Elimination of Foxo triplets following glucocorticoid incubation dampened metabolic stress and enhanced anti-viral response targets based on transcriptomic analysis

Abstract

Glucocorticoids, both endogenous and exogenous, are known anti-inflammatory agents with associated adverse effects when administered chronically or in excess. Foxo family members, specifically Foxo1, Foxo3 and Foxo4 have demonstrated to be major regulators of metabolic complications following glucocorticoid action. We employed mouse embryonic fibroblasts as model system and using tamoxifen induced Cre+ recombinase activation, we achieved deletion of the Foxo triplets- Foxo1, Foxo3, and Foxo4. Following incubation of dexamethasone in both wild type and Foxo triplet deleted group, RNA sequencing was performed to reveal the transcriptome. Interestingly, the transcripts involved in initiating metabolic stress like PDK4 and 11 Beta HSD1 were downregulated, whereas transcripts involved in anti-viral response were upregulated following Foxo triplet deletion. The anti-inflammatory property of glucocorticoids was kept intact based on transcripts evaluated including GILZ and COX2. In summary, our study reveals a unique phenomenon where we will be able to manipulate glucocorticoid action by deleting Foxo triplets eliminating the metabolic stress components but enhancing anti-viral response and maintaining their clinical use as an anti-inflammatory agent. This work will lay foundation for a paradigm shift in clinical use of glucocorticoids according to therapeutic advantage with lesser adverse effects