Glucose Challenge Uncovers Temporal Fungibility of Metabolic Homeostasis Throughout the Day

Malik, D. M.; Rhoades, S. D.; Zhang, S. L.; Sengupta, A.; Barber, A.; Haynes, P.; Arnadottir, E. S.; Pack, A.; Kibbey, R. G.; Sehgal, A.; Weljie, A. M.

doi:10.1101/2023.10.30.564837

bioRxiv · 10.1101/2023.10.30.564837

Glucose Challenge Uncovers Temporal Fungibility of Metabolic Homeostasis Throughout the Day

Malik, D. M.·Rhoades, S. D.·Zhang, S. L.·Sengupta, A.·Barber, A.·Haynes, P.·Arnadottir, E. S.·Pack, A.·Kibbey, R. G.·Sehgal, A.·Weljie, A. M.

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Abstract

Rhythmicity is a cornerstone of behavioral and biological processes, especially metabolism, yet the mechanisms behind metabolite cycling remain elusive. This study uncovers a robust oscillation in key metabolite pathways downstream of glucose in humans. A purpose-built 13C6-glucose isotope tracing platform was used to sample Drosophila every 4h and probe these pathways, revealing a striking peak in biosynthesis shortly after lights-on in wild-type flies. A hyperactive mutant (fumin) demonstrates increased Krebs cycle labelling and dawn-specific glycolysis labelling. Surprisingly, neither underlying feeding rhythms nor the presence of food availability explain the rhythmicity of glucose processing across genotypes, suggesting a robust internal mechanism for metabolic control of glucose processing. These results align with clinical data highlighting detrimental effects of mistimed energy intake. Our approach offers a unique insight into the dynamic range of daily metabolic processing and provides a mechanistic foundation for exploring circadian metabolic homeostasis in disease contexts.

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Malik, D. M., Rhoades, S. D., Zhang, S. L., Sengupta, A., Barber, A., Haynes, P., Arnadottir, E. S., Pack, A., Kibbey, R. G., Sehgal, A., Weljie, A. M.. 2023-11-02. Glucose Challenge Uncovers Temporal Fungibility of Metabolic Homeostasis Throughout the Day. https://doi.org/10.1101/2023.10.30.564837

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