An adult clock regulator links circadian rhythms to pancreatic β-cell maturation.

Abstract

The circadian clock attunes metabolism to daily energy cycles, but how it regulates maturation of metabolic tissues is poorly understood. Here we show that DEC1, a clock transcription factor induced in adult islet β cells, coordinates their glucose responsiveness by synchronizing energetic and secretory rhythms. DEC1 binds and regulates maturity-linked genes to integrate insulin exocytosis with energy metabolism, and β-cell Dec1 ablation disrupts their transcription synchrony. Dec1-disrupted mice develop lifelong glucose intolerance and insulin deficiency, despite normal islet formation and intact Clock/Bmal1 genes. Metabolic dysfunction upon β-cell Dec1 loss stems from poor coupling of insulin secretion to glucose metabolism, reminiscent of fetal/neonatal 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 β-cell metabolic maturation, revealing a hierarchy for how the clock programs metabolic tissue specialization.