AbstractCirculating adrenal glucocorticoids exhibit characteristic circadian and ultradian rhythms, important for maintaining homeostasis and regulating multiple physiological processes. Glucocorticoids exert genomic actions on target cells via a ligand activated transcription factor, the glucocorticoid receptor (GR). In the liver, GR regulates transcription of many critical determinants of carbohydrate and fat metabolism. Furthermore, glucocorticoids been implicated in metabolic disorders including insulin resistance, hyperlipidaemia and non-alcoholic fatty liver disease. Despite the increasing prevalence of metabolic disease in western society, the relative contribution of glucocorticoid rhythm disturbance, particularly ultradian dysregulation, has been largely unexplored.
Using GR ChIP-Seq of livers taken from corticosterone treated adrenalectomised (ADX) rats, I have found that ultradian replacement induces ~3,000 GR binding events at the pulse peak, all of which are lost at the pulse nadir. I have further demonstrated that constant corticosterone infusion results in prolonged GR binding. To assess effects on gene transcription, I have also performed RNA polymerase II ChIP-Seq with an antibody specific for the actively transcribing form of the complex. Using pSer2 RNA polymerase II binding as proxy for active gene transcription, I found similarly synchronised, predominantly down-regulated transcriptional modulation in response to corticosterone pulses. Whereas in response to constant corticosterone, prolonged and mostly upregulated transcription was detected.
Notably, functional pathway analysis showed that differentially regulated targets were involved in glucose, carbohydrate, cholesterol, fatty acid, lipid, proliferative and necrotic pathways. My findings support the hypothesis that glucocorticoid pattern dysregulation leads to dysregulation of key metabolic targets in the liver, potentially contributing to the development of metabolic syndrome.
Finally, I present the development of a novel rodent corticosterone replacement model that incorporates both circadian and ultradian rhythms for use in longer duration studies where I plan to test the metabolic outcome of chronic glucocorticoid dysregulation. This approach shows great potential for ultradian research, particularly for translational studies.
|Date of Award||1 Oct 2019|
|Supervisor||Becky L Conway-Campbell (Supervisor) & Stafford L Lightman (Supervisor)|