Joanna Chiu, Ph.D., University of California, Davis
Recent studies investigating circadian disruptions and metabolic diseases, which impact millions, suggested a strong correlation between these two groups of human disorders, but the causative relationships are just starting to emerge. The animal circadian timing system is composed of a hierarchical and interconnected network of tissue specific oscillators and plays an indispensable role in synchronizing cellular rhythms in physiology and metabolism to the perpetual 24-hour day-night cycle. To investigate the mechanisms by which metabolic signals regulate the circadian clock and understand the co-occurrence of circadian and metabolic disorders, we applied an integrated metabolomics and proteomics approach on a Drosophila Type 2 diabetes (T2D) model, i.e. flies fed on high fat diet (HFD). We observed that HFD attenuates circadian locomotor rhythmicity, suggesting a disruption of central clock. Comparison of metabolome profiles between flies fed with HFD and normal diet uncovered significant differences in the circadian profile of metabolites that affect protein 0-GlcNAcylation, a nutrient-sensitive post-translational modification (PTM) that modulates function of cellular proteins, including clock proteins. Phosphorylation has emerged as a central mechanism that regulate clock protein function and circadian physiology. Since there is extensive crosstalk between phosphorylation and 0-GlcNAcylation, we hypothesize that metabolic signals regulate circadian physiology via regulation of PTM status of cellular proteins.