mTOR signaling regulates central and peripheral circadian clock function

Chidambaram Ramanathan, Nimish D. Kathale, Dong Liu, Choogon Lee, David A. Freeman, John B. Hogenesch, Ruifeng Cao, Andrew C. Liu

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

The circadian clock coordinates physiology and metabolism. mTOR (mammalian/mechanistic target of rapamycin) is a major intracellular sensor that integrates nutrient and energy status to regulate protein synthesis, metabolism, and cell growth. Previous studies have identified a key role for mTOR in regulating photic entrainment and synchrony of the central circadian clock in the suprachiasmatic nucleus (SCN). Given that mTOR activities exhibit robust circadian oscillations in a variety of tissues and cells including the SCN, here we continued to investigate the role of mTOR in orchestrating autonomous clock functions in central and peripheral circadian oscillators. Using a combination of genetic and pharmacological approaches we show that mTOR regulates intrinsic clock properties including period and amplitude. In peripheral clock models of hepatocytes and adipocytes, mTOR inhibition lengthens period and dampens amplitude, whereas mTOR activation shortens period and augments amplitude. Constitutive activation of mTOR in Tsc2–/–fibroblasts elevates levels of core clock proteins, including CRY1, BMAL1 and CLOCK. Serum stimulation induces CRY1 upregulation in fibroblasts in an mTOR-dependent but Bmal1- and Period-independent manner. Consistent with results from cellular clock models, mTOR perturbation also regulates period and amplitude in the ex vivo SCN and liver clocks. Further, mTOR heterozygous mice show lengthened circadian period of locomotor activity in both constant darkness and constant light. Together, these results support a significant role for mTOR in circadian timekeeping and in linking metabolic states to circadian clock functions.

Original languageEnglish (US)
Article numbere1007369
JournalPLoS Genetics
Volume14
Issue number5
DOIs
StatePublished - May 1 2018

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Circadian Clocks
Sirolimus
circadian rhythm
fibroblasts
metabolism
adipocytes
Suprachiasmatic Nucleus
hepatocytes
protein
locomotion
oscillation
cell growth
synchrony
physiology
protein synthesis
entrainment
serum
liver
mice
energy

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

Cite this

Ramanathan, C., Kathale, N. D., Liu, D., Lee, C., Freeman, D. A., Hogenesch, J. B., ... Liu, A. C. (2018). mTOR signaling regulates central and peripheral circadian clock function. PLoS Genetics, 14(5), [e1007369]. https://doi.org/10.1371/journal.pgen.1007369

mTOR signaling regulates central and peripheral circadian clock function. / Ramanathan, Chidambaram; Kathale, Nimish D.; Liu, Dong; Lee, Choogon; Freeman, David A.; Hogenesch, John B.; Cao, Ruifeng; Liu, Andrew C.

In: PLoS Genetics, Vol. 14, No. 5, e1007369, 01.05.2018.

Research output: Contribution to journalArticle

Ramanathan, C, Kathale, ND, Liu, D, Lee, C, Freeman, DA, Hogenesch, JB, Cao, R & Liu, AC 2018, 'mTOR signaling regulates central and peripheral circadian clock function', PLoS Genetics, vol. 14, no. 5, e1007369. https://doi.org/10.1371/journal.pgen.1007369
Ramanathan C, Kathale ND, Liu D, Lee C, Freeman DA, Hogenesch JB et al. mTOR signaling regulates central and peripheral circadian clock function. PLoS Genetics. 2018 May 1;14(5). e1007369. https://doi.org/10.1371/journal.pgen.1007369
Ramanathan, Chidambaram ; Kathale, Nimish D. ; Liu, Dong ; Lee, Choogon ; Freeman, David A. ; Hogenesch, John B. ; Cao, Ruifeng ; Liu, Andrew C. / mTOR signaling regulates central and peripheral circadian clock function. In: PLoS Genetics. 2018 ; Vol. 14, No. 5.
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