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mTOR signaling regulates central and peripheral circadian clock function.

Title: mTOR signaling regulates central and peripheral circadian clock function.
Name(s): Ramanathan, Chidambaram, author
Kathale, Nimish D, author
Liu, Dong, author
Lee, Choogon, author
Freeman, David A, author
Hogenesch, John B, author
Cao, Ruifeng, author
Liu, Andrew C, author
Type of Resource: text
Genre: Journal Article
Date Issued: 2018-05-11
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: 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.
Identifier: FSU_pmch_29750810 (IID), 10.1371/journal.pgen.1007369 (DOI), PMC5965903 (PMCID), 29750810 (RID), 29750810 (EID), PGENETICS-D-17-02178 (PII)
Grant Number: R01NS054794 , NS099813
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at
Subject(s): 3T3-L1 Cells
Cell Line
Cells, Cultured
Circadian Clocks/genetics
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Signal Transduction/genetics
Suprachiasmatic Nucleus/cytology
Suprachiasmatic Nucleus/metabolism
TOR Serine-Threonine Kinases/genetics
TOR Serine-Threonine Kinases/metabolism
Tuberous Sclerosis Complex 2 Protein
Tumor Suppressor Proteins/genetics
Tumor Suppressor Proteins/metabolism
Persistent Link to This Record:
Host Institution: FSU
Is Part Of: PLoS genetics.
Issue: iss. 5, vol. 14

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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. Retrieved from