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

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 and 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 suggests a pharmacological approach to resetting the clock in obesity. [Display omitted] •We construct a mathematical model of the mammalian liver clock and metabolic sensors•The model integrates feeding and fasting cycles with the clock•The model accurately reproduces high-fat-diet-induced loss of NAD+ oscillations•NAD+ oscillations are predicted to be rescued by timed delivery of clock modifiers Woller et al. construct a mathematical model that describes a link between the mammalian circadian clock and metabolic cycles in the liver. They use this model to understand how specific diets may disrupt the clock and to predict how such clock disruptions might be alleviated.