Orexins stimulate corticosterone secretion of rat adrenocortical cells, through the activation of the adenylate cyclase-dependent signaling cascade

Orexins-A and B are two novel hypothalamic peptides, which, like leptin and neuropeptide-Y (NPY), are involved in the central regulation of feeding. S ince leptin and NPY were found to modulate adrenal function, we have examin ed whether orexins are able to directly affect rat adrenal steroid secretio n. Both orexin-A and orexin-B raised basal corticosterone secretion of disp ersed rat zona fasciculata-reticularis (ZF/R) cells, their maximal effectiv e concentration being 10(-8) M. In contrast, orexins did not affect either maximally ACTH (10(-9) M)-stimulated corticosterone production by ZF/R cell s or the basal and agonist-stimulated aldosterone secretion of dispersed zo na glomerulosa cells. The ACTH-receptor antagonist corticotropin-inhibiting peptide (10(-6) M) annulled corticosterone response of ZF/R cells to ACTH (10-9 M), but not to orexins (10-8 M). Orexins (10(-8) M) enhanced cyclic-A MP release by ZF/R cells, and the selective inhibitor of protein-kinase A ( PKA) H-89 (10(-5) M) abolished corticosterone responses to both ACTH (10(-9 ) M) and orexins (10-8 M). A subcutaneous injection of both orexins (5 or 1 0 nmol/kg) evoked a clear-cut increase in the plasma concentration of corti costerone (but not aldosterone), the effect of orexin-A being significantly more intense than that of orexin-B. Collectively, these findings suggest t hat orexins exert a selective and direct glucocorticoid secretagogue action on the rat adrenals, acting through a receptor-mediated activation of the adenylate cyclase/PKA-dependent signaling pathway. (C) 1999 Elsevier Scienc e Ltd. All rights reserved.