Mammalian metabolism is highly circadian and major hormonal circuits involving 
nuclear hormone receptors display interlinked diurnal cycling. However, 
mechanisms that logically explain the coordination of nuclear hormone receptors 
and the clock are poorly understood. Here we show that two circadian 
co-regulators, cryptochromes 1 and 2, interact with the glucocorticoid receptor 
in a ligand-dependent fashion and globally alter the transcriptional response to 
glucocorticoids in mouse embryonic fibroblasts: cryptochrome deficiency vastly 
decreases gene repression and approximately doubles the number of 
dexamethasone-induced genes, suggesting that cryptochromes broadly oppose 
glucocorticoid receptor activation and promote repression. In mice, genetic loss 
of cryptochrome 1 and/or 2 results in glucose intolerance and constitutively 
high levels of circulating corticosterone, suggesting reduced suppression of the 
hypothalamic-pituitary-adrenal axis coupled with increased glucocorticoid 
transactivation in the liver. Genomically, cryptochromes 1 and 2 associate with 
a glucocorticoid response element in the phosphoenolpyruvate carboxykinase 1 
promoter in a hormone-dependent manner, and dexamethasone-induced transcription 
of the phosphoenolpyruvate carboxykinase 1 gene was strikingly increased in 
cryptochrome-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.