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.
Relevance: This project is aimed at elucidating the molecular signaling mechanisms of circadian nutritional reprogramming of the hepatic clock that are communicated by the gut microbiome. The specific aims of this proposal are designed to decipher the detailed transcriptional and epigenetic reprogramming axes of the liver clock, using a novel mouse model that harbors a clock mutation in the gut. These findings will provide exciting new information regarding the inter-tissue communication of peripheral clocks that regulate aspects of metabolic homeostasis.