A. Zeng, A. Mihut, M. Anandapadamanaban, A. Goity, L. L. de Barros Dantas, S.-Y. Peak Chew, E. A. Hayter, L. C. Andersson, T. Smith, E. Seinkmane, A. Stangherlin, N. R. James, C. Beresford, J. Farnsworth, J. Menzies, A. al-Rawi, L. J. Holt, E. Derivery, R. S. Edgar, R. R. Madsen, D. A. Bechtold, L. F. Larrondo, A. N. Dodd, J. Rihel, G. M. Ratto, J. Williams, P. Newham, C. Hilgendorf, A. D. Beale, C. Lodovichi, J. S. O'Neill
Circadian rhythms in transcription are facilitated by well-defined genetic circuits, but how molecular clocks drive daily rhythms in mammalian physiology is poorly understood. The mechanistic target-of-rapamycin (mTOR) complex integrates daily systemic and circadian intracellular timing cues for input into the cellular timekeeping machinery. Here we demonstrate that mTOR is a major clock output pathway whose activity is required for most daily variation in cellular and organismal physiology, with PERIOD2 shown to interact directly with mTORC1. Acute mTOR inhibition abolishes functional rhythms in cells and most daily variation in mouse liver physiology. mTOR activity is not required for clock protein or locomotor rhythms, indicating that mTOR is not part of the cellular or central circadian timekeeping mechanism. In the forebrain, mTOR activity is required for most detectable daily rhythms in protein abundance and phosphorylation; however, the daily architecture of the sleep/wake cycle is remarkably preserved in mice and zebrafish under mTOR blockade, with a significant increase in wakefulness. Clock outputs in Arabidopsis (plant) and Neurospora (fungus) are also more sensitive to mTOR inhibition than core clock mechanisms indicating evolutionary conservation of mTOR as a circadian effector. We conclude that most but not all daily physiological rhythms in mammalian cells and tissues depend on rhythmic regulation by the mTOR pathway.