Intracellular regeneration of glucocorticoids by 11beta-hydroxysteroid dehydrogenase (11beta-HSD)-1 plays a key role in regulation of the hypothalamic-pituitary-adrenal axis: analysis of 11beta-HSD-1-deficient mice.
11beta-Hydroxysteroid dehydrogenases (11beta-HSDs) catalyze interconversion of active corticosterone and inert 11-dehydrocorticosterone, thus regulating glucocorticoid access to intracellular receptors in vivo. 11beta-HSD type 1 is a reductase, locally regenerating active glucocorticoids. To explore the role of this isozyme in the brain, we examined hypothalamic-pituitary-adrenal axis (HPA) regulation in mice homozygous for a targeted disruption of the 11beta-HSD-1 gene. 11beta-HSD-1-deficient mice showed elevated plasma corticosterone and ACTH levels at the diurnal nadir, with a prolonged corticosterone peak, suggesting abnormal HPA control and enhanced circadian HPA drive. Despite elevated corticosterone levels, several hippocampal and hypothalamic glucocorticoid-sensitive messenger RNAs were normally expressed in 11beta-HSD-1-deficient mice, implying reduced effective glucocorticoid activity within neurons. 11beta-HSD-1-deficient mice showed exaggerated ACTH and corticosterone responses to restraint stress, with a delayed fall after stress, suggesting diminished glucocorticoid feedback. Indeed, 11beta-HSD-1-deficient mice were less sensitive to exogenous cortisol suppression of HPA activation. Thus 11beta-HSD-1 amplifies glucocorticoid feedback on the HPA axis and is an important regulator of neuronal glucocorticoid exposure under both basal and stress conditions in vivo.
Harris
H J
HJ
Molecular Endocrinology, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, Scotland, United Kingdom.
Kotelevtsev
Y
Y
Mullins
J J
JJ
Seckl
J R
JR
Holmes
M C
MC
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D002940:Circadian Rhythm; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D005246:Feedback; D005938:Glucocorticoids / Q000378:metabolism*; D006720:Homozygote; D006854:Hydrocortisone / Q000494:pharmacology; D006913:Hydroxysteroid Dehydrogenases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology*
D005938:Glucocorticoids; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D006913:Hydroxysteroid Dehydrogenases; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003345:Corticosterone; D006854:Hydrocortisone