Strengthening circadian signals to enhance cardiometabolic function

项目总结 越来越多的证据来自实验室和现场研究，这些证据扰乱了昼夜节律功能， 特别是节律性行为的幅度和稳定性降低是 人类的心脏代谢疾病(CMD)。生物钟在所有组织中普遍存在的令人兴奋的证据 以及它们在新陈代谢中的关键作用，不仅为理解 心脏代谢性疾病发病机制中中枢和外周时钟的相互作用 治疗干预以重建彼此之间的中央和外围时钟之间的同步性 与外部物理和社会环境的关系。研究表明，喂食可以使外设的时钟同步 纸巾。动物研究表明，将喂养限制在活动期可以降低CMD的风险，而 在人类中，晚上卡路里摄入量减少与较低的体重指数(BMI)有关。这个 褪黑素的幅度可以被认为是中枢昼夜节律功能强健的标志，但褪黑素 也有生理上的影响，超越了整个身体的昼夜节律。最近的观察表明 证明褪黑激素水平低是糖尿病和高血压的危险因素 与睡眠时间无关。总而言之，证据表明，旨在同步进食的策略 行为和夜间增强褪黑素信号可以积极地影响心脏代谢功能。我们 建议采用一种创新的方法，将有关馈送/快速模式在时钟上的作用的最新数据结合起来 受调节的代谢活动和对中枢和外周效应的科学兴趣的重新出现 褪黑素对心脏代谢功能的影响 昼夜节律失调与肥胖相关的CMD风险的关系。这将通过以下方式实现 通过延长隔夜禁食(EOF)和 外源性褪黑素对超重肥胖中年人夜间昼夜节律信号的增强作用 以及年长的成年人。此外，这项研究将提供有关昼夜节律重要性的重要信息。 设计未来针对超重和肥胖成年人的CMD临床试验的时机。这是一个关键的时刻 基于昼夜节律的预防和治疗策略最有可能产生最大影响的寿命 关于CMD风险。该项目将招募100名成年人(40-65岁)参加平行的(4个手臂干预) 一项安慰剂对照研究，旨在确定一项为期六周的延长通宵禁食(EOF)计划是否对 14小时和/或小剂量(3毫克)褪黑素可增强昼夜节律幅度并增强 心脏代谢功能，以及评估两者相结合的方案的潜在有益影响 接近了。这项研究的结果将展示基于机械的新方法 在生命中的关键时期维持和改善昼夜节律代谢健康 慢性阻塞性肺疾病患病率增加。

PROJECT SUMMARY There is a growing body of evidence from both laboratory and field studies that disrupted circadian function, particularly decreased amplitude and stability of rhythmic behaviors represent significant risk factors for cardiometabolic disease (CMD) in humans. The exciting evidence of the ubiquity of circadian clocks in all tissues and their critical role in metabolism, not only opens up new avenues for understanding the mechanistic interactions between central and peripheral clocks in cardiometabolic disease pathogenesis, but also to develop therapeutic interventions to re-establish synchrony between central and peripheral clocks with each other and with the external physical and social environments. Feeding has been shown to synchronize clocks in peripheral tissues. Animal studies have demonstrated that restricting feeding to the active period decreases CMD risk, while in humans decreased caloric intake in the evening is associated with a lower body mass index (BMI). The amplitude of melatonin can be considered a marker of robustness of central circadian function, but melatonin also has physiological effects beyond circadian regulation throughout the body. Recent observations have demonstrated that having a low melatonin level is a risk factor for incident diabetes and hypertension independent of sleep duration. Together, the evidence suggests that strategies aimed at synchronizing feeding behavior and enhancing the nocturnal melatonin signal can positively impact cardiometabolic function. We propose to take an innovative approach that combines the recent data on the role of feed/fast patterns on clock regulated metabolic activity and the reemergence of scientific interest of the central and peripheral effects of melatonin on cardiometabolic function to elucidate the physiological and molecular mechanisms that underlie the relationship between circadian dysregulation and obesity associated CMD risk. This will be accomplished by strengthening the amplitude of circadian metabolic signals via extended overnight fasting (EOF) and enhancement of nocturnal circadian signaling with exogenous melatonin in overweight and obese middle aged and older adults. In addition, this study will provide crucial information regarding the importance of circadian timing for the design of future clinical trials on CMD in overweight and obese adults. This is a critical time in the lifespan when circadian based strategies for prevention and treatment are most likely to have the greatest impact on CMD risk. This project will enroll 100 adults (40-65 years) to participate in a parallel (4 arm intervention) placebo controlled study to determine whether a six- week program of extended overnight fasting (EOF) of 12- 14 hours and/or low dose (3 mg) melatonin administration will enhance circadian amplitude and enhance cardiometabolic function, as well as to evaluate the potential beneficial effects of a regimen that combines both approaches. The results from this study will demonstrate novel mechanistically based approaches for maintaining and improving circadian-metabolic health during a critical time in the lifespan when there is a rapid increase in the prevalence of CMD.