Metabolic clock generates nutrient anticipation rhythms in mTOR signaling

Abstract

The mTOR signaling pathway modulates metabolic processes with respect to nutrient availability and other growth-related cues. According to the existing paradigm, mTOR complex 1 (mTORC1) activityin vivo is induced by food and gradually decreases during fasting. We found that mTORC1 activity is controlled by an internal clock mechanism different from the known light-entrainable circadian clock. We observed 24-hr rhythms in phosphorylation of mTORC1 downstream targets, which were entrained by food, persisted during fasting and could be uncoupled from oscillating expression of the canonical circadian clock genes. Furthermore, these rhythms were present in tissues of mice with disrupted light-entrainable circadian clock. We propose tissue-specific rhythms in the expression of tor and its negative regulator deptor as the molecular mechanism of the mTORC1 activity oscillation. Our data demonstrate the existence of at least two independent molecular circadian clocks: one providing metabolic adaptation to periodic light/darkness and the other - to feeding.