Intracellular Regeneration of Glucocorticoids by 11β-Hydroxysteroid Dehydrogenase (11β-HSD)-1 Plays a Key Role in Regulation of the Hypothalamic-Pituitary-Adrenal Axis: Analysis of 11β-HSD-1-Deficient Mice**The Wellcome Trust supported this work through a program grant (to J.J.M. and J.R.S.) and a Career Development Fellowship (to M.C.H.)

Autor: John J. Mullins, Yuri Kotelevtsev, Hayley J. Harris, Jonathan R. Seckl, Megan C. Holmes
Rok vydání: 2001
Předmět:
Zdroj: Endocrinology. 142:114-120
ISSN: 1945-7170
0013-7227
DOI: 10.1210/endo.142.1.7887
Popis: 11β-Hydroxysteroid dehydrogenases (11β-HSDs) catalyze interconversion of active corticosterone and inert 11-dehydrocorticosterone, thus regulating glucocorticoid access to intracellular receptors in vivo. 11β-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 11β-HSD-1 gene. 11β-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 11β-HSD-1-deficient mice, implying reduced effective glucocorticoid activity within neurons. 11β-HSD-1-deficient mice showed exaggerated ACTH and corticosterone responses to restraint stress, with a delayed fall after stress, suggesting diminished glucocorticoid feedback. Indeed, 11β-HSD-1-deficient mice were less sensitive to exogenous cortisol suppression of HPA activation. Thus 11β-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.
Databáze: OpenAIRE
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