The glucocorticoid receptor (GR) is a nuclear receptor, a major drug target, and the end point of the hypothalamic-pituitary-adrenal axis. Glucocorticoids (GC) are essential for life, but in excess cause disordered energy metabolism, including increased weight gain, adiposity and hepatosteatosis; all programmes modulated by the circadian clock. Secretion of GC is regulated by the circadian clock, but could their actions be also? Here, using mouse as a model, we found that while the anti-inflammatory GC actions were maintained irrespective of dosing time, the liver was significantly more GC sensitive during the day. The time of day variation in GC action was underpinned by a physical interaction of GR with circadian transcription factor REVERBa, and co-binding with liver specific HNF transcription factors on chromatin. REVERBa promoted efficient GR recruitment to chromatin during the day, acting in part by maintaining histone acetylation, with REVERBa dependent GC-responses providing segregation of carbohydrate and lipid metabolism. Importantly, deletion of Reverba inverted circadian liver GC sensitivity, and protected mice from hepatosteatosis induced by chronic GC administration. Our results reveal a mechanism by which the circadian clock acts through REVERBa in liver on elements bound by HNF4A/HNF6 to direct GR action on energy metabolism.
18 - 21 May 2019
European Society of Endocrinology