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A mathematical model for understanding disruptions of the hepatic clock

par Marc LEFRANC - publié le

Our organism is continuously subjected to the alternation of days, where we are active and fed, and of nights, where we rest and fast. To orchestrate our metabolism accordingly, our organism needs to anticipate the periodic variations induced by this alternation. Thus, the liver, a major metabolic organ which in particular regulates glycemia, is continuously informed about the current phase of the cycle by an internal clock, which primarily synchronizes to food timing. The importance of the clock is shown by the occurrence of severe metabolic disorders when it is inactivated.

Nutritional stress such as induced by high-fat diets disrupts the hepatic clock, which is also perturbed in obese people. In order to improve our understanding the mechanisms leading to disruption, researchers from the Unit "Nuclear receptors, cardio-vascular diseases and diabetes" at the Pasteur Institute of Lille and from the PhLAM laboratory have worked together to construct the first mathematical model describing how the hepatic clock is synchronized by the cyclic variations of the energetic state of cells. To this aim, they ave extended previous models by incorporating the metabolic sensors AMPK and SIRT1, which modulate a number of core clock actors in response to the levels of AMP and NAD+, two important metabolites.

This model agrees very well with experimental data about the clock oscillations observed in mouse livers . Remarkably, it reproduces the main perturbations of the clock observed in mice upon a high-fat diet. These results suggest the daily cycling of the activity of the AMPK protein is important to synchronize the clock and that perturbations of this cycle affect the clock. Last, the researchers have simulated numerically the administration of a substance enhancing the activity of the Rev-Erb a protein, a core clock actor, in a situation where the clock is disrupted. They show that if the administration time is carefully chosen, normal clock oscillations are recovered.

These results will hopefully allow researchers to identify the main mechanisms leading to clock disruption in nutritional stress, and to design a chronotherapeutical protocol that can restore the normal behavior of the clock when it as affected by metabolic disorders.

Reference : Aurore Woller (1,2), Hélène Duez (1), Bart Staels (1), Marc Lefranc (2), A Mathematical Model of the Liver Circadian Clock Linking Feeding and Fasting Cycles to Clock Function, Cell Reports 1, 1097 (2016), DOI