Modeling clock-related metabolic syndrome due to conflicting light and food cues

Most organisms possess a light- and food- entrainable circadian clock system enabling their adaptation to daily environmental changes in sunlight and food availability. The mammalian circadian system is composed of multiple clocks throughout the body. These local clocks are entrained by nutrient, neural, endocrine and temperature cues and drive diverse physiological functions including metabolism. In particular, the clock of the pancreatic β cell rhythmically regulates the transcription of genes involved in glucose-stimulated insulin secretion. Perturbations of this fine-tuned oscillatory network increase the susceptibility to diseases. Besides chronic jet lag and shift work, common perturbations are ill-timed eating patterns which can lead to metabolic troubles (such as hypoinsulinemia). We have built a mathematical model describing the clock-dependent pancreatic regulation of glucose homeostasis in rodents. After calibrating the model using experimental data, we have investigated the effect of restricting food access to the normal rest phase. Our simulations show that the conflict between the light-dark cycle and the feeding-fasting cycle creates a differential phase shift in the expression of core clock genes (consistent with experimental observations). Our model further predicts that this induces a non-concomitance between nutrient cues and clock-controlled cues driving metabolic outputs which results in hypoinsulinemia, hyperglycemia as well as in a loss of food anticipation.