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Hepatic transcriptome response to glucocorticoid receptor activation in rainbow trout.

ABSTRACT: Stress induced elevation in plasma cortisol levels is shown to be involved in the metabolic re-adjustments to stress but the genetic basis of this response is still unclear. Cortisol signaling in teleosts is thought to be mediated predominantly by the glucocorticoid receptor (GR), a ligand-bound transcription factor and previous studies have shown that RU486, a GR antagonist offsets corticosteroid signaling in teleosts. In order to elucidate the genetic basis of GR-mediated metabolic re-adjustments, we exposed in vitro primary culture of trout hepatocytes to cortisol (100 ng/ml; stressed levels) or RU486 (1000 ng/ml) or a combination of both (RU486 + Cortisol), and analyzed the transcriptional responses using a low density custom-made targeted trout cDNA array. These results were further validated using quantitative real-time PCR. Cortisol treatment significantly increased glucose production in hepatocytes and this response is blocked by RU486 suggesting the activation of GR-mediated corticosteroid signaling. Cortisol treatment significantly modulated the transcript abundance of several genes, previously shown to be involved in molecular and biochemical responses to stress and most of these effects are abolished by RU486, suggesting GR-mediated effects. In addition, cortisol treatment affected key genes involved in reproduction supporting previous findings on inhibitory effects of cortisol on reproduction. Taken together, our results provide evidence on the transcriptional changes involved in cortisol signaling in response to stress. Keywords: cDNA microarray, RU486, Cortisol, GR signaling, rainbow trout, hepatocytes

ORGANISM(S): Oncorhynchus mykiss

PROVIDER: GSE7671 | GEO | 2007/05/02

SECONDARY ACCESSION(S): PRJNA99721

REPOSITORIES: GEO

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Project description:This a model from the article: Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability. Gupta S, Aslakson E, Gurbaxani BM, Vernon SD. Theor Biol Med Model 2007 Feb 14;4:8 17300722 , Abstract: BACKGROUND: The body's primary stress management system is the hypothalamic pituitary adrenal (HPA) axis. The HPA axis responds to physical and mental challenge to maintain homeostasis in part by controlling the body's cortisol level. Dysregulation of the HPA axis is implicated in numerous stress-related diseases. RESULTS: We developed a structured model of the HPA axis that includes the glucocorticoid receptor (GR). This model incorporates nonlinear kinetics of pituitary GR synthesis. The nonlinear effect arises from the fact that GR homodimerizes after cortisol activation and induces its own synthesis in the pituitary. This homodimerization makes possible two stable steady states (low and high) and one unstable state of cortisol production resulting in bistability of the HPA axis. In this model, low GR concentration represents the normal steady state, and high GR concentration represents a dysregulated steady state. A short stress in the normal steady state produces a small perturbation in the GR concentration that quickly returns to normal levels. Long, repeated stress produces persistent and high GR concentration that does not return to baseline forcing the HPA axis to an alternate steady state. One consequence of increased steady state GR is reduced steady state cortisol, which has been observed in some stress related disorders such as Chronic Fatigue Syndrome (CFS). CONCLUSION: Inclusion of pituitary GR expression resulted in a biologically plausible model of HPA axis bistability and hypocortisolism. High GR concentration enhanced cortisol negative feedback on the hypothalamus and forced the HPA axis into an alternative, low cortisol state. This model can be used to explore mechanisms underlying disorders of the HPA axis. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Gupta S, Aslakson E, Gurbaxani BM, Vernon SD. (2007) - version=1.0 The original CellML model was created by: Catherine Lloyd c.lloyd@auckland.ac.nz The University of Auckland This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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Hepatic transcriptome response to glucocorticoid receptor activation in rainbow trout.

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