Research Paper|Volume 6, Issue 8|pp 675—689

Metabolic clock generates nutrient anticipation rhythms in mTOR signaling

Rohini V. Khapre¹, Sonal A. Patel¹, Anna A. Kondratova², Amol Chaudhary¹, Nikkhil Velingkaar¹, Marina P. Antoch³, Roman V. Kondratov¹

¹Center for Gene Regulation in Health and Diseases, BGES, Cleveland State University, Cleveland, OH 44115, USA
²Department of Molecular Genetics, Cleveland Clinic, Cleveland, OH 44115, USA
³Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo NY 14263, USA

Received: August 20, 2014Accepted: August 24, 2014Published: August 26, 2014

https://doi.org/10.18632/aging.100686

Copyright: © 2014 Khapre et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The mTOR signaling pathway modulates metabolic processes with respect to nutrient availability and other growth-related cues. According to the existing paradigm, mTOR complex 1 (mTORC1) activity in vivo is induced by food and gradually decreases during fasting. We found that mTORC1 activity is controlled by an internal clock mechanism different from the known light-entrainable circadian clock. We observed 24-hr rhythms in phosphorylation of mTORC1 downstream targets, which were entrained by food, persisted during fasting and could be uncoupled from oscillating expression of the canonical circadian clock genes. Furthermore, these rhythms were present in tissues of mice with disrupted light-entrainable circadian clock. We propose tissue-specific rhythms in the expression of tor and its negative regulator deptor as the molecular mechanism of the mTORC1 activity oscillation. Our data demonstrate the existence of at least two independent molecular circadian clocks: one providing metabolic adaptation to periodic light/darkness and the other - to feeding.