BMAL1 and CLOCK, Two Essential Components of the Circadian Clock, Are Involved in Glucose Homeostasis

TLDR

Circadian timing is generated by a molecular clock of autoregulatory interactions that produce well‑characterized behavioral rhythms and can be altered by asynchronous dietary cues. The study investigates the role of Bmal1 and Clock in regulating glucose homeostasis. Loss of Bmal1 or Clock abolishes diurnal glucose and triglyceride rhythms, suppresses gluconeogenesis, preserves counterregulatory hormone responses to insulin‑induced hypoglycaemia, and, under a high‑fat diet, amplifies circadian glucose tolerance and insulin sensitivity, with Clock mutation restoring the normal phenotype, demonstrating that these clock genes critically control glucose homeostasis and recovery from hypoglycaemia.

Abstract

Circadian timing is generated through a unique series of autoregulatory interactions termed the molecular clock. Behavioral rhythms subject to the molecular clock are well characterized. We demonstrate a role for Bmal1 and Clock in the regulation of glucose homeostasis. Inactivation of the known clock components Bmal1 (Mop3) and Clock suppress the diurnal variation in glucose and triglycerides. Gluconeogenesis is abolished by deletion of Bmal1 and is depressed in Clock mutants, but the counterregulatory response of corticosterone and glucagon to insulin-induced hypoglycaemia is retained. Furthermore, a high-fat diet modulates carbohydrate metabolism by amplifying circadian variation in glucose tolerance and insulin sensitivity, and mutation of Clock restores the chow-fed phenotype. Bmal1 and Clock, genes that function in the core molecular clock, exert profound control over recovery from insulin-induced hypoglycaemia. Furthermore, asynchronous dietary cues may modify glucose homeostasis via their interactions with peripheral molecular clocks.