Abstract
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.
Highlights
Life on Earth is subject to periodic changes in its environment as induced by Earth’s rotation
Dbp served as an example of a clock-controlled gene, other theoretical studies assumed that it belongs to the clock network (Korencic et al, 2012)
We did not take into account post-translational protein modifications except those induced by SIRT1 and AMPK, nor compartmentalization, considering that transport between cytoplasm and nucleus is fast on a circadian timescale
Summary
Life on Earth is subject to periodic changes in its environment as induced by Earth’s rotation. Most organisms anticipate these daily variations and orchestrate biological processes by relying on a circadian clock, a network of molecular interactions generating biochemical oscillations within a period close to 24 hr (Dibner et al, 2010). As the alternation of day and night is the primary environmental signal, light is generally the dominant circadian cue at the organismal level. Most cells contain a self-sustained circadian oscillator (Dibner et al, 2010) that does not, receive the light signal directly. The mammalian circadian system relies on a central synchronizer, the suprachiasmatic nucleus (SCN), a group of neurons that receives photic inputs and drives other circadian oscillators in the brain and in other organs through various channels (Dibner et al, 2010)
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