A Mathematical Model of the Liver Circadian Clock Linking Feeding and Fasting Cycles to Clock Function

Aurore Woller (1, 2) , Helene Duez (1) , Bart Staels (1) , Marc Lefranc (2)

1 RNMCD - Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011
2 PhLAM - Laboratoire de Physique des Lasers, Atomes et Molécules - UMR 8523

To maintain energy homeostasis despite variable energy supply and consumption along the diurnal cycle, the liver relies on a circadian clock synchronized to food timing. Perturbed feeding/fasting cycles have been associated with clock disruption and metabolic diseases, however the mechanisms are unclear. To address this question, we have constructed a mathematical model of the mammalian circadian clock incorporating the metabolic sensors SIRT1 and AMPK. The clock response to various temporal patterns of AMPK activation was simulated numerically, mimicking the effects of a normal diet, fasting and a high-fat diet. The model reproduces the dampened clock gene expression and NAD+ rhythms reported for mice on a high-fat diet, and predicts that this effect may be pharmacologically rescued by timed REV-ERB agonist administration. Our model thus identifies altered AMPK signaling as a mechanism leading to clock disruption and its associated metabolic effects, and a pharmacological approach to reset the clock in obesity.

Mots clés: mammalian circadian clock; metabolism; mathematical model; SIRT1; AMPK; NAMPT; NAD+; REV-ERB; metabolic disorders

Domaines: Bio-Informatique, Biologie Systémique [q-bio.QM]

Aurore Woller, Helene Duez, Bart Staels, Marc Lefranc. A Mathematical Model of the Liver Circadian Clock Linking Feeding and Fasting Cycles to Clock Function. Cell Reports, 2016, 17 (4), pp.1087-1097. ⟨10.1016/j.celrep.2016.09.060⟩. ⟨hal-03142705⟩