Tissue-specific expression of 11β-HSD and its effects on plasma corticosterone during the stress response

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis is under complex regulatory control at multiple levels. Enzymatic regulation plays an important role in both circulating levels of glucocorticoids and target tissue exposure. Three key enzyme pathways are responsible for the immediate control of glucocorticoids. De novo synthesis of glucocorticoid from cholesterol involves a multistep enzymatic cascade. This cascade terminates with 11β-hydroxylase, responsible for the final conversion of 11-deoxy precursors into active glucocorticoids. Additionally, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) controls regeneration of glucocorticoids from inactive metabolites, providing a secondary source of active glucocorticoids. Localized inactivation of glucocorticoids is under the control of Type 2 11β-HSD (11β-HSD2). The function of these enzymes is largely unexplored in wild species, particularly songbirds. Here, we investigated the contribution of both clearance and generation of glucocorticoids to regulation of the hormonal stress response via the use of pharmacological antagonists. Additionally, we mapped 11β-HSD gene expression. We found 11β-HSD1 primarily in liver, kidney and adrenal glands, although it was detectable across all tissue types. 11β-HSD2 was predominately expressed in the adrenal glands and kidney with moderate gonadal and liver expression. Inhibition of glucocorticoid generation by metyrapone was found to decrease levels peripherally, while both peripheral and central administration of the 11β-HSD2 inhibitor DETC resulted in elevated concentrations of corticosterone. These data suggest that during the stress response, peripheral antagonism of the 11β-HSD system has a greater impact on circulating glucocorticoid levels than central control. Further studies should aim to elucidate the respective roles of the 11β-HSD and 11β-hydroxylase enzymes.

Keywords: 11β-HSD; Corticosterone; Glucocorticoid; HPA axis; Hypothalamic–pituitary–adrenal axis; Negative feedback; Songbird; Stress.