Vagal REV-ERB as a Circadian Regulator of Satiation Signaling

迷走神经 REV-ERB 作为饱足信号的昼夜节律调节器

• 批准号: 10640260
• 负责人: Caroline Elyse Geisler
• 金额: $ 7.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10640260
• 关键词: Ablation; Adult; Affect; Afferent Neurons; American; Animal Model; Arousal; Basic Science; Behavior; Behavior Therapy; Behavioral; Biological Clocks; Body Weight decreased; Body mass index; Brain; Cells; Chemicals; Cholecystokinin; Circadian Dysregulation; Circadian Rhythms; Circadian desynchrony; Communication; Coupled; Cues; Darkness; Data; Development; Disease Management; Diurnal Rhythm; Eating; Economic Burden; Economics; Energy Intake; Energy Metabolism; Epidemic; Exhibits; Failure; Feedback; Feeding Patterns; Feeding behaviors; Feeling; Food Patterns; Functional disorder; Gastrointestinal tract structure; Gene Expression; Genes; Genetic Polymorphism; Goals; Health; High Fat Diet; Homeostasis; Human; Hunger; Hyperphagia; Impairment; Individual; International; Knock-out; Life Style Modification; Light; Link; Locomotion; LoxP-flanked allele; Measures; Mechanics; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Monitor; Motor Activity; Mus; Nerve; Neuropeptides; Nodose Ganglion; Nutritional; Obesity; Overweight; Pattern; Periodicity; Peripheral; Phase; Phenotype; Physiological; Play; Population; Prevalence; Process; Public Health; Regulation; Research; Role; Satiation; Satiety Response; Signal Transduction; Sleep; Sleep Wake Cycle; Sleep disturbances; Stomach; System; Testing; Therapeutic; Thinness; Tissues; Transfection; Viral; Wakefulness; Weight Gain; Work; afferent nerve; circadian; circadian regulation; cohort; design; detection of nutrient; diet-induced obesity; falls; feeding; gastrointestinal; gene function; glucagon-like peptide 1; improved; knock-down; neurotransmission; novel; novel strategies; obesity risk; obesity treatment; pharmacologic; rev Genes; shift work; sleep behavior; sleep pattern; sleep quality; transcription factor; transcriptome; transcriptome sequencing

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.

项目概要 肥胖是一种国际流行病，会对健康和经济造成严重后果。 饥饿/饱腹感失调在很大程度上导致生活方式改变无法维持 因此，基础科学研究调查了调节进食的生理机制。 行为和能量稳态对于开发有效的抗肥胖疗法更为相关 比以往任何时候都正常的每日食物摄入量（活动阶段高，非活动阶段低） 肥胖症患者的胃迷走神经传入神经会减弱，传递来自胃肠道 (GI) 的营养信息。 消化道（胃的机械扩张和胃肠道释放的神经肽）到大脑以调节进食 暗示，迷走神经传入在非活动期和胃扩张更敏感。 同样，胃肠道神经肽胆囊收缩素 (CCK) 在非活动阶段更容易产生饱腹感。 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，肥胖会消除迷走神经对胃扩张的敏感性的昼夜节律，并减弱 胃肠道饱腹感因素通过不完全了解的机制产生饱腹感，从而得出假设 肥胖引起的食欲亢进部分是由于饮食行为的昼夜节律失调造成的。 基因是昼夜节律依赖性过程的分子调节剂，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，独特地协调能量。 昼夜节律线索的稳态，以及它们在外周饱足感信号和每日食物摄入控制中的作用 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) 小鼠测试迷走神经 REV-ERBα/β 调节昼夜节律的假设 对 GI 衍生的饱足感信号的敏感性具体目标 1 将评估迷走神经 REV-ERB DKD 的影响。 使用 BioDAQ 食物摄入监测系统进行膳食模式以及 CCK（胰高血糖素样）的饱腹感 肽-1 和 4 个不同昼夜节律时间点的胃扩张 饮食和清醒的昼夜模式。 是高度耦合的，肥胖除了进食行为外，还会扰乱睡眠模式。 II 将使用 CLAMS 代谢笼来研究迷走神经 REV-ERB DKD 对昼夜模式的作用 此外，我们将使用 RNA-seq 来分析昼夜节律。 迷走神经基因表达模式并识别饱足信号中的 REV-ERBα/β 调节基因 正如我们提出的，迷走神经 REV-ERBα/β 信号传导的改变是肥胖诱发的基础。 进食行为失调，我们预计迷走神经 REV-ERB DKD 会减弱食物的昼夜变化 这项工作将增强我们对分子的理解。 调节进食行为昼夜节律的机制，目的是确定新的药理作用 目标是治疗与肥胖相关的昼夜节律失调、食欲过盛和体重增加。

项目成果

Metabolic hormone action in the VTA: Reward-directed behavior and mechanistic insights.

VTA 中的代谢激素作用：奖励导向行为和机制见解。

• 发表时间: 2023-09-01
• 影响因子: 2.9
• 作者: Geisler, Caroline E;Hayes, Matthew R
• 通讯作者: Hayes, Matthew R

Tirzepatide suppresses palatable food intake by selectively reducing preference for fat in rodents.

替泽帕肽通过选择性降低啮齿动物对脂肪的偏好来抑制可口食物的摄入。

• 发表时间: 2023-01
• 作者: Geisler, Caroline E;Antonellis, Meghan P;Trumbauer, Wolfgang;Martin, Jennifer A;Coskun, Tamer;Samms, Ricardo J;Hayes, Matthew R
• 通讯作者: Hayes, Matthew R