The circadian clock orchestrates physiological and behavioral processes over a 24-hour cycle
and plays a critical role in human health. Circadian disruption is associated with metabolic,
malignant, and psychological disorders. Developing an in silico representation of this complex
system could help identify key mechanisms underlying circadian desynchronization and support
preventive strategies.
Due to the intrinsic complexity of circadian regulation, involving multi-scale and multi-formalism
interactions, a systemic and hybrid modeling approach is required. In this work, we propose a
multi-agent framework integrating circadian regulation, metabolism, and hormonal dynamics.
Each group of cells (e.g., myocytes, hepatocytes, pancreatic beta cells) is modeled as an
autonomous agent interacting through both a shared environment representing the bloodstream
and explicit message exchanges.
Discrete formalisms based on the René Thomas framework are used to capture circadian
oscillations, while continuous formalisms with dynamic thresholds describe hormonal secretion
and metabolic fluxes. Such hybrid architecture enables the coupling of regulatory networks with
physiological dynamics across scales while avoiding excessive model complexity.
First simulation results of the integrated model reproduce key qualitative features of circadian
physiology, including oscillatory hormonal secretion patterns, synchronization between spatially
separated circadian clocks through indirect interactions, daily glucose fluctuations, and coherent
energy production cycles. These results are consistent with known biological behaviors and
support the relevance of the proposed approach.
This work constitutes a first step toward comprehensive systemic modeling of circadian
regulation and provides a foundation for studying pathological desynchronization, as well as for
the design of hybrid multi-agent models in systems biology.

Co-authors: Nadia Abchiche Mimouni, Franck Delaunay