“Insulin/IGF-1 drives PERIOD synthesis to entrain circadian rhythms with feeding time”

In mammals, endogenous circadian clocks sense and respond to daily feeding and lighting cues, adjusting internal ~24h 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 associated with increased incidence of chronic diseases (e.g., T2 diabetes, cancer). We show that feeding-regulated hormones insulin and IGF-1 reset circadian clocks in vivo and in vitro by induction of PERIOD proteins, and that mistimed insulin signalling disrupts circadian organisation of mouse behavior and clock gene expression. Insulin/IGF-1 receptor signalling is sufficient to determine essential circadian parameters, principally via increased PERIOD protein synthesis. This requires coincident mTOR activation, increased phosphoinositide signalling and microRNA down-regulation. Besides its well-known homeostatic functions, we propose insulin/IGF-1 is the primary signal of feeding time to cellular clocks throughout the body.

 

John O’Neill

MRC Laboratory of Molecular Biology (MRC LMB), Cambridge