Regulation of glucose homeostasis via the molecular clock machinery and the hepatic vagus nerve after Roux-en-Y gastric bypass

本申请描述了一个结构化的研究计划，旨在探索分子“时钟”的作用- 它负责维持内源性昼夜节律-在葡萄糖调节机制中 胃旁路手术后据估计，约有3000万美国人患有糖尿病（主要是2型）， 与胰岛素抵抗和肥胖密切相关。此外，目前每3个美国人中就有1个肥胖。 到2020年，估计有75%的人会超重或肥胖。减肥手术证明 在减轻体重和逆转大多数与肥胖相关的合并症（如 如糖尿病），其影响持续长达20年。新出现的证据表明，Roux-en-Y胃 旁路（RYGB）通过调节肠道之间的神经元-激素通路诱导其代谢效应 和能量调节中心。我们开发了一种RYGB小鼠模型， 大多数人类的发现和这个模型可以用来进一步剖析这种潜在的机制， 手术在这个提议中，我们表明RYGB逆转了高脂饮食（HFD）对昼夜节律的破坏， 摄食行为它会导致在黑暗周期中消耗的食物摄入百分比增加 （生理进食时间）恢复到在健康瘦动物中观察到的时间。RYGB还纠正了HFD- 诱导的肝时钟基因振荡以及室旁核的改变， 下丘脑RYGB后葡萄糖代谢的改善主要是由于 减少肝葡萄糖产生和改善肝胰岛素敏感性。分子钟 机械（肝脏和大脑的某些区域内）在脂质、碳水化合物和 异生物质代谢与禁食/进食周期同步。在这里，我们表明，RYGB诱导 在clock β 19突变小鼠（clock β 19缺陷小鼠）中对体重减轻和葡萄糖改善的减弱反应 基因）与野生型对照相比。此外，我们获得的新数据显示，选择性前脑 Bmal 1（另一个核心时钟基因）的缺失破坏了正常的昼夜节律进食，导致肝脏异常。 葡萄糖产量与体重无关。有趣的是，选择性肝迷走神经切断术纠正了这种代谢， 异常这些数据表明，分子钟在RYGB的葡萄糖调节作用中发挥作用， 涉及肝迷走神经的通路。目标1将测试RYGB对葡萄糖稳态的影响 需要功能性中枢（即下丘脑）和外周（即肝）分子钟。目标2将测试是否 RYGB重编程中央时钟基因表达以通过以下机制调节葡萄糖代谢： 肝迷走神经确定RYGB用于诱导其代谢益处的途径将有望有助于 肥胖和2型糖尿病的微创治疗的未来发展。

This application describes a structured research plan targeted to explore the role of the molecular “clock” – which is responsible for maintaining endogenous circadian rhythm - in the mechanism of glucose regulation after gastric bypass. It is estimated that ~ 30 million Americans have diabetes (mainly type 2) which has been tightly associated with insulin resistance and obesity. Furthermore, 1 in every 3 Americans is currently obese and by the year 2020 it’s estimated that ~ 75% will be either overweight or obese. Bariatric surgery proved to be very effective in reducing body weight and reversing most of the obesity associated co-morbidities (such as diabetes) with effects lasting as long as 20 years. Emerging evidence suggests that Roux-en-Y gastric bypass (RYGB) induces its metabolic effects by modulating neuronal-hormonal pathways between the gut and energy regulating centers within the brain. We developed a mouse model of RYGB that can recapitulate most of the human findings and this model can be used to further dissect the underlying mechanism of this surgery. In this proposal, we show that RYGB reverses the disruption caused by high fat diet (HFD) on diurnal food intake behavior. It causes an increase in the percentage of food intake consumed during the dark cycle (physiologic feeding time) back to that observed in healthy lean animals. RYGB also corrects the HFD- induced alteration in hepatic clock gene oscillation as well as the paraventricular nucleus of the hypothalamus. The improvement in glucose metabolism after RYGB was shown to be primarily due to reduction in hepatic glucose production and amelioration of hepatic insulin sensitivity. The molecular clock machinery (within the liver and certain areas of the brain) plays a key role in lipid, carbohydrate, and xenobiotic metabolism in synchrony with the fasting/feeding cycle. Here, we show that RYGB induces an attenuated response to weight loss and glucose improvement in clock∆19 mutant mice (deficient in the Clock gene) compared to wild-type controls. In addition, we acquired new data showing that selective forebrain deletion of Bmal1 (another core clock gene) disrupts normal circadian feeding and results in abnormal hepatic glucose production independent of weight. Interestingly, selective hepatic vagotomy corrects this metabolic abnormality. This data suggest that the molecular clock play a role in the gluco-regulatory effects of RYGB in a pathway involving the hepatic vagus nerve. Aim#1 will test if the effects of RYGB on glucose homeostasis require a functional central (i.e hypothalamic) and peripheral (i.e. hepatic) molecular clock. Aim#2 will test if RYGB reprograms central clock gene expression to regulate glucose metabolism via a mechanism involving the hepatic vagus. Identifying pathways used by RYGB to induce its metabolic benefits will hopefully assist in future development of less invasive therapies for obesity and type 2 diabetes.