Cellular localization of apelin and its receptor in the anterior pituitary: evidence for a direct stimulatory action of apelin on ACTH release

Abstract

Reaux-Le Goazigo A, Alvear-Perez R, Zizzari P, Epelbaum J, Bluet-Pajot MT, Llorens-Cortes C. Cellular localization of apelin and its receptor in the anterior pituitary: evidence for a direct stimulatory action of apelin on ACTH release. Am J Physiol Endocrinol Metab 292: E7-E15, 2007. First published August 8, 2006; doi:10.1152/ajpendo.00521.2005.-Apelin is a bioactive peptide recently identified as the endogenous ligand of the human orphan G protein-coupled receptor APJ. The presence of apelin-immunoreactive nerve fibers, together with the detection of apelin receptor mRNA in the parvocellular part of the paraventricular nucleus and the stimulatory action of apelin on corticotropin-releasing hormone release, indicate that apelin modulates adrenocorticotropin (ACTH) release via an indirect action on the hypothalamus. However, a direct action of apelin in the anterior pituitary cannot be excluded. Here, we provided evidence for the existence of an apelinergic system within the adult male rat pituitary gland. Double immunofluorescence staining indicated that apelin is highly coexpressed in the anterior pituitary, mainly in corticotrophs (96.5 Ϯ 0.3%) and to a much lower extent in somatotropes (3.2 Ϯ 0.2%). Using in situ hybridization combined with immunohistochemistry, a high expression of apelin receptor mRNA was also found in corticotrophs, suggesting a local interaction between apelin and ACTH. In an ex vivo perifusion system of anterior pituitaries, apelin 17 (K17F, 10 Ϫ6 M) significantly increased basal ACTH release by 41%, whereas apelin 10 (R10F, 10 Ϫ6 M), an inactive apelin fragment, was ineffective. In addition, K17F but not R10F induced a dose-dependent increase in K ϩ -evoked ACTH release, with maximal increase being observed for a 10 Ϫ6 M concentration. Taken together, these data outline the potential role of apelin as an autocrine/paracrine-acting peptide on ACTH release and provide morphological and neuroendocrine basis for further studies that explore the physiological role of apelin in the regulation of anterior pituitary functions.hypothalamo-pituitary-adrenal axis; apelin; apelin receptor; adrenocorticotropin APELIN IS A BIOACTIVE PEPTIDE recently isolated from bovine stomach extracts and identified as the endogenous ligand of the human orphan G protein-coupled receptor APJ (26,40). Apelin is a 36-amino acid peptide derived from 77-amino acid precursor proapelin, for which cDNAs have been cloned from humans, cattle, rats, and mice (12,18,40). This precursor exhibits a fully conserved COOH-terminal sequence between Trp-55 and Phe-77, including the COOH-terminal 17 (LysPhe-Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-ProMet-Pro-Phe, apelin 17, or K17F) and 13 (Gln-Arg-Pro-ArgLeu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe, apelin 13, or Q13F) amino acid sequences. In vivo, in the rat hypothalamus and plasma, we have characterized the predominant molecular forms of endogenous apelin as corresponding to the pyroglutamyl form of Q13F (pE13F) and, to a lesser extent, to K17F (8). These apelin fragments display the...

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

“…Apelin may potentially stimulate the secretion of ACTH either directly at the level of the pituitary corticotroph or via an indirect action on the hypothalamus involving the release of both VP and CRH. Consistent with the expression of apelin and APJ in anterior pituitary corticotrophs, administration of apelin-17 directly increases the release of ACTH, while also augmenting K C -stimulated ACTH release, in an ex vivo perfusion system of anterior pituitary glands, suggesting possible autocrine or paracrine functions for apelin in this tissue (Reaux-Le Goazigo et al 2007). Central administration of (Pyr 1 )apelin-13 in rats also increases plasma ACTH and CORT levels while decreasing prolactin, luteinising hormone and follicle-stimulating hormone levels (Taheri et al 2002).…”

“…Further studies focusing on the PVN, SON, median eminence and dorsolateral accessory magnocellular nucleus have shown strong labelling for apelin and co-localisation with VP (Brailoiu et al 2002) and with oxytocin (OT; Brailoiu et al 2002) in the SON and PVN. Apelin is also co-localised with adrenocorticotrophin (ACTH) in corticotrophs and to a lesser extent with growth hormone in somatotropes in the anterior pituitary (Reaux-Le Goazigo et al 2007).…”

Effects of antihypertensive treatment on plasma apelin, resistin, and visfatin concentrations

“…6 Immunoactivity of apelin and its receptor have been also found in the brain, including hypothalamus. 7 This is consistent with a potential role of apelin in the control of pituitary hormone release, 8 body fluid equilibrium, and drinking behavior. 9 It has been shown that apelin expression is increased by tumor necrosis factor α (TNF-α) 10 and hypoxia-inducible factor 1-α 11 (HIF-1α) and decreased by aldosterone.…”

Apelin and the proopiomelanocortin system: a new regulatory pathway of hypothalamic α-MSH release

“…Apelin receptor antisense and sense cRNA probes were synthesized by in vitro transcription as previously described (20,58). Sections were hybridized with the apelin receptor antisense and sense cRNA probes as previously described (20,63).…”