RYGB）是治疗肥胖和相关2型糖尿病的最有效方法。有趣的是，RYGB后的改善在体重减轻之前开始发生，这些效果的机制尚不清楚。我们实验室最近的发现已经确定胆汁酸是这种代谢改善的重要部分。我们的实验室已经成功地建立了类似于人类的RYGB小鼠模型。为了了解胆汁酸在RYGB代谢改善中的潜在作用，我们创建了一种新的小鼠模型，该模型能够将胆汁酸转移到小肠的各个部分，而不会改变胃的解剖结构。我们的初步研究表明，胆道改道回肠产生更好的减肥和保护高脂肪饮食诱导的肥胖比RYGB。这些发现表明，胆汁酸可能是导致RYGB后肥胖改善和糖尿病治愈的主要信号。该提案将研究胆汁酸代谢/动力学和信号传导如何通过胆流改道改变的分子机制，以产生与RYGB相比更有效和持续的体重减轻和对饮食诱导的肥胖的抵抗。这项工作可能会发现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.