Circadian rhythms control numerous aspects of behavior and physiology, and specifically in the liver, the clock is required for regulating a number of metabolic processes that are critical for organismal homeostasis. Additionally, increasing evidence shows that circadian disruptions in humans and genetic mouse models can produce a host of metabolic disorders including obesity, diabetes, and impaired cardiovascular health. Given the important role of the clock in maintaining strict specificity in timekeeping, the hepatic circadian clock is remarkably plastic to environmental inputs such as food intake. Timing of food intake, nutritional challenge and food deprivation act as robust and powerful entrainment mechanisms to temporally alter circadian gene expression. Yet, the detailed mechanisms of diet-induced circadian disruption are only recently being elucidated. The metabolic benefits of fasting have been described in mice and humans to decrease weight, enhance insulin sensitivity, and improve markers of aging. To date, the molecular mechanisms of food deprivation using a fasting mimicking diet (FMD) have not been explored in the context of the circadian clock.
The specific aims of this proposal are designed to determine the detailed transcriptional and metabolic reprogramming of the liver clock that occurs in response to a FMD. This grant will provide a wealth of high-throughput information to the scientific community on how food deprivation regimens alter circadian metabolism in the liver, the purpose of which is to better understand prevention and treatment of metabolic syndrome and obesity.
This project is aimed at elucidating the molecular signaling mechanisms of prolonged fasting on the hepatic circadian clock, the time keeping ability of which is intimately re-wired depending on food intake and nutritional deprivation. The specific aims of this proposal are designed to understanding two different transcriptional and post-translational reprogramming circuits that are intimately linked to metabolic control by the liver clock. These studies are imperative to mechanistically understanding common dietary regimens that are used worldwide for the prevention of metabolic syndrome, obesity, cardiovascular disease and aging.