An adult clock component links circadian rhythms to pancreatic ß-cell maturation
The circadian clock attunes metabolism to daily energy cycles, but how it regulates metabolic tissue maturation is not well understood. Here we show that DEC1, a clock transcription factor induced in adult islet ß cells, coordinates their glucose responsiveness by synchronizing energetic and secretory rhythms. DEC1 binds maturity-linked genes regulating integration of energy metabolism and insulin exocytosis, and ß-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 ß-cell Dec1 loss stems from poor coupling of insulin secretion to glucose metabolism, reminiscent of fetal/neonatal immaturity. We find that stunted maturation reflects an energetic deficit, marked by reduced glycolysis and compromised mitochondrial dynamics and respiration, which is rescued by increasing metabolic flux. Thus, DEC1 links circadian clockwork to ß-cell metabolic maturation, revealing a hierarchy for how the clock programs metabolic tissue specialization. Overall design: ChIP-sequencing of fixed Beta-TC6 cells