Cryptochromes mediate rhythmic repression of the glucocorticoid receptor

Abstract

Mammalian metabolism is highly circadian and major hormonal circuits involving nuclear hormone receptors (NRs) display interlinked diurnal cycling1,2. However, mechanisms that logically explain the coordination of NRs and the clock are poorly understood. Here we show that two circadian co-regulators, cryptochromes 1 (Cry1) and 2 (Cry2), interact with the glucocorticoid receptor (GR) in a ligand-dependent fashion and globally alter the transcriptional response to glucocorticoids in mouse embryonic fibroblasts (MEFs): Cry deficiency vastly decreases gene repression and approximately doubles the number of dexamethasone (Dex) induced genes suggesting that cryptochromes broadly oppose GR activation and promote repression. In mice, genetic loss of Cry1 and/or Cry2 resulted in glucose intolerance and constitutively high levels of circulating corticosterone, suggesting reduced suppression of the hypothalamic-pituitary-adrenal (HPA) axis coupled with increased glucocorticoid transactivation in the liver. Genomically, Cry1 and Cry2 associate with a glucocorticoid response element (GRE) in the phosphoenolpyruvate carboxykinase 1 (Pck1) promoter in a hormone-dependent manner, and Dex-induced transcription of pck1 was strikingly increased in Cry-deficient livers. These results reveal a specific mechanism through which cryptochromes couple the activity of clock and receptor target genes to complex genomic circuits underpinning normal metabolic homeostasis.

Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines

“…CRY proteins are known to regulate glucose homeostasis by at least two different mechanisms. They bind to and repress glucocorticoid receptors (37), which regulate transcription of gluconeogenic genes. CRY proteins also bind to and inhibit G α s function, thereby attenuating GPCR-activation-dependent increase in intracellular cAMP (38).…”

Circadian Rhythm Disruption and Metabolic Syndrome

“…간에서만 Bmal1을 제거한 연구에서는 간에서 당을 조절하는 유 전자들(glucose-6-phosphate translocase 1, g l u c o k i n a s e, p y r u v a t e k i n a s e, g l u c o s e transporter 2등)의 리듬조절이 소실되었으며 간에서 의 당 생성에 결함이 생겼다 [21]. Clock과 Bmal1에 의 해 조절되는 Cry1의 증가는 cAMP의 증가를 억제하고 이어서 C r e b (c A M P r e s p o n s e e l e m e n tbindingprotein)의 인산화를 억제하여 포도당신생합성 에 관여하는 유전자들의 발현을 줄이며, Cry1 -/-과 Cry2 -/-마우스에서 시상하부-뇌하수체-부신축의 억 제를 줄여 순환성 코티코스테론의 증가를 통해 내당능 장애가 발생한다는 연구도 있다 [22,23].…”

Horloges circadiennes et métabolisme : intégration des signaux métaboliques et environnementaux

“…Par ailleurs, une délétion de bmal1 spéci-fiquement dans le foie entraîne une hypoglycémie durant la phase de repos, une augmentation de la clairance du glucose et des altérations du rythme circadien des gènes du métabolisme hépatique du glucose [14]. Une déficience pour Cry provoque, au contraire, une dérépres-sion de la gluconéogenèse et une hyperglycémie [15,16]. Ces données suggèrent qu'il existe un rôle spécifique des composants de l'horloge qui dépendent de l'organe et de la phase du cycle (utilisation ou stockage contre synthèse de novo).…”

“…Plusieurs autres récepteurs nucléaires font partie du coeur du mécanisme de l'horloge. Rev-erb/ et ROR-, qui régulent et sont régulés par l'hétérodimère CLOCK/BMAL1, interagissent également avec Per2 et Cry [15,34,50,51]. Rev-erb et Rev-erb corégulent les gènes de la lipogenèse de façon circadienne permettant d'assurer l'homéostasie lipidique.…”