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Cell. 2019 May 2;177(4):896-909.e20. doi: 10.1016/j.cell.2019.02.017. Epub 2019 Apr 25.

Insulin/IGF-1 Drives PERIOD Synthesis to Entrain Circadian Rhythms with Feeding Time.

Author information

1
MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
2
MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK; Hubrecht Institute, Utrecht 3584 CT, the Netherlands.
3
Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK.
4
Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge CB4 0FZ, UK.
5
Hubrecht Institute, Utrecht 3584 CT, the Netherlands; Princess Máxima Centre, Utrecht 3584 CS, the Netherlands.
6
MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. Electronic address: oneillj@mrc-lmb.cam.ac.uk.

Abstract

In mammals, endogenous circadian clocks sense and respond to daily feeding and lighting cues, adjusting internal ∼24 h rhythms to resonate with, and anticipate, external cycles of day and night. The mechanism underlying circadian entrainment to feeding time is critical for understanding why mistimed feeding, as occurs during shift work, disrupts circadian physiology, a state that is associated with increased incidence of chronic diseases such as type 2 (T2) diabetes. We show that feeding-regulated hormones insulin and insulin-like growth factor 1 (IGF-1) reset circadian clocks in vivo and in vitro by induction of PERIOD proteins, and mistimed insulin signaling disrupts circadian organization of mouse behavior and clock gene expression. Insulin and IGF-1 receptor signaling is sufficient to determine essential circadian parameters, principally via increased PERIOD protein synthesis. This requires coincident mechanistic target of rapamycin (mTOR) activation, increased phosphoinositide signaling, and microRNA downregulation. Besides its well-known homeostatic functions, we propose insulin and IGF-1 are primary signals of feeding time to cellular clocks throughout the body.

KEYWORDS:

IGF-1; PERIOD; circadian; food entrainment; insulin; mTORC1; miRNA

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