Dynamic responses of the adrenal steroidogenic regulatory network.
Proceedings of the National Academy of Sciences
National Academy of Sciences
Copyright © 2017 National Academy of Sciences. This is an open access article.
The hypothalamic-pituitary-adrenal axis is a dynamic system regulating glucocorticoid hormone synthesis in the adrenal glands. Many key factors within the adrenal steroidogenic pathway have been identified and studied, but little is known about how these factors function collectively as a dynamic network of interacting components. To investigate this, we developed a mathematical model of the adrenal steroidogenic regulatory network that accounts for key regulatory processes occurring at different timescales. We used our model to predict the time evolution of steroidogenesis in response to physiological adrenocorticotropic hormone (ACTH) perturbations, ranging from basal pulses to larger stress-like stimulations (e.g., inflammatory stress). Testing these predictions experimentally in the rat, our results show that the steroidogenic regulatory network architecture is sufficient to respond to both small and large ACTH perturbations, but coupling this regulatory network with the immune pathway is necessary to explain the dissociated dynamics between ACTH and glucocorticoids observed under conditions of inflammatory stress.
This work was funded by the Medical Research Council (MRC) Grant MR/J008893/1 (to F.S., E.Z., J.J.W., Z.Z., J.R.T., and S.L.L.) and Fellowship MR/N008936/1 (to J.J.W.); the Wellcome Trust Grant WT105618MA (to J.J.W. and J.R.T.); and the Engineering and Physical Sciences Research Council (EPSRC) Grant EP/N014391/1 (to J.J.W., J.R.T., and S.L.L.).
This is the final version of the article. Available from National Academy of Sciences via the DOI in this record.
Available online 17 July 2017
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