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PLoS Genet. 2018 May 11;14(5):e1007369. doi: 10.1371/journal.pgen.1007369. eCollection 2018 May.

mTOR signaling regulates central and peripheral circadian clock function.

Author information

1
Department of Biological Sciences, University of Memphis, Memphis, Tennessee, United States of America.
2
Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, Minnesota, United States of America.
3
Department of Biomedical Sciences, Program in Neuroscience, College of Medicine, Florida State University, Tallahassee, Florida, United States of America.
4
Divisions of Human Genetics and Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
5
Department of Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
6
Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida, United States of America.

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.

PMID:
29750810
PMCID:
PMC5965903
DOI:
10.1371/journal.pgen.1007369
[Indexed for MEDLINE]
Free PMC Article

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