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Biomarkers of hypothalamic–pituitary–adrenal axis activity in mice lacking 11β-HSD1 and H6PDH
- Source :
- The Journal of Endocrinology
- Publication Year :
- 2012
- Publisher :
- BioScientifica, 2012.
-
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 H6PDH derived from double 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. KO of 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.
- Subjects :
- Male
medicine.medical_specialty
endocrine system
Hypothalamo-Hypophyseal System
Endocrinology, Diabetes and Metabolism
Metabolite
Urinary system
Pituitary-Adrenal System
030209 endocrinology & metabolism
Biology
Gas Chromatography-Mass Spectrometry
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Endocrinology
Corticosterone
Internal medicine
11-beta-Hydroxysteroid Dehydrogenase Type 1
Adrenal Glands
medicine
Animals
Circadian rhythm
030304 developmental biology
Mice, Knockout
0303 health sciences
Sex Characteristics
Adrenal Hyperplasia, Congenital
Regular Papers
Heterozygote advantage
Organ Size
medicine.anatomical_structure
chemistry
Carbohydrate Dehydrogenases
Female
Steroids
Cortisone
Hypothalamic–pituitary–adrenal axis
Glucocorticoid
hormones, hormone substitutes, and hormone antagonists
Biomarkers
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 14796805 and 00220795
- Volume :
- 214
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- The Journal of Endocrinology
- Accession number :
- edsair.doi.dedup.....f9d2aea2fda5e660af1629b28c0bdc05