In mammals, the circadian oscillator has emerged as a critical orchestrator of metabolism and energy homeostasis. Importantly, circadian dysfunction due to environmental factors commonly found in modern lifestyles (jet lag, rotating shift work, artificially-extended photoperiod, western diets) has been linked to weight gain, metabolic syndrome, and diabetes. An important connection between the circadian clock and energy metabolism occurs at the level of epigenetic control. However, how the clock bears upon genomic regulation of energy homeostasis through epigenetic mechanisms is not fully understood. In particular, the effects that chronodisruption and western-style diets have on the function of epigenetic regulators and the mechanisms by which they, in turn, contribute to the development of metabolic disease remains unknown. We previously described the JmjC-class lysine demethylase JARID1a as a non-redundant component of the circadian oscillator. Recently, we have observed that liver-specific ablation of JARID1a results in disruptions to glucose metabolism. This proposal uses a combination of novel tissue-specific genetic murine models, light-dark schedule and dietary manipulations, molecular biology techniques, and genomic approaches to characterize JARID1a as a novel epigenetic link between chronodisruptive environmental variables and metabolic dysfunction. Based on preliminary data, this proposal tests the central hypothesis that JARID1a is an epigenetic link between the circadian clock and genomic regulation of glucose metabolism through opposing modulation of the transcription factors CREB and ChREBP, and whose dysfunction disrupts glucose homeostasis. In our first aim, we interrogate the impact of a high-fat diet, fatty acids, fasting, acute feeding, chronodisrupted light schedules, and metabolic signaling pathways on JARID1a function. In our second aim, we investigate the molecular mechanisms by which JARID1a regulates energy metabolism through opposing control of two important regulators of glucose homeostasis: the transcription factors CREB and ChREBP.
The circadian clock coordinates metabolism with the time of day, and its dysfunction contributes to obesity, metabolic syndrome, and type 2 diabetes. Here, we explore novel mechanisms linking the circadian clock and glucose metabolism. This work is relevant to public health because it addresses biological mechanisms underlying metabolic syndrome and type-2 diabetes that may help develop new therapies.
