Circadian clocks in peripheral organs are set by metabolic cues. Lamia et al. (see also the commentary by Bass) investigated whether circadian clocks regulate metabolism and found that the cryptochrome proteins Cry1 and Cry2, which are components of the circadian clock, interact with various nuclear hormone receptors, including the glucocorticoid receptor. The interaction of Cry1 with the glucocorticoid receptor was enhanced by the synthetic glucocorticoid dexamethasone and decreased the ability of the glucocorticoid receptor to transcriptionally activate a luciferase reporter gene. Compared with fibroblasts from wild-type mice, dexamethasone treatment of fibroblasts from mice deficient in both cytochromes (cry1–/–;cry2–/–) decreased the number of genes that were transcriptionally repressed, increased the number of genes that were transcriptionally activated, and increased the extent of transcriptional activation of a specific target gene (sgk1, which encodes serum- and glucocorticoid-regulated kinase 1). At night, glucocorticoids are less effective at inducing the expression of pck1, the gene encoding the gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1, and the association of Cry1 and Cry2 with the glucocorticoid response element in the pck1 promoter increased at night after dexamethasone treatment. In addition, dexamethasone-triggered induction of pck1 expression was increased in livers from cry1–/–;cry2–/– mice compared with those from wild-type mice. Long-term dexamethasone treatment suppressed production of endogenous corticosterone to a lesser extent in cry1–/–;cry2–/– mice than in wild-type mice, which suggests a role for cryptochromes in the negative-feedback loop that suppresses glucocorticoid synthesis. Long-term dexamethasone treatment also triggered more pronounced fasting hyperglycemia and glucose intolerance in cry1–/–;cry2–/– mice compared with wild-type mice. Thus, cryptochromes inhibit glucose metabolism by suppressing transcription through the glucocorticoid receptor.
K. A. Lamia, S. J. Papp, R. T. Yu, G. D. Barish, N. H. Uhlenhaut, J. W. Jonker, M. Downes, R. M. Evans, Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature 480, 552–556 (2011). [PubMed]
J. Bass, On time metabolism. Nature 480, 466-467 (2011). [Online Journal]