Mammalian metabolism is highly circadian and major hormonal circuits involving nuclear hormone receptors display interlinked diurnal cycling1,2. 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.
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We thank S. Kaufman for assistance with glucose tolerance tests, J. Alvarez for RNA sample preparation, H. Juguilon for luciferase assays, J. Vaughan for corticosterone and ACTH measurements, antigenic peptide design and peptide-KLH coupling reactions, H. Cho for sharing unpublished plasmids and R. Shaw for comments on the manuscript. This work was supported by National Institutes of Health grants DK057978 and DK062434 (to R.M.E.) and DK090188 (to K.A.L.), by support from the Glenn Foundation for Aging Research (to R.M.E. and K.A.L.), from the Helmsley Trust (to R.M.E.) and by a Merck fellowship from the Life Sciences Research Foundation (to K.A.L.).
The authors declare no competing financial interests.
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Lamia, K., Papp, S., Yu, R. et al. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature 480, 552–556 (2011). https://doi.org/10.1038/nature10700
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