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

Roux-en-Y胃绕道手术后通过分子钟机制和肝迷走神经调节葡萄糖稳态

• 批准号: 9886571
• 负责人: Mohamad Mokadem
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9886571
• 关键词: ARNTL gene; Adrenergic Fibers; Affect; American; Animals; Area; Attenuated; Back; Behavior; Body Weight; Body Weight decreased; Brain; Calories; Cardiovascular Diseases; Cell Nucleus; Cells; Circadian Dysregulation; Circadian Rhythms; Consumption; Data; Denervation; Development; Diabetes Mellitus; Diet; Disease; Diurnal Rhythm; Dorsal; Eating; Eating Behavior; Energy Metabolism; Fasting; Feeding behaviors; Fiber; Food; Future; Gastric Bypass; Gene Expression; Genes; Gluconeogenesis; Glucose; Hepatic; High Fat Diet; Hormonal; Human; Hyperglycemia; Hypothalamic structure; Insulin Resistance; Knockout Mice; Leptin; Light; Liver; Measures; Mediating; Medical; Metabolic; Modeling; Motor; Mus; Mutant Strains Mice; Nerve; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Obesity Epidemic; Operative Surgical Procedures; Overweight; Pathway interactions; Pattern; Periodicity; Peripheral; Phase; Physiological; Play; Prosencephalon; Regulatory Pathway; Research; Risk Factors; Role; Signal Transduction; Sleep; Sleep Wake Cycle; Structure; Syndrome; Testing; Thinness; Time; Vagotomy; Vagus nerve structure; Veterans; Weight; Work; Xenobiotic Metabolism; bariatric surgery; base; blood glucose regulation; carbohydrate metabolism; circadian; comorbidity; energy balance; feeding; food consumption; glucose metabolism; glucose production; glycogenolysis; high risk; improved; insulin sensitivity; lipid metabolism; molecular clock; mouse model; novel; obesity management; paraventricular nucleus; response; restoration; shift work; suprachiasmatic nucleus

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.

这项申请描述了一项结构化的研究计划，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型糖尿病)，这种疾病已经 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人肥胖 据估计，到2020年，大约75%的人将超重或肥胖。减肥手术被证明是 在减轻体重和扭转大多数与肥胖相关的并发症(如 如糖尿病)，其影响持续长达20年。新的证据表明Roux-en-Y胃 体外循环(RYGB)通过调节肠道之间的神经-激素通路来诱导其代谢效应 以及大脑中的能量调节中心。我们开发了一种RYGB小鼠模型，可以概括 大多数人类的发现和这个模型可以用来进一步剖析这一潜在的机制 做手术。在这项建议中，我们证明RYGB逆转了高脂饮食(HFD)对昼夜节律的干扰 食物摄取行为。它导致黑暗周期中食物摄入量的百分比增加。 (生理喂食时间)恢复到健康瘦肉动物的观察结果。RYGB还更正了HFD- 大鼠肝钟基因振荡和室旁核的改变 下丘脑。RYGB治疗后葡萄糖代谢的改善主要是由于 减少肝脏葡萄糖产生，改善肝脏胰岛素敏感性。分子钟 机械(在肝脏和大脑的某些区域)在脂肪、碳水化合物和 异源生物代谢与禁食/喂食周期同步。在这里，我们展示了RYGB诱导了一个 时钟∆19突变小鼠(时钟缺陷)对体重减轻和血糖改善的反应减弱 基因)与野生型对照进行比较。此外，我们还获得了新的数据，表明选择性前脑 BMal1(另一个核心时钟基因)的缺失扰乱了正常的昼夜摄食，并导致肝脏异常 葡萄糖的产生与重量无关。有趣的是，选择性肝迷走神经切断术纠正了这种代谢 反常现象。这一数据表明，分子时钟在RYGB的血糖调节作用中发挥作用。 一条涉及肝脏迷走神经的通路。目标1将测试RYGB对血糖稳态的影响 需要一个功能正常的中枢(即下丘脑)和外周(即肝脏)分子钟。目标2将测试是否 RYGB重新编程中央时钟基因的表达，通过一种机制调节葡萄糖代谢 肝脏迷走神经。确定RYGB用于诱导其代谢益处的途径有望有助于 肥胖症和2型糖尿病侵入性较小疗法的未来发展。