Communicating Clocks: Unraveling the nutritional link between the gut microbiome and liver reprogramming

项目摘要 昼夜节律控制着生理学的许多方面，特别是在肝脏中，生物钟是 调节许多代谢过程。值得注意的是，肝脏生物钟是相当可塑的， 能够适应食物摄入量和营养挑战的变化。然而，人类和其他生物的昼夜节律紊乱 生物体可以产生大量的代谢紊乱，包括肥胖、糖尿病和心血管受损。 健康通常，这些昼夜节律的紊乱可能是由于营养的挑战，然而， 饮食诱导的昼夜节律破坏的详细分子机制还不完全清楚。此外，在 在生理节律领域，很少强调外周组织中的时钟之间的通信， 这些生物钟中心在昼夜代谢调整中的作用。越来越多的证据表明， 表明肠道微生物组能够将营养提示传达给周围的其他代谢时钟， 如肝脏。为了进一步阐明这一点，我们开发了一种新的小鼠模型， 特别是在肠道生物钟中，这随后导致肠道细菌的急剧改变， 人口该提案的具体目的旨在通过以下方式表征这种新型小鼠模型： 确定肝脏营养特异性重编程的详细分子机制 生物钟，由肠道微生物传递。为了解释肝脏昼夜节律的程度 通过高脂饮食（HFD）重编程，PPAR γ和SREBP依赖性转录轴， 将在肝脏中分析表观遗传控制的相应变化。此外，这些分子途径将 以无偏见、高通量的方式进行解剖，以确定微生物组诱导的 在一些实施方案中，HFD是肝脏中响应于HFD而发生的转录/表观遗传和代谢重新布线。这笔赠款将 为科学界提供丰富的高通量信息，了解营养是如何被感知的， 通过微生物组传达到外周代谢时钟，其目的是更好地设计 代谢综合征的预防和治疗。

Project Summary Circadian rhythms control numerous aspects of physiology, and specifically in the liver, the clock is required for regulating a number of metabolic processes. Remarkably, the hepatic circadian clock is quite plastic and is able to adapt to changes in food intake and nutritional challenge. Yet, circadian disruption in humans and other organisms can produce a host of metabolic disorders including obesity, diabetes , and impaired cardiovascular health. Often, these disturbances in circadian timing can be specifically due to nutritional challenge, yet the detailed molecular mechanisms of diet-induced circadian disruption are not fully known. Moreover, within the circadian field, little emphasis has been placed on the communication between clocks in peripheral tissues and the contribution these clock centers play in circadian metabolic alignment. As an example, increasing evidence shows that the gut microbiome is able to communicate nutritional cues to other surrounding metabolic clocks, such as the liver. To further elucidate this, we have developed a novel mouse model that harbors a mutation specifically in the intestinal clock which subsequently results in drastic alterations to the gut bacterial population. The specific aims of this proposal are designed to characterize this novel mouse model by determining the detailed molecular mechanisms underlying nutrient-specific reprogramming of the hepatic circadian clock, that are communicated by gut microbes. To decipher the extent of hepatic circadian reprogramming by high fat diet (HFD), the PPAR and SREBP-dependent transcriptional axes and corresponding changes in epigenetic control will be analyzed in the liver. Also, these molecular pathways will be dissected in an unbiased, high-throughput manner to determine the mechanisms of microbiome-induced transcriptional/epigenetic and metabolic rewiring that occurs in response to HFD in the liver. This grant will provide a wealth of high-throughput information to the scientific community on how nutrition is sensed and communicated to peripheral metabolic clocks by the microbiome, the purpose of which is to better design prevention and treatment of metabolic syndrome.