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Endocrinology Vol. 142, No. 1 114-120
Copyright © 2001 by The Endocrine Society

ARTICLES

Intracellular Regeneration of Glucocorticoids by 11ß-Hydroxysteroid Dehydrogenase (11ß-HSD)-1 Plays a Key Role in Regulation of the Hypothalamic-Pituitary-Adrenal Axis: Analysis of 11ß-HSD-1-Deficient Mice1

Hayley J. Harris, Yuri Kotelevtsev, John J. Mullins, Jonathan R. Seckl and Megan C. Holmes

Molecular Endocrinology, Molecular Medicine Centre, (H.J.H., J.R.S.) and Department of Clinical Neurosciences (M.C.H.), University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, Scotland, United Kingdom; and Molecular Physiology, Wilkie Building (Y.K., J.J.M.), University of Edinburgh, Edinburgh, EH8, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Dr. Megan C. Holmes, Molecular Endocrinology, Molecular Medicine Centre, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, United Kingdom. E-mail: megan.holmes{at}ed.ac.uk

11ß-Hydroxysteroid dehydrogenases (11ß-HSDs) catalyze interconversion of active corticosterone and inert 11-dehydrocorticosterone, thus regulating glucocorticoid access to intracellular receptors in vivo. 11ß-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 11ß-HSD-1 gene. 11ß-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 11ß-HSD-1-deficient mice, implying reduced effective glucocorticoid activity within neurons. 11ß-HSD-1-deficient mice showed exaggerated ACTH and corticosterone responses to restraint stress, with a delayed fall after stress, suggesting diminished glucocorticoid feedback. Indeed, 11ß-HSD-1-deficient mice were less sensitive to exogenous cortisol suppression of HPA activation. Thus 11ß-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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