Steroid hormones are important regulators of many physiological processes. The steroid precursor pregnenolone is converted through several enzymatic steps into all types of steroids, including the stress hormone cortisol. Mitochondrial steroidogenic cytochrome P450 (CYP) enzymes crucially relying on electron transfer from the redox partner ferredoxin (FDX1) are involved in key steps of the cortisol biosynthesis pathway.
Cortisol is well-known regulator of glucose metabolism; however, only little is known about the impact of cortisol deficiency on metabolic pathways during embryonic development. Zebrafish represents a vertebrate model using cortisol as main glucocorticoid hormone. Thus, it lends itself as a whole organism model to study the impact of cortisol deficiency on metabolism during development. By genomic engineering we have generated a mutant fdx1b null-allele zebrafish line. Fdx1b represents the zebrafish equivalent of human FDX1. fdx1b deficient embryos appear darker due to a failure in their Visual Background Adaptation (VBA) behaviour, a glucocorticoid mediated pigmentation response in teleosts. Being in line with this observation, hyperpigmentation due to cortisol deficiency is also observed in humans with primary adrenal insufficiency. Interestingly, hyperpigmentation in the fdx1b mutants can be rescued after glucocorticoid replacement with dexamethasone suggesting dysregulation of the stress axis after fdx1b disruption. Indeed, in fdx1b mutant larvae pomc is significantly increased and cortisol synthesis and signalling is significantly impaired. Moreover, fdx1b mutant larvae have a blunted cortisol response to stress. Metabolomic analysis by nuclear magnetic resonance (NMR) spectroscopy reveals severe changes on the global metabolome in fdx1b null-alleles impairing metabolites also linked with human pathogenesis.
In conclusion, the fdx1b mutant line is a promising in vivo model to explore the pathophysiologic impact of glucocorticoid deficiency on energy metabolism relevant to early development and potentially adult life.