Abstract
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.
Highlights
Most living organisms adapt to predictable daily changes in food availability and sunlight thanks to a light- and food-entrainable circadian clock system
Animals develop metabolic symptoms such as hypoinsulinemia, hypertriglyceridemia and hyperglycemia (Fig. 1B,C). This leads to the following question: If everything is inverted compared to the physiological situation, why do animals exhibit metabolic symptoms? In other words, if the inversion of food access leads to a 12 h phase shift in food intake and peripheral clock gene expression, why is it that nutrient- and clock-responsive gene transcription and insulin secretion is disturbed rather than just shifted by 12 h? A careful observation of experimental data[18] indicates that while food intake and nutrient cues are shifted by 12 h, there is a gene-specific phase shift in clock gene expression: some genes are shifted by 12 h while others only shift by 8 h (Fig. 1D–F)
Our model predicts that this induces a non-concomitance between nutrient cues and clock-controlled exocytosis cues controlling insulin secretion which results in hypoinsulinemia, hyperglyceridemia as well as in a loss of food anticipation
Summary
Most living organisms adapt to predictable daily changes in food availability and sunlight thanks to a light- and food-entrainable circadian clock system. Mukherji et al have investigated the metabolic effect of shifting mice from nighttime to daytime feeding (Fig. 1A)[18,19] In this case, the phase of metabolic markers (levels of blood glucose, insulin, free fatty acids,...) and clock gene expression is inverted. A careful observation of experimental data[18] indicates that while food intake and nutrient cues are shifted by 12 h, there is a gene-specific phase shift in clock gene expression: some genes are shifted by 12 h while others only shift by 8 h (Fig. 1D–F) This 8 h shift in clock gene expression is observed in several tissues including liver and pancreas. Our model enables us to discuss the role of the widespread circadian control of metabolism by comparing the properties of the physiological network with those of alternative architectures (last section)
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