The effects of apelin on hypothalamic–pituitary–adrenal axis neuroendocrine function are mediated through corticotrophin-releasing factor- and vasopressin-dependent mechanisms

The apelinergic system has a widespread expression in the central nervous system (CNS) including the paraventricular nucleus, supraoptic nucleus and median eminence, and isolated cells of the anterior lobe of the pituitary. This pattern of expression in hypothalamic nuclei known to contain corticotrophin-releasing factor (CRF) and vasopressin (AVP) and to co-ordinate endocrine responses to stress has generated interest in a role for apelin in the modulation of stress, perhaps via the regulation of hormone release from the pituitary. In this study, to determine whether apelin has a central role in the regulation of CRF and AVP neurones, we investigated the effect of i.c.v. administration of pGlu-apelin-13 on neuroendocrine function in male mice pre-treated with the CRF receptor antagonist, α-helical CRF(9–41), and in mice-lacking functional AVP V1b receptors (V1bR KO). Administration of pGlu-apelin-13 (1 mg/kg i.c.v.) resulted in significant increases in plasma ACTH and corticosterone (CORT), which were significantly reduced by pre-treatment with α-helical CRF(9–41), indicating the involvement of a CRF-dependent mechanism. Additionally, pGlu-apelin-13-mediated increases in both plasma ACTH and CORT were significantly attenuated in V1bR KO animals when compared with wild-type controls, indicating a role for the vasopressinergic system in the regulation of the effects of apelin on neuroendocrine function. Together, these data confirm that the in vivo effects of apelin on hypothalamic–pituitary–adrenal neuroendocrine function appear to be mediated through both CRF- and AVP-dependent mechanisms.