Vagal REV-ERB as a Circadian Regulator of Satiation Signaling

项目摘要 肥胖症是一种具有重大健康和经济后果的国际流行病。过量摄入卡路里 而饥饿/饱腹感的失调在很大程度上导致了生活方式的改变无法维持 减肥。因此，基础科学研究探索调节摄食的生理机制 行为和能量的动态平衡对于开发有效的减肥疗法更具针对性 比以往任何时候都多。正常的每日食物摄入量模式(活跃期高，非活跃期低) 在肥胖的情况下是弱化的。胃迷走传入神经从胃肠道(GI)传递营养信息 胃束(胃的机械扩张和胃肠道释放的神经肽)到大脑调节摄食 行为。有趣的是，迷走神经传入在非活动期对胃扩张更敏感 类似地，胃肠神经肽CCK(CCK)在非活动期更为饱足。我们建议 餐后饱腹感机制效力的日变化加强了每日食物摄入量的模式。 然而，肥胖消除了迷走神经对胃扩张的昼夜节律敏感性，并降低了 GI饱腹感因子通过不完全了解的机制产生的饱腹感效应导致了这一假说 肥胖引起的吞噬亢进部分是由于饮食行为的昼夜节律失调所致。钟 基因是昼夜节律依赖过程的分子调节器，我们的初步数据显示迷走神经 传入神经表达时钟基因REV-ERBα和β。REV-ERBα/β唯一协调能量 昼夜节律提示的动态平衡，但它们在外周饱足信号和每日食物摄入量控制中的作用 是完全未被开发的。本申请中提出的研究利用了迷走神经的新模型-- 迷走神经α/β双基因敲除小鼠验证迷走神经α/β调节昼夜节律的假说 对GI衍生的饱和信号的敏感度。特定目标1将评估迷走神经REV-ERB DKD对 BioDaq摄食量监测系统的进食模式及CCK、类胰高血糖素的饱食效应 在4个不同的昼夜时点出现胃胀。白天进食和清醒的模式 是高度耦合的，除了进食行为外，肥胖还会扰乱睡眠模式。相应地，具体目标 II将使用文蛤代谢笼来研究迷走神经REV-ERB DKD对大鼠昼夜节律的影响 运动活动，以及睡眠行为的指示器。此外，我们还将使用rna-seq来分析昼夜节律。 迷走神经基因的表达模式及REV-ERBα/β调控的饱和信号和信号转导相关基因 神经传递。我们认为迷走神经REV-ERBα/β信号的改变是肥胖诱导的基础 摄食行为失调，我们预计迷走神经REV-ERB DKD会减弱食物的昼夜变化 摄入量、对饱食信号的敏感度和运动。这项工作将加深我们对分子的理解。 调节摄食行为昼夜节律的机制，目的是确定新的药物 目标是治疗与肥胖相关的昼夜节律失调、吞噬过度和体重增加。

Project Summary Obesity is an international epidemic with significant health and economic consequences. Excess caloric intake and dysregulated feeling of hunger/fullness largely contribute to the failure of lifestyle modifications to maintain weight loss. Accordingly, basic science research investigating the physiological mechanisms regulating feeding behavior and energy homeostasis for the development of effective anti-obesity therapeutics is more pertinent than ever. The normal diurnal patterns of food intake (high during the active phase, low during the inactive phase) are muted in obesity. Gastric vagal afferent nerves convey nutritional information from the gastrointestinal (GI) tract (mechanical distension of the stomach and GI-released neuropeptides) to the brain to regulate feeding behavior. Interestingly, vagal afferents are more sensitive to gastric distension during the inactive phase and similarly the GI-neuropeptide cholecystokinin (CCK) is more satiating during the inactive phase. We propose that diurnal variations in the potency of postprandial satiety mechanisms reinforces diurnal patterns of food intake. Obesity, however, eliminates the circadian rhythms of vagal nerve sensitivity to gastric distension and diminishes the satiating effects of GI satiety factors through incompletely understood mechanisms, leading to the hypothesis that obesity-induced hyperphagia is due in part to dysregulated circadian patterns of ingestive behavior. Clock genes are molecular regulators of circadian dependent processes and our preliminary data show that vagal afferent nerves express the clock genes REV-ERBα and β. REV-ERBα/β uniquely coordinate energy homeostasis with circadian cues, yet their role in peripheral satiation signaling and diurnal control of food intake is completely unexplored. The research proposed in this application utilizes the novel model of vagal REV- ERBα/β double knockdown (DKD) mice to test the hypothesis that vagal REV-ERBα/β regulate diurnal sensitivity to GI-derived satiation signals. Specific Aim 1 will assess the impact of vagal REV-ERB DKD on meal patterning using a BioDAQ Food Intake Monitoring System and the satiating effect of CCK, glucagon-like peptide-1, and gastric distension at 4 different circadian timepoints. Diurnal patterns of eating and wakefulness are highly coupled, and obesity disrupts sleep patterns in addition to feeding behavior. Accordingly, Specific Aim II will use CLAMS metabolic cages to investigate the role of vagal REV-ERB DKD on diurnal patterns of locomotor activity, and indicator of sleep behavior. Additionally, we will use RNA-seq to analyze circadian patterns of vagal gene expression and identify REV-ERBα/β regulated genes in satiation signaling and neurotransmission. As we propose that altered vagal REV-ERBα/β signaling underlies obesity-induced dysregulations in feeding behavior, we expect that vagal REV-ERB DKD will blunt diurnal variations in food intake, sensitivity to satiation signals, and locomotion. This work will enhance our understanding of the molecular mechanisms regulating circadian rhythms of feeding behavior with the goal of identifying new pharmacologic targets to treat the circadian misalignment, hyperphagia, and weight gain associated with obesity.