mTOR signalling, not clock gene rhythms, organises daily physiology

Abstract

Daily rhythms in mammalian physiology are widely attributed to rhythmic transcription of "clock-controlled genes" driven by the circadian transcriptional/translational feedback loop (TTFL). Here we show that daily physiology can be uncoupled from the TTFL: inhibiting the mechanistic target of rapamycin (mTOR) abolishes most daily variation in cellular and organismal physiology, whilst clock protein rhythms persist. In cultured cells and mouse liver, functional rhythms are lost, including the proteome, RNA abundance, substrate utilisation and drug metabolism. In forebrain, most daily variation in protein abundance and phosphorylation is lost, yet locomotor activity and sleep-wake architecture are largely preserved in mice and zebrafish. PERIOD2 binds mTORC1 and limits its activity, providing a route by which clock proteins shape daily mTOR signalling. mTOR inhibition preferentially suppresses output over clock gene rhythms in Arabidopsis and Neurospora. We conclude that mTOR is a conserved conduit through which circadian and environmental timing impose daily organisation on physiology.