The role of endocannabinoids in circadian disruption induced metabolic dysregulation

内源性大麻素在昼夜节律紊乱引起的代谢失调中的作用

• 批准号: 10542446
• 负责人: Ilia Nicholas Karatsoreos
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542446
• 关键词: Acceleration; Adipose tissue; Affect; Behavior; Biological; Biological Clocks; Bioluminescence; Blood; Body Weight decreased; CNR1 gene; Calories; Cardiovascular Diseases; Cardiovascular Pathology; Circadian Dysregulation; Circadian Rhythms; Circadian desynchrony; Darkness; Data; Development; Diabetes Mellitus; Diet; Eating; Endocannabinoids; Environment; Environmental Risk Factor; Epidemiology; Exercise; Exposure to; Fatty Liver; Gene Expression; Genes; Genetic; Glucocorticoids; Goals; Hepatic; Human; Hyperinsulinism; Insulin; Knockout Mice; Laboratories; Life; Light; Link; Liver; Mass Spectrum Analysis; Measures; Metabolic; Metabolic syndrome; Methods; Modeling; Modernization; Mus; Muscle; Mutation; Nature; Obesity; Organ; Outcome Assessment; Pathogenesis; Pathway interactions; Periodicity; Pharmacology; Physiological; Physiology; Plasma; Public Health; Publishing; Resistance; Rodent Model; Role; Signal Transduction; Sleep; Sleep Deprivation; Societies; Stress; Techniques; Time; Time-restricted feeding; Tissues; Transcript; Triglycerides; Weight Gain; Work; behavioral phenotyping; circadian; circadian pacemaker; comorbidity; cytokine; diet-induced obesity; endocannabinoid signaling; endogenous cannabinoid system; feeding; food consumption; genetic manipulation; hypercortisolemia; in vivo; insight; metabolic phenotype; novel; obesity development; pharmacologic; response; shift work; tool

ABSTRACT: Obesity and its co-morbid pathologies cardiovascular disease and diabetes are significant and growing public health problems. Obesity occurs as a result of interactions between multiple organs (e.g. liver, muscle, adipose), genetic factors, physiological factors (e.g. insulin, cytokines, and glucocorticoids), and environmental factors, particularly those associated with modern life (e.g. diet, lack of exercise, stress). Growing evidence suggests one of the most insidious of these environmental factors is the change in our circadian (daily) rhythms, driven by inappropriately timed exposure to light, shiftwork, and a 24h “always-on” society. Both epidemiologic and experimental data, including work from our own laboratory, support a role for circadian disruption in metabolic dysregulation. As such, manipulating environmental light-dark (LD) cycles could serve as a powerful tool to probe the mechanisms of environmentally driven metabolic dysregulation. Importantly, the mechanisms that link environmental circadian desynchronization (CD) to metabolic dysregulation remain unknown, limiting our mechanistic understanding of the role of circadian rhythms in the development of obesity. This proposal builds upon our published findings in mouse showing CD caused by shortening the LD cycle from 24h to 20h (LD10:10) results in weight gain, hyperinsulinemia, and other aspects of metabolic syndrome. Our focus now is to determine the mechanisms by which this environmental challenge leads to obesity. New data from our lab demonstrates that the endocannabinoid (eCB) system may be an important link between circadian rhythms and metabolic dysregulation. This is strengthened by recent data in humans that show rhythmic profiles of eCBs in the blood, that sleep/circadian disruption can alter these rhythms, and that over-activity in the eCB system is associated with obesity. The objective of this proposal is to mechanistically determine if the eCB system is an essential factor by which environmental and genetic circadian disruption contribute to changes in metabolic function, including increases in adiposity. We will use state-of-the art behavioral and metabolic phenotyping, gene expression and mass spectrometry to assess outcomes, and targeted pharmacology and tissue specific genetic manipulations to probe the mechanistic links between eCB signaling, circadian desynchronization, and metabolic dysregulation.

摘要： 肥胖及其共病疾病心血管疾病和糖尿病是重要的和日益增长的公共疾病 健康问题。肥胖是多个器官(如肝脏、肌肉、脂肪)相互作用的结果， 遗传因素、生理因素(如胰岛素、细胞因子和糖皮质激素)和环境因素， 尤其是那些与现代生活相关的问题(如节食、缺乏锻炼、压力)。越来越多的证据表明 这些环境因素中最隐蔽的因素之一是我们昼夜节律的变化，由 不适当的时间暴露在阳光下，轮班工作，以及一个24小时不间断的社会。无论是流行病学还是 实验数据，包括我们自己实验室的工作，支持昼夜节律紊乱在新陈代谢中的作用 监管失调。因此，操纵环境明暗(LD)周期可以作为探测的有力工具 环境驱动的代谢失调的机制。重要的是，连接的机制 环境昼夜节律去同步化(CD)到代谢失调仍不清楚，限制了我们的 从机制上理解昼夜节律在肥胖发展中的作用。这项建议建立了 根据我们在小鼠身上发表的发现，通过将LD周期从24小时缩短到20小时而导致CD(LD10：10) 导致体重增加、高胰岛素血症和代谢综合征的其他方面。我们现在的重点是确定 这种环境挑战导致肥胖的机制。我们实验室的新数据表明 内源性大麻素(ECB)系统可能是昼夜节律和代谢之间的重要联系 监管失调。这一点在最近的人体数据中得到了加强，这些数据显示了血液中ECB的节律特征， 睡眠/昼夜节律的干扰会改变这些节律，而欧洲央行系统中的过度活动与 与肥胖有关。这项提议的目标是机械地确定欧洲央行体系是否是一个必要的 环境和遗传昼夜节律紊乱导致代谢功能改变的因素， 包括肥胖症的增加。我们将使用最先进的行为和代谢表型，基因 表达和质谱学评估结果，以及靶向药理学和组织特异性基因 探索ECB信号、昼夜节律去同步化和代谢之间的机制联系的操作 监管失调。