Biomarkers of hypothalamic-pituitary-adrenal axis activity in mice lacking 11β-HSD1 and H6PDH.
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.
School of Clinical and Experimental Medicine, Institute of Biomedical Research, Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Lianne
L
Abrahams
Nina M
NM
Semjonous
Phil
P
Guest
Agnieszka
A
Zielinska
Beverly
B
Hughes
Gareth G
GG
Lavery
Paul M
PM
Stewart
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000311:Adrenal Glands / Q000473:pathology / Q000502:physiology; D000312:Adrenal Hyperplasia, Congenital / Q000175:diagnosis / Q000201:enzymology / Q000652:urine; D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000652:urine; D002237:Carbohydrate Dehydrogenases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods*; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D010913:Pituitary-Adrenal System / Q000502:physiology*; D012727:Sex Characteristics; D013256:Steroids / Q000032:analysis / Q000652:urine
D015415:Biomarkers; D013256:Steroids; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003345:Corticosterone