The role of endocannabinoids in circadian disruption induced metabolic dysregulation

摘要： 肥胖及其共病病理心血管疾病和糖尿病是显着和日益增长的公众 健康问题肥胖是多个器官（例如肝脏、肌肉、脂肪）之间相互作用的结果， 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， 特别是与现代生活有关的问题（如饮食、缺乏锻炼、压力）。越来越多的证据表明 这些环境因素中最阴险的一个是我们昼夜节律的变化， 不适当的时间暴露在光线下，轮班工作，以及24小时“永远在线”的社会。流行病学和 实验数据，包括我们自己实验室的工作，支持昼夜节律中断在代谢中的作用， 失调因此，操纵环境光暗（LD）周期可以作为一个强大的工具来探测 环境驱动的代谢失调的机制。重要的是， 环境昼夜节律失调（CD）代谢失调仍然是未知的，限制了我们的研究。 生理节律在肥胖症发展中的作用的机械理解。这一建议建立 根据我们在小鼠中发表的研究结果，显示LD周期从24小时缩短至20小时（LD 10：10）导致CD 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， 失调最近的人体数据证实了这一点，这些数据显示血液中eCB的节律性特征， 睡眠/昼夜节律紊乱可以改变这些节律，eCB系统过度活动与 肥胖症本提案的目的是从机制上确定eCB系统是否是 环境和遗传昼夜节律破坏导致代谢功能变化的因素， 包括肥胖的增加。我们将使用最先进的行为和代谢表型，基因 表达和质谱分析来评估结果，以及靶向药理学和组织特异性遗传学。 操作来探测eCB信号传导、昼夜节律去极化和代谢之间的机制联系， 失调

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.