The Circadian Metabolome and its Interplay with Nutritional Challenges

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DESCRIPTION (provided by applicant): The circadian clock controls a remarkable array of physiological and metabolic functions. As both genetic mutations and non-genetic interferences that disrupt the circadian clock lead to metabolic disorders, it is essential to understand how circadian rhythms and metabolic processes interact on a cell and tissue-specific level. That circadian gene expression contributes to tissue-specific metabolic homeostasis is known but how metabolites play into this picture is almost completely unknown. As small metabolites are well known ligands of nuclear receptors. many of which control the metabolic state of the cell and are also known to oscillate in expression, the role of the metabolome in circadian clock maintenance is seminal to understanding the intimate links between metabolic homeostasis and circadian rhythms. The research proposed here will help to fill this void by identifying the circadian metabolome and to establish how it changes to induce obesity or whether it changes as a result of obesity. We will also link the metabolome to the circadian transcriptome, which will establish whether these two cycle in a coordinated manner. As accumulating evidence stresses the role of the circadian clock in linking epigenetic control and cellular metabolism, this researc has far-reaching implications for human physiology and disease.