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: 10553163
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553163
• 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; Darkness; Data; Denervation; Development; Diabetes Mellitus; 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; Homeostasis; Hormonal; Human; Hyperglycemia; Hyperinsulinism; Hypothalamic structure; Insulin Resistance; Knockout Mice; Leptin deficiency; 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; Persons; Phase; Physiological; Play; Prosencephalon; Regulatory Pathway; Research; Risk Factors; Role; Shift-Work Sleep Disorder; Signal Transduction; Sleep; Sleep Wake Cycle; Sleep disturbances; Structure; Syndrome; Testing; Thinness; Time; Vagotomy; Vagus nerve structure; Veterans; Weight; Work; Xenobiotic Metabolism; bariatric surgery; blood glucose regulation; carbohydrate metabolism; circadian; comorbidity; diet-induced obesity; energy balance; feeding; food consumption; glucose metabolism; glucose production; glycogenolysis; high risk; improved; insulin sensitivity; lipid metabolism; molecular clock; mouse model; novel; obesity management; obesity treatment; paraventricular nucleus; programs; 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.

该应用程序描述了一个结构化的研究计划，旨在探索分子“时钟”的作用 - 在葡萄糖调节机制中负责维持内源性昼夜节律 胃绕道手术后。据估计，约 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 人肥胖 到 2020 年，预计约 75% 的人将超重或肥胖。事实证明，减肥手术 在减轻体重和逆转大多数与肥胖相关的并发症（例如 如糖尿病），其影响可持续长达 20 年。新的证据表明 Roux-en-Y 胃 旁路（RYGB）通过调节肠道之间的神经元激素途径来诱导其代谢作用 和大脑内的能量调节中心。我们开发了一种 RYGB 小鼠模型，可以重述 大多数人类发现和该模型可用于进一步剖析这一现象的根本机制 外科手术。在此提案中，我们表明 RYGB 逆转了高脂肪饮食 (HFD) 对昼夜节律造成的干扰 食物摄入行为。它会导致暗循环期间消耗的食物摄入量百分比增加 （生理喂养时间）回到健康瘦动物中观察到的时间。 RYGB 还纠正了 HFD- 诱导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 减少肝脏葡萄糖的产生并改善肝脏胰岛素敏感性。分子钟 机器（在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 时钟Δ19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）与野生型对照相比。此外，我们获得的新数据表明，选择性前脑 Bmal1（另一个核心时钟基因）的缺失会扰乱正常的昼夜节律喂养并导致肝脏异常 葡萄糖的产生与体重无关。有趣的是，选择性肝迷走神经切断术可以纠正这种代谢 紊乱 etc。该数据表明分子钟在 RYGB 的血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 是否对葡萄糖稳态有影响 需要功能性的中枢（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表达，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 未来开发针对肥胖和 2 型糖尿病的微创疗法。