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mTOR signaling regulates central and peripheral circadian clock function.

Chidambaram Ramanathan1, Nimish D Kathale1, Dong Liu2

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The mammalian/mechanistic target of rapamycin (mTOR) pathway regulates the body's internal clock. mTOR activity influences circadian clock speed and strength in cells and tissues, linking metabolism to timekeeping.

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Area of Science:

  • Chronobiology
  • Molecular Biology
  • Metabolism

Background:

  • The circadian clock regulates physiological and metabolic processes.
  • Mammalian/mechanistic target of rapamycin (mTOR) integrates nutrient and energy signals.
  • mTOR is known to influence the central circadian clock in the suprachiasmatic nucleus (SCN).

Purpose of the Study:

  • To investigate the role of mTOR in regulating autonomous clock functions in central and peripheral circadian oscillators.
  • To determine how mTOR affects intrinsic clock properties like period and amplitude.
  • To explore the link between metabolic status and circadian clock function via mTOR.

Main Methods:

  • Genetic and pharmacological approaches were used to manipulate mTOR activity.
  • Peripheral clock models (hepatocytes, adipocytes, fibroblasts) and ex vivo SCN and liver clocks were utilized.
  • Locomotor activity rhythms in mTOR heterozygous mice were analyzed.

Main Results:

  • mTOR inhibition lengthened circadian period and dampened amplitude in peripheral clocks.
  • mTOR activation shortened period and augmented amplitude in peripheral clocks.
  • mTOR perturbation affected period and amplitude in ex vivo SCN and liver clocks, and in mice.

Conclusions:

  • mTOR plays a significant role in regulating intrinsic circadian clock properties (period and amplitude).
  • mTOR activity influences circadian timekeeping in both central and peripheral oscillators.
  • The findings highlight mTOR's function in connecting metabolic states to circadian clock mechanisms.