BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis.
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.
Rudic
R Daniel
RD
Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
McNamara
Peter
P
Curtis
Anne-Maria
AM
Boston
Raymond C
RC
Panda
Satchidananda
S
Hogenesch
John B
JB
Fitzgerald
Garret A
GA
D056930:ARNTL Transcription Factors; D000704:Analysis of Variance; D000821:Animal Feed; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D015992:Body Mass Index; D056926:CLOCK Proteins; D002940:Circadian Rhythm; D003345:Corticosterone / Q000378:metabolism; D004032:Diet; D017353:Gene Deletion; D005934:Glucagon / Q000378:metabolism; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis; D007003:Hypoglycemia / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D003345:Corticosterone; D005934:Glucagon; D005947:Glucose; D007328:Insulin; D015534:Trans-Activators; D014280:Triglycerides; C538961:Bmal1 protein, mouse; C538944:Clock protein, mouse