DEC1 is an adult clock regulator that links circadian rhythms to functional β-cell maturation

Abstract

Circadian clocks attune metabolism to daily energy cycles, but how they regulate functional maturation of metabolic tissues is poorly understood. Here we show that DEC1, a clock transcription factor induced in adult islet {beta} cells, coordinates their glucose responsiveness by synchronizing energetic and secretory rhythms. DEC1 binds and regulates maturity-linked genes to integrate insulin exocytosis with {beta}-cell energy metabolism, and {beta}-cell-specific Dec1 ablation disrupts their transcription synchrony. Dec1-disrupted mice develop lifelong glucose intolerance and insulin deficiency, despite normal islet formation. Metabolic dysfunction upon {beta}-cell Dec1 loss stems from poor coupling of islet insulin secretion to glucose metabolism, reminiscent of fetal/neonatal islet immaturity. We link stunted maturation to a deficit in circadian bioenergetics, prompted by compromised glucose utilization, mitochondrial dynamics, and respiratory metabolism, which is rescued by increased metabolic flux. Thus, DEC1 links circadian clockwork to {beta}-cell metabolic maturation, revealing a hierarchy for how the clock programs metabolic tissue specialization.