ESPE Abstracts (2022) 95 RFC5.3

ESPE2022 Rapid Free Communications Adrenals and HPA Axis (6 abstracts)

Towards understanding the metabolic phenotype of glucocorticoid deficiency in 21-hydroxylase deficiency

Irina Bacila 1,2 , Nan Li 2 , Helen Eachus 2 , Karl-Heinz Storbeck 3 , Vincent T Cunliffe 2,4 & Nils P Krone 1,2,5

1The University of Sheffield, Sheffield, United Kingdom; 2The Bateson Centre, Sheffield, United Kingdom; 3Stellenbosch University, Stellenbosch, South Africa; 4Department of Biomedical Science, Sheffield, United Kingdom; 5University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

Background: Steroid 21-hydroxylase deficiency (21OHD) is the most common form of congenital adrenal hyperplasia. Patients present with cortisol and aldosterone deficiency as well as with hyperandrogenism, leading to virilisation in females and early adrenarche in both sexes. Requiring life-long glucocorticoid (GC) replacement, patients frequently experience daily fluctuations between GC overexposure and deficiency. Increased prevalence of metabolic disease contributes to raised morbidity and mortality in 21OHD. However, there is limited knowledge regarding the mechanisms leading to increased risk of metabolic disease. We previously established a zebrafish model of 21OHD deficiency in which we demonstrated interrenal hyperplasia in larvae. We aimed to explore the metabolic phenotype of cyp21a2-deficient zebrafish, in order to gain insight into the pathophysiology of metabolic problems in 21OHD.

Methods: We assessed the adult phenotype of cyp21a2-/- zebrafish and studied differential gene expression between mutant and wild-type fish in both 5-day-old larvae and 18 months-old adult fish livers by transcriptomic analysis following RNA-sequencing.

Results: Although steroid hormone analysis by LC/MSMS confirmed severe cortisol deficiency, cyp21a2-/- mutant zebrafish reached adulthood, had normal secondary sexual characteristics and were able to reproduce in the absence of hormonal replacement. Body measurements showed that adult cyp21a2-/- mutants were significantly larger than wild-type fish (P< 0.001, n=8-10), with greater weight and length. Macroscopic analysis following dissections revealed increased visceral and subcutaneous fat in mutants compared to wild-type siblings. Blood sugar levels varied widely with no significant difference between mutants and wild-type fish. Differential gene expression and statistical overrepresentation analysis of gene ontology terms showed significant (P<10-5) dysregulation of several metabolic processes (small molecule, alpha-amino acid, organic acid, carboxylic acid, lipid metabolism) in both mutant larvae and adult livers. In mutant larvae the most prominent findings were downregulation of gluconeogenesis, glycolysis, insulin signalling, triglyceride and fatty acid biosynthesis. Transcriptomic analysis of adult livers indicated downregulation of fatty acid oxidation and upregulation of fatty acid biosynthesis, deranged lipid transport and adipocyte differentiation with increased lipid accumulation.

Conclusion: Our findings suggest a dynamic dysregulation of several metabolic pathways in the cortisol-deficient cyp21a2 zebrafish model in keeping with their adult phenotype characterised by increased fat mass. Overall, our results suggest that GC deficiency contributes to the metabolic co-morbidities presented by patients with 21OHD, further highlighting the need for further research into the molecular and cellular mechanisms underlying this condition, and the importance of establishing optimised replacement regimes for patients that minimise lack and overexposure to GCs.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

Browse other volumes

Article tools

My recent searches

No recent searches.