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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.

2023-11-02 systems biology
10.1101/2023.10.30.564837 bioRxiv
Show 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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