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Mtor Signaling Regulates Central And Peripheral Circadian Clock Function

Title: Mtor Signaling Regulates Central And Peripheral Circadian Clock Function.
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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
Text
Journal Article
Date Issued: 2018-05-01
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: The circadian clock coordinates physiology and metabolism. mTOR (mammalianmechanistic 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_libsubv1_wos_000434016500019 (IID), 10.1371/journal.pgen.1007369 (DOI)
Keywords: gene-expression, metabolism, entrainment, phosphorylation, suprachiasmatic nucleus, mice, physiology, translational control, mammals, pathway
Publication Note: The publisher’s version of record is available at https://doi.org/10.1371/journal.pgen.1007369
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_libsubv1_wos_000434016500019
Owner Institution: FSU
Is Part Of: Plos Genetics.
1553-7404
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 http://purl.flvc.org/fsu/fd/FSU_libsubv1_wos_000434016500019