Abrahams, L, Semjonous, NM, Guest, P et al. (4 more authors) (2012) Biomarkers of hypothalamic-pituitary-adrenal axis activity in mice lacking 11β-HSD1 and H6PDH. Journal of Endocrinology, 214 (3). 367 - 372. ISSN 0022-0795
Abstract
Glucocorticoid concentrations are a balance between production under the negative feedback control and diurnal rhythm of the hypothalamic-pituitary-adrenal (HPA) axis and peripheral metabolism, for example by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which catalyses the reduction of inactive cortisone (11-dehydrocorticosterone (11-DHC) in mice) to cortisol (corticosterone in mice). Reductase activity is conferred upon 11β-HSD1 by hexose-6-phosphate dehydrogenase (H6PDH). 11β-HSD1 is implicated in the development of obesity, and selective 11β-HSD1 inhibitors are currently under development. We sought to address the concern regarding potential up-regulation of the HPA axis associated with inhibition of 11β-HSD1. We assessed biomarkers for allele combinations of 11β-HSD1 and H6PD Hderived fromdouble heterozygous mouse crosses. H6PDH knock out (KO) adrenals were 69% larger than WT while 11β-HSD1 KO and double KO (DKO) adrenals were ~30% larger than WT - indicative of increased HPA axis drive in KO animals. ACTH-stimulated circulating corticosterone concentrations were 2.2-fold higher in H6PDH KO animals and ~1.5-fold higher in 11β-HSD1 KO and DKO animals compared with WT, proportional to the observed adrenal hypertrophy. KOof H6PDH resulted in a substantial increase in urinary DHC metabolites in males (65%) and females (61%). KO of 11β-HSD1 alone or in combination with H6PDH led to significant increases (36 and 42% respectively) in urinary DHC metabolites in females only. Intermediate 11β-HSD1/H6PDH heterozygotes maintained a normal HPA axis. Urinary steroid metabolite profile by gas chromatography/ mass spectrometry as a biomarker assay may be beneficial in assaying HPA axis status clinically in cases of congenital and acquired 11β-HSD1/H6PDH deficiency.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2012 Society for Endocrinology. This is an Open Access article distributed under the terms of the Society for Endocrinology’s Re-use Licence which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. For terms and conditions go to http://www.endocrinology-journals.org/site/misc/Reuse_licence.xhtml |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Medicine & Health Faculty Office (Leeds) > Faculty Office Functions (FOMH) (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 05 Nov 2014 10:20 |
Last Modified: | 06 Nov 2014 17:56 |
Published Version: | http://dx.doi.org/10.1530/JOE-12-0178 |
Status: | Published |
Publisher: | BioScientifica |
Identification Number: | 10.1530/JOE-12-0178 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:81082 |