Vagal REV-ERB as a Circadian Regulator of Satiation Signaling

项目摘要 肥胖症是一种国际流行病，具有重大的健康和经济后果。热量摄入过多 饥饿感/饱腹感失调在很大程度上导致生活方式改变无法维持 减肥.因此，研究调节摄食的生理机制的基础科学研究 行为和能量稳态的发展有效的抗肥胖疗法是更中肯的 比以往任何时候食物摄入的正常昼夜模式（活动期高，非活动期低） 在肥胖症中是沉默的。胃迷走神经传入神经传递来自胃肠（GI）的营养信息 消化道（胃的机械扩张和GI释放的神经肽）到大脑以调节进食 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，GI-神经肽胆囊收缩素（CCK）在非活动期更有饱腹感。我们建议 餐后饱腹感机制效力的昼夜变化强化了食物摄入的昼夜模式。 然而，肥胖消除了迷走神经对胃扩张敏感性的昼夜节律， 通过不完全理解的机制，GI饱腹感因素的饱腹感作用，导致假设 肥胖引起的暴食症部分是由于摄食行为的昼夜节律模式失调。时钟 基因是昼夜节律依赖过程的分子调节因子，我们的初步数据表明迷走神经 传入神经表达时钟基因REV-ERBα和β。REV-ERBα/β唯一配位能 动态平衡与昼夜节律线索，但他们的作用，外周饱食信号和昼夜控制的食物摄入量 完全没有被探索过本申请中提出的研究利用了迷走神经REV的新模型， ERBα/β双敲低（DKD）小鼠，以检验迷走REV-ERBα/β调节昼夜节律的假设。 对GI衍生的饱足信号的敏感性。具体目标1将评估迷走REV-ERB DKD对 使用BioDAQ食物摄入监测系统的膳食模式和CCK、胰高血糖素样肽 肽-1和胃扩张在4个不同的昼夜节律时间点。饮食和觉醒的昼夜模式 是高度耦合的，除了进食行为外，肥胖还会扰乱睡眠模式。因此，具体目标 II将使用CLAMS代谢笼来研究迷走REV-ERB DKD对昼夜模式的作用。 自发活动和睡眠行为的指标。此外，我们将使用RNA-seq来分析昼夜节律， 迷走神经基因表达的模式，并确定REV-ERBα/β调节的基因在饱足信号和 神经传递我们认为，迷走神经REV-ERBα/β信号转导的改变是肥胖诱导的 摄食行为失调，我们预计迷走REV-ERB DKD将钝化食物的昼夜变化， 摄入量、对饱足信号的敏感性和运动。这项工作将增强我们对分子生物学的理解。 调节摄食行为昼夜节律的机制，目的是确定新的药理学 治疗与肥胖相关的昼夜节律失调、暴食和体重增加的目标。

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.