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bioRxiv · 10.64898/2025.12.17.694837

Thermo-Dynamic Flux Balance Analysis, a novel approach to simulate circadian metabolism

Messa, G. M.·Liu, P.·Napolitano, F.·tegner, j.·Gao, X.·Orlando, V.
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Abstract

Circadian metabolism arises from complex, time-dependent interactions across organs, yet experimental characterization in humans remains limited. Current whole-body metabolic models are either too large for dynamic simulation or insufficiently detailed to capture temporal physiology. We developed a multi-tissue human metabolic reconstruction, HGEM1.19+, an extensively curated model for dynamic simulation. We introduced Thermo-Dynamic Flux Balance Analysis (tdFBA), a novel formulation that integrates thermodynamic constraints, organ-specific enzyme capacities, solubility limits, osmotic balance and pH buffering. Murine circadian transcriptomics and metabolomics were integrated with human datasets to parameterize temporal dynamics. A genetic algorithm optimized internal parameters under CHOW diet conditions and model performance was evaluated using circadian metabolomics and gene-sage patterns. The framework recapitulated key metabolic oscillations under CHOW diet and partially reconstructed perturbed states including HFD, BMAL1 knockout, and tissue-specific re-entrainment. tdFBA enables physiologically grounded, multi-organ dynamic simulations and provides a foundation for exploring human circadian metabolism and perturbation responses.

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Messa, G. M., Liu, P., Napolitano, F., tegner, j., Gao, X., Orlando, V.. 2025-12-19. Thermo-Dynamic Flux Balance Analysis, a novel approach to simulate circadian metabolism. https://doi.org/10.64898/2025.12.17.694837

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