The mTOR pathway drives daily physiology

Abstract

How molecular clocks drive daily rhythms in mammalian physiology remains poorly understood. Here we show that the mechanistic target of rapamycin (mTOR) pathway is required for most daily variation in cellular and organismal physiology. PERIOD2 binds to mTORC1 and limits its activity, providing a route by which the clock shapes daily mTOR signalling. Pharmacological mTOR inhibition abolishes functional rhythms in cultured cells and most daily variation in mouse hepatic physiology, including the proteome, RNA abundance, substrate utilisation and drug metabolism. In forebrain, mTOR activity is required for most daily variation in protein abundance and phosphorylation, yet sleep-wake architecture is largely preserved in mice and zebrafish, with a selective increase in wakefulness. Clock protein and locomotor rhythms persist throughout, and output rhythms are preferentially suppressed in Arabidopsis and Neurospora. We conclude that mTOR acts as a conserved conduit through which circadian and environmental timing signals impose daily organisation on physiology.