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

Summary

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.

Graphical Abstract

Highlights

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  Insulin and IGF-1 are a systemic synchronizing cue for circadian rhythms in mammals

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  Insulin and IGF-1 signaling rapidly upregulates translation of PERIOD clock proteins

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  Coincident signaling facilitates selective induction of PERIOD synthesis

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  Circadian disruption is recapitulated by mistimed insulin in cell and animal models

Abstract

Feeding-associated hormones insulin and IGF-1 entrain circadian rhythms throughout the body by induction of PERIOD clock proteins.