Glucocorticoid regulation of the circadian clock modulates glucose homeostasis.
Circadian clock genes are regulated by glucocorticoids; however, whether this regulation is a direct or secondary effect and the physiological consequences of this regulation were unknown. Here, we identified glucocorticoid response elements (GREs) at multiple clock genes and showed that 3 were directly regulated by the glucocorticoid receptor. We determined that a GRE within the core clock gene Per2 was continuously occupied during rhythmic expression and essential for glucocorticoid regulation of that gene in vivo. We further demonstrated that mice with a genomic deletion spanning this GRE expressed elevated leptin levels and were protected from glucose intolerance and insulin resistance on glucocorticoid treatment but not from muscle wasting. We conclude that Per2 is an integral component of a particular glucocorticoid regulatory pathway and that glucocorticoid regulation of the peripheral clock is selectively required for some actions of glucocorticoids.
So
Alex Y -L
AY
Department of Pediatrics, University of California, 513 Parnassus Drive, San Francisco, CA 94143, USA.
Bernal
Teresita U
TU
Pillsbury
Marlisa L
ML
Yamamoto
Keith R
KR
Feldman
Brian J
BJ
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D020738:Leptin / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics; D056950:Period Circadian Proteins; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic
C470968:Bhlhb3 protein, mouse; D018797:Cell Cycle Proteins; D005938:Glucocorticoids; D020738:Leptin; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors; D005947:Glucose