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

Priya Crosby,Ryan Hamnett,Marrit Putker,Nathaniel P Hoyle,Martin Reed,Carolyn J Karam,Elizabeth S Maywood,Alessandra Stangherlin,Johanna E Chesham,Edward A Hayter,Lyn Rosenbrier-Ribeiro,Peter Newham,Hans Clevers,David A Bechtold,John S O’Neill

doi:10.1016/j.cell.2019.02.017

Abstract

SummaryIn 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.

Highlights

Circadian rhythms, endogenous $24 h oscillations, are intrinsic to the biology of most multicellular organisms (Dunlap, 1999; Roenneberg and Merrow, 2005), controlling the temporal organization of many physiological and cellular functions (Green et al, 2008)
A small increase (14% ± 5%) in subsequent amplitude of PER2::LUC rhythms was evident (Figure 3D) suggesting that insulin has some activity in the suprachiasmatic nucleus (SCN), but network coupling renders rhythms robust against the resetting seen in other cell types
Insulin and insulin-like growth factor 1 (IGF-1) Increases PER Protein Selectively We investigated the selectivity of clock gene induction by insulin by comparing induction of PER2 by insulin with other growth factors (Figure S3)

Summary

Introduction

Endogenous $24 h oscillations, are intrinsic to the biology of most multicellular organisms (Dunlap, 1999; Roenneberg and Merrow, 2005), controlling the temporal organization of many physiological and cellular functions (Green et al, 2008). Circadian timekeeping has a cell-autonomous basis (Balsalobre et al, 2000a; Welsh et al, 2005) with a machinery that comprises several interlinked transcriptional, translational, and post-translational feedback mechanisms. This drives the cycling auto-repression of ‘‘clock gene’’ transcription factors PER1/2/3 and CRY1/2 and rhythmic regulation of myriad clock-controlled genes (Takahashi, 2017). Nighttime feeding elicits conflicting cues, associated with reduced amplitude of physiological and clock gene rhythms (Archer et al, 2014; Dijk et al, 2012), and adverse metabolic and cardiovascular consequences (Salgado-Delgado et al, 2013; Scheer et al, 2009). Understanding how the body’s cellular clocks respond and adapt to changes in feeding time will inform strategies for maintaining individual fitness, supporting healthy aging, and public health policy

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