Bile Diversion: A Simple and Effective Method of Treating Obesity

 描述（由申请人提供）：减肥手术，特别是Roux-en-Y胃旁路术（RYGB），是病态肥胖症最有效和最持久的治疗方法，也是2型糖尿病（T2 D）的潜在可行治疗方法。RYGB后T2 D的解决率接近80%，远远超过单独的医疗管理。这种改进的分子基础还不完全清楚。我们假设RYGB后胆汁酸（BA）的肠肝循环改变介导了代谢改善，这是术后T2 D消退的基础。在这个建议中，我们将确定BA如何有助于改善RYGB后的脂质和葡萄糖稳态，胰岛素敏感性和能量消耗。我们将对饮食诱导的肥胖（DIO）小鼠应用一种新的外科手术，其中胆汁从胆囊（GB）转移到十二指肠（GB-D，假手术）、空肠（GB-J）或回肠（GB-IL）。胆道分流术（BD）允许检查胆汁流量的改变，与RYGB后观察到的相似，与胃肠道解剖结构的改变无关。值得注意的是，GB-IL程序，而不是GB-D或GB-J，概括了RYBG后观察到的许多有益的代谢和生理结果。具体目标1将阐明改变的脂肪吸收、乳糜微粒生成和清除对GB-IL或RYGB疗效的贡献。特定目标2中的研究旨在确定膜结合BA受体TGR 5对RYGB和GB-IL后葡萄糖稳态的作用。在具体目标3中，我们将研究扩展到核BA受体，法尼醇X受体（FXR），研究RYGB和BD在肠和肝脏特异性FXR缺陷基因工程小鼠中的疗效。这项工作的长期目标是了解减肥手术后代谢改善的机制，并开发技术上简单的程序和药理学策略来治疗肥胖及其后遗症。

 DESCRIPTION (provided by applicant): Bariatric surgery, specifically Roux-en-Y gastric bypass (RYGB), is the most effective and durable treatment for morbid obesity and potentially a viable treatment for type 2 diabetes (T2D). The resolution rate of T2D following RYGB approaches 80% and far surpasses that achieved by medical management alone. The molecular basis for this improvement is not entirely understood. We hypothesize that the altered enterohepatic circulation of bile acids (BA) after RYGB mediates the metabolic improvements that underlie the resolution of T2D after the procedure. In this proposal we will determine how BA contribute to improved lipid and glucose homeostasis, insulin sensitivity and energy expenditure after RYGB. We will apply a novel surgical procedure to diet-induced obese (DIO) mice where bile is diverted from the gallbladder (GB) to the duodenum (GB-D, a sham procedure), the jejunum (GB-J), or ileum (GB-IL). The biliary diversion (BD) procedure permits examination of altered bile flow, similar to that observed after RYGB, independent of alterations in gastrointestinal tract anatomy. Remarkably, the GB-IL procedure, but not GB-D or GB-J, recapitulates many of the beneficial metabolic and physiologic outcomes observed after RYBG. Specific Aim 1 will elucidate the contribution of altered fat absorption, chylomicron generation and clearance in the efficacy of GB-IL or RYGB. Studies in Specific Aim 2 are designed to define the role of membrane-bound BA receptor, TGR5, on glucose homeostasis after RYGB and GB-IL. In Specific Aim 3 we extend our investigations to the nuclear BA receptor, farnesoid x receptor (FXR), investigating the efficacy of RYGB and BD in mice genetically-engineered for intestine- and liver-specific FXR deficiency. The long-term goal of this work is to understand the mechanisms of metabolic improvement after bariatric procedures and to develop technically simple procedures and pharmacologic strategies to treat obesity and its sequelae.