Pancreatic β cell clocks attune insulin secretion to daily energy cycles, and desynchrony from genetic or behavioral disruptions triggers metabolic dysfunction, fueling type 2 diabetes risk. How ubiquitous circadian clocks orchestrate β cell-specific outputs, however, is not well understood. In particular, major questions remain as to how core vs. ancillary clock components synchronize β cell genes to coordinate overall metabolism.
To dissect the control of metabolism by state specific clock components, we studied DEC1, as it partakes in the transcriptional regulatory circuit defining mature β-cell identity. We show that DEC1 is specifically induced in adult β cells, and coordinates their glucose responsiveness by synchronizing energy metabolism and secretory gene oscillations. Dec1-ablated mice develop lifelong hypo-insulinemic diabetes, despite normal islet formation and intact circadian Clock and Bmal1 activators. Dec1-/- mice show normal food intake and patterns of activity and energy expenditure, with delayed phase onset but sustained period length. Yet, Dec1-/- mice show low energy expenditure during the active phase, consistent with a hypometabolic state. DEC1, but not CLOCK/BMAL1, binds maturity-linked genes that mediate respiratory metabolism and insulin exocytosis, and Dec1 loss disrupts their transcription synchrony. Accordingly, β-cell Dec1 ablation causes hypo-insulinemia due to poor insulin responses to glucose, as with immature fetal/neonatal islets. Thus, DEC1 links circadian clockwork to the β-cell maturation process, aligning metabolism to diurnal energy cycles.
These findings show that synchrony of energy metabolism pathways by adult-specific clockwork is critical for physiological coordination of metabolism. As clocks are activated in metabolic tissues during onset of feeding-fasting rhythms, an intriguing possibility is that they unlock phenotypic maturity by optimizing specialized cellular tasks to daily cycles in energy availability.
J.R. Alvarez: None.
