REV-ERBα alters circadian rhythms by modulating mTOR signaling

Dec 7, 2020Molecular and cellular endocrinology

REV-ERBα may change daily biological rhythms by affecting mTOR signaling

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Inhibition of liver mTORC1 by leucine results in low-amplitude circadian rhythms.

REV-ERBα is involved in the regulation of the mTORC1 signaling pathway.
Overexpression of REV-ERBα activates mTORC1 by inhibiting its natural inhibitor, Tsc1.
Activation of mTORC1 is associated with increased phosphorylation of the circadian clock protein BMAL1.
Changes in mTORC1 activity can alter circadian rhythms in mouse muscle.
Both activation and inhibition of mTORC1 may influence circadian rhythms.

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REV-ERBα is a nuclear receptor that inhibits Bmal1 transcription as part of the circadian clock molecular mechanism. Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a master regulator of cell and whole-body energy homeostasis, that serves as an important link between metabolism and circadian clock, in part, by regulating BMAL1 activity. While the connection of REV-ERBα to the circadian clock molecular mechanism is well characterized, the interaction between mTORC1, REV-ERBα and the circadian clock machinery is not very clear. We used leucine and rapamycin to modulate mTORC1 activation and evaluate this effect on circadian rhythms. In the liver, mTORC1 was inhibited by leucine. REV-ERBα overexpression activated the mTORC1 signaling pathway via transcription inhibition of mTORC1 inhibitor, Tsc1, antagonizing the effect of leucine, while its silencing downregulated mTORC1 signaling. Activation of mTORC1 led to increased BMAL1 phosphorylation. Activation as well as inhibition of mTORC1 led to altered circadian rhythms in mouse muscle. Inhibition of liver mTORC1 by leucine or rapamycin led to low-amplitude circadian rhythms. In summary, our study shows that leucine inhibits liver mTORC1 pathway leading to dampened circadian rhythms. REV-ERBα activates the mTORC1 pathway, leading to phosphorylation of the clock protein BMAL1.

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REV-ERBα alters circadian rhythms by modulating mTOR signaling

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