Strengthening circadian signals to enhance cardiometabolic function

项目摘要 越来越多的实验室和实地研究证据表明，昼夜节律功能被破坏， 特别是节律行为的幅度和稳定性下降是导致心律失常的重要危险因素。 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，不仅为理解代谢机制开辟了新的途径， 在心脏代谢疾病发病机制中，中枢和外周时钟之间的相互作用， 治疗干预，以重新建立中枢和外周时钟之间的同步， 与外界的物质环境和社会环境相联系。喂食已被证明可以同步外周神经系统中的时钟。 组织中动物研究表明，限制在活跃期进食可降低CMD风险， 在人类中，晚上热量摄入的减少与较低的体重指数（BMI）有关。的 褪黑激素的幅度可以被认为是中枢昼夜节律功能稳健性的标志，但褪黑激素 还具有超出整个身体的昼夜节律调节的生理效应。最近的观察 表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。总之，证据表明，旨在同步进食的策略 行为和增强夜间褪黑激素信号可以积极影响心脏代谢功能。我们 我建议采取一种创新的方法，结合最近的数据，饲料/快速模式的作用，时钟 调节代谢活动和重新出现的科学兴趣的中央和外周的影响， 褪黑激素对心脏代谢功能的影响，以阐明其生理和分子机制， 昼夜节律失调与肥胖相关CMD风险之间的关系。这将通过 通过延长过夜禁食（ESTA）加强昼夜代谢信号的幅度， 外源性褪黑素对超重和肥胖中年人夜间昼夜节律信号的增强作用 和老年人。此外，这项研究将提供有关昼夜节律的重要性的重要信息， 为将来在超重和肥胖成人中设计CMD临床试验的时机。这是一个关键时刻， 在基于昼夜节律的预防和治疗策略最有可能产生最大影响时， CMD风险。该项目将招募100名成人（40-65岁）参加平行（4组干预） 安慰剂对照研究，以确定是否有一个为期六周的计划，延长过夜禁食（ESTA）的12- 14小时和/或低剂量（3 mg）褪黑激素施用将增强昼夜节律幅度并增强 心脏代谢功能，以及评估结合两者的方案的潜在有益效果 接近。这项研究的结果将证明新的机制为基础的方法， 在生命周期的关键时期，当有快速的新陈代谢时， CMD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.