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.
Endocrinology
; 142(1): 114-20, 2001 Jan.
Article
em En
| MEDLINE
| ID: mdl-11145573
ABSTRACT
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sistema Hipófise-Suprarrenal
/
Glucocorticoides
/
Hidroxiesteroide Desidrogenases
/
Sistema Hipotálamo-Hipofisário
Limite:
Animals
Idioma:
En
Revista:
Endocrinology
Ano de publicação:
2001
Tipo de documento:
Article
País de afiliação:
Reino Unido