Glucocorticoid deficiency causes transcriptional and post-transcriptional reprogramming of glutamine metabolism

Abstract

BackgroundDeficient glucocorticoid biosynthesis leading to adrenal insufficiency is life-threatening and is associated with significant co-morbidities. The affected pathways underlying the pathophysiology of co-morbidities due to glucocorticoid deficiency remain poorly understood and require further investigation.MethodsTo explore the pathophysiological processes related to glucocorticoid deficiency, we have performed global transcriptional, post-transcriptional and metabolic profiling of a cortisol-deficient zebrafish mutant with a disrupted ferredoxin (fdx1b) system.Findingsfdx1b−/− mutants show pervasive reprogramming of metabolism, in particular of glutamine-dependent pathways such as glutathione metabolism, and exhibit changes of oxidative stress markers. The glucocorticoid-dependent post-transcriptional regulation of key enzymes involved in de novo purine synthesis was also affected in this mutant. Moreover, fdx1b−/− mutants exhibit crucial features of primary adrenal insufficiency, and mirror metabolic changes detected in primary adrenal insufficiency patients.InterpretationOur study provides a detailed map of metabolic changes induced by glucocorticoid deficiency as a consequence of a disrupted ferredoxin system in an animal model of adrenal insufficiency. This improved pathophysiological understanding of global glucocorticoid deficiency informs on more targeted translational studies in humans suffering from conditions associated with glucocorticoid deficiency.FundMarie Curie Intra-European Fellowships for Career Development, HGF-programme BIFTM, Deutsche Forschungsgemeinschaft, BBSRC.

Glucocorticoid receptor activities in the zebrafish model: a review

“…The VBA assay is based on the neuroendocrine response determining the shrinkage of zebrafish melanocytes when larvae are exposed to bright background (Kurrasch et al 2009). Nowadays, this test is used in strains defective in the synthesis of GCs for the preliminary selection of homozygous recessive larvae, in which this response is lost (Griffiths et al 2012, Griffin et al 2016, Eachus et al 2017, Facchinello et al 2017, Weger et al 2018, Gans et al 2020, Marchi et al 2020.…”

“…Knockdown of the other paralog gene, fdx1, severely impairs early zebrafish development, thus preventing the analysis of its effects on the steroidogenic pathway (Griffin et al 2016). Subsequent analysis by Weger et al (2018) of the fdx1b cortisol-deficient zebrafish line focused both on metabolic changes and on the expression of genes involved in metabolic pathways. Results were then compared with those obtained both from a zebrafish model of secondary adrenal insufficiency, the chokh/rx3 strong mutant fish line that presents corticotrope cells deficiency associated with reduced cortisol levels (Dickmeis et al 2007), and from human patients affected by primary insufficiency.…”

Zebrafish for Personalized Regenerative Medicine; A More Predictive Humanized Model of Endocrine Disease

“…For instance, the diet of diabetic larva model is not similar to its adult model or various mutations (yet similar) result in fatty liver in larva and adult zebrafish. T1DM, Type1 diabetes mellitus; T2DM, Type2 diabetes mellitus; NAFLD, Non-alcoholic fatty liver disease; NASH, Nonalcoholic steatohepatitis; Tg, Transgenic line; IGF1R, Insulin-like growth factor1 receptor; EGFP, Enhanced green fluorescent protein; NTR, Nitroreductase; MTZ, Metronidazole; AgRP, Agouti-related protein; cyp2r1, Cytochrome p450 family2 subfamily R member1; plxnd1, Plexin D1; cdipt, Cytidine diphosphate-diacylglycerol-inositol 3-phosphatidyltransferase; pck1, Phosphoenolpyruvate-carboxykinase, Luc2, Luciferase gene; vmp1, Vacuole membrane protein1; il1b, Interleukin 1 beta; fdx1, Ferredoxin1; rx3, Retinal homeobox gene3; lia, Limabsent; ndr2, Nodal related gene (Cyclops) (9,50,62,85,86,(93)(94)(95)(96)(97)(98)(99)(100)(101)(102)(103)(104).…”

Redox-mediated Kick-Start of Mitochondrial Energy Metabolism drives Resource-efficient Seed Germination

“…combined for each biological replicate. Extraction and quantification of metabolites by UPLC or GC-MS was performed as described (63)(64)(65) and normalized to seed dry weight. Dry seeds were imbibed at 25 °C for 0 h, 1 h or 4 h in unsealed reaction tubes with 250 µL H2O at 25 °C under gentle shaking before metabolite extraction.…”