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.

该应用程序描述了一个旨在探索分子“时钟”作用的结构化研究计划 - 负责维持内源性昼夜节律 - 葡萄糖调节机制 胃旁路后。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名美国人中有1人肥胖 到2020年，估计约有75％的人超重或肥胖。减肥手术被证明是 在减轻体重和逆转大多数肥胖相关的合并症方面非常有效（这样 作为糖尿病），其影响持续了长达20年。新兴的证据表明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 和能量调节集中在大脑内。我们开发了一个可以概括的RYGB的鼠标模型 大多数人类发现和该模型可用于进一步剖析此的基本机制 外科手术。在此提案中，我们表明RYGB逆转了昼夜高脂饮食（HFD）造成的破坏 食物摄入行为。这会导致在黑暗周期中消耗的食物摄入量的百分比增加 （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- 诱导的肝时钟基因振荡的改变以及 下丘脑。 RYGB后葡萄糖代谢的改善被证明是主要的 肝葡萄糖产生的降低和肝胰岛素敏感性的改善。分子时钟 机械（在大脑的肝脏和某些区域内）在脂质，碳水合物和 与禁食/进食周期同步的异生物代谢。在这里，我们表明RYGB引起了 时钟∆19突变小鼠对体重减轻和葡萄糖改善的反应减弱（时钟不足 与野生型对照相比，基因）。此外，我们获得了新数据，显示了选择性前脑 BMAL1（另一个核心时钟基因）的删除会破坏正常的昼夜节律进食，并导致异常肝 葡萄糖产生与重量无关。有趣的是，选择性肝迷失术纠正了这种代谢 紊乱 etc。该数据表明，分子时钟在RYGB在RYGB中的葡萄糖调节作用中起作用 涉及肝迷走神经的途径。 AIM＃1将测试RYGB对葡萄糖稳态的影响是否 需要功能性中心（即下丘脑）和外周（即肝）分子钟。 AIM＃2将测试是否 RYGB重新编程中心时钟基因表达以通过涉及的机制调节葡萄糖代谢 肝之迷。识别RYGB用于诱导其代谢益处的途径将有望帮助 肥胖症和2型糖尿病的侵入性疗法的未来发展。