mTOR signaling contributes to system-driven rhythmic gene expression in mouse liver

Rhythmic gene expression is essential to the temporal organization of biological processes across the day. While this rhythmicity is regulated by the circadian clock present in nearly every cell, accumulating evidence indicates that cycling transcriptomes are also controlled by rhythmic systemic signals that originate from the daily rhythm of food intake and that bypass peripheral clocks to initiate rhythmic transcription. The underlying mechanisms remain however largely unknown. Here, we show that signaling through the nutrient-sensing kinase mTOR is both necessary and sufficient to mediate food intake-driven rhythmic gene expression in mouse liver. Pharmacological inhibition of mTOR just before the active phase desynchronizes the phase of mTOR-driven rhythmic genes without affecting clock-controlled rhythmic genes. Importantly, clock-driven and mTOR-driven genes regulate similar biological pathways, suggesting that desynchronization between clock and systemic signals, such as in shift workers, contributes to desynchronized rhythms in gene expression and consequently to disease. Our findings also suggest that using mTOR inhibitors to re-synchronize rhythms driven by systemic signals may help alleviate circadian rhythm disorders.