Glucocorticoids are important regulators of systemic homeostasis. However, the role of these steroid hormones has been mainly studied by using synthetic glucocorticoids or in states of glucocorticoid excess. Thus, the pathophysiologic consequences of cortisol deficiency on metabolic and biosynthesis pathways remain largely elusive. Zebrafish is a well-established vertebrate model for studying whole organism biology. Similar to humans, zebrafish are day active and the key glucocorticoid in zebrafish is cortisol. Thus zebrafish are an ideal model to study the pathophysiologic impact of cortisol deficiency in vivo. Our recently published ferredoxin (fdx1b) null-allele zebrafish line, disrupted in mitochondrial glucocorticoid synthesis, has massively decreased cortisol concentrations and a severely impaired stress response. This study aimed to define the global pathophysiologic response in vivo to glucocorticoid deficiency. To address this question, systemic profiling of the fdx1b null-allele zebrafish line was performed by a combination of RNA-sequencing and metabolomics analysis. Our results revealed an enrichment of genes in the fdx1b null-allele zebrafish line linked with pathways linked to metabolic disease. This includes significant alteration in expression of genes acting in pathways of energy and biomolecule synthesis (e.g., amino acids), and also antioxidant pathways. Metabolic profiling using Nuclear Magnetic Resonance spectroscopy/ Mass spectrometry approaches supported the observed transcriptome changes of the affected pathways. In addition, we discovered post-transcriptional regulation of genes of nucleotide metabolism by glucocorticoids. For the first time, we provide in vivo evidence on the global pathophysiologic effects of glucocorticoid deficiency. Such data are vital improving the understanding of the pathophysiology of adrenal insufficiency in humans and develop more physiologic replacement strategies.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology