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

Rhythmic gene expression is essential to the daily organization of biological processes. While cycling transcriptomes are regulated by circadian clocks present in nearly every cell, accumulating evidence indicates that they can also be initiated by rhythmic food-driven systemic signals independently of circadian clocks. The underlying mechanisms remain however largely unknown. Here, we show that signaling through the nutrient-sensing kinase mechanistic target of rapamycin (mTOR) is both necessary and sufficient to mediate food-driven hepatic rhythmic gene expression, rhythmic regulation of the liver metabolome, and endoplasmic reticulum stress response. Acute inhibition of mTOR before the active phase desynchronizes the phase of mTOR-driven rhythmic genes without affecting clock-controlled rhythmic genes, indicating that alignment of rhythmic mTOR activity to the circadian cycle is critical for overt cycling transcriptomes. These findings may explain how misalignment between clock and systemic signals contributes to disease and underscore the use of mTOR inhibitors for resynchronizing system-driven rhythms and alleviating circadian rhythm disorders.