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PHD Defense :Aurore Woller

par Webmestre - publié le

« Entrainment of the mammalian circadian clock by metabolism in the liver : a quantitative mathematical model  »

Faculté de Pharmacie de Lille, Amphithéâtre Jouvet
3 Rue du Professeur Laguesse – 59000 LILLE


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.