JARID1a in circadian control of hepatic energy metabolism

JARID1a 对肝脏能量代谢的昼夜节律控制

• 批准号: 9750671
• 负责人: Luciano DiTacchio
• 金额: $ 34.43万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750671
• 关键词: 5' -AMP-activated protein kinase; Ablation; Acute; Address; Amino Acids; Architecture; Binding; Binding Sites; Biological; Biological Assay; CREB1 gene; Cell Line; Cells; Characteristics; Circadian Dysregulation; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diabetes Mellitus; Diet; Energy Metabolism; Environmental Impact; Environmental Risk Factor; Epigenetic Process; Fasting; Fatty Acids; Functional disorder; Genes; Genetic; Genetic Transcription; Genomic approach; Genomics; Glare; Goals; Hepatic; Hepatocyte; High Fat Diet; Histone Deacetylation; Homeostasis; Individual; Insulin; Intervention; Jet Lag Syndrome; Knowledge; Life Style; Light; Link; Liver; Lysine; Mammals; Mechanics; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Metabolism; Modernization; Molecular; Molecular Biology Techniques; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obese Mice; Obesity; Organ; Pharmacology; Phenotype; Photoperiod; Physiology; Protein Kinase; Proteins; Public Health; Regulation; Reporter; Research; Role; Schedule; Signal Pathway; Signal Transduction; Testing; Time; Tissues; Transactivation; Transcriptional Regulation; Ursidae Family; Weight Gain; Wild Type Mouse; Work; base; blood glucose regulation; circadian; circadian pacemaker; dietary manipulation; environmental stressor; feeding; glucose metabolism; in vivo; molecular dynamics; mouse model; novel; novel therapeutics; promoter; response; shift work; transcription factor; western diet

PROJECT SUMMARY In mammals, the circadian oscillator has emerged as a critical orchestrator of metabolism and energy homeostasis. Importantly, circadian dysfunction due to environmental factors commonly found in modern lifestyles (jet lag, rotating shift work, artificially-extended photoperiod, western diets) has been linked to weight gain, metabolic syndrome, and diabetes. An important connection between the circadian clock and energy metabolism occurs at the level of epigenetic control. However, how the clock bears upon genomic regulation of energy homeostasis through epigenetic mechanisms is not fully understood. In particular, the effects that chronodisruption and western-style diets have on the function of epigenetic regulators and the mechanisms by which they, in turn, contribute to the development of metabolic disease remains unknown. We previously described the JmjC-class lysine demethylase JARID1a as a non-redundant component of the circadian oscillator. Recently, we have observed that liver-specific ablation of JARID1a results in disruptions to glucose metabolism. This proposal uses a combination of novel tissue-specific genetic murine models, light-dark schedule and dietary manipulations, molecular biology techniques, and genomic approaches to characterize JARID1a as a novel epigenetic link between chronodisruptive environmental variables and metabolic dysfunction. Based on preliminary data, this proposal tests the central hypothesis that JARID1a is an epigenetic link between the circadian clock and genomic regulation of glucose metabolism through opposing modulation of the transcription factors CREB and ChREBP, and whose dysfunction disrupts glucose homeostasis. In our first aim, we interrogate the impact of a high-fat diet, fatty acids, fasting, acute feeding, chronodisrupted light schedules, and metabolic signaling pathways on JARID1a function. In our second aim, we investigate the molecular mechanisms by which JARID1a regulates energy metabolism through opposing control of two important regulators of glucose homeostasis: the transcription factors CREB and ChREBP.

项目概要 在哺乳动物中，昼夜节律振荡器已成为新陈代谢和能量的关键协调者 体内平衡。重要的是，现代人中常见的环境因素导致的昼夜节律失调 生活方式（时差、轮班工作、人为延长光周期、西方饮食）与体重有关 增益、代谢综合征和糖尿病。生物钟和能量之间的重要联系 新陈代谢发生在表观遗传控制的水平上。然而，时钟如何影响基因组调控 通过表观遗传机制实现的能量稳态尚未完全了解。特别是，影响 时间紊乱和西式饮食对表观遗传调节因子的功能及其机制的影响 它们反过来又导致代谢疾病的发展仍然未知。我们之前 将 JmjC 类赖氨酸脱甲基酶 JARID1a 描述为昼夜节律振荡器的非冗余组件。 最近，我们观察到 JARID1a 的肝脏特异性消融会导致葡萄糖代谢中断。 该提案结合了新型组织特异性遗传小鼠模型、明暗时间表和饮食 操作、分子生物学技术和基因组方法将 JARID1a 表征为一种新型 时间破坏性环境变量与代谢功能障碍之间的表观遗传联系。基于 初步数据，该提议测试了中心假设，即 JARID1a 是 通过相反的转录调节来调节葡萄糖代谢的生物钟和基因组 CREB ​​和 ChREBP 因子，其功能障碍会破坏葡萄糖稳态。在我们的第一个目标中，我们 询问高脂肪饮食、脂肪酸、禁食、急性喂养、时间紊乱的光照时间表的影响，以及 JARID1a 功能的代谢信号通路。在我们的第二个目标中，我们研究分子机制 JARID1a 通过对两个重要的葡萄糖调节因子的相反控制来调节能量代谢 体内平衡：转录因子 CREB ​​和 ChREBP。