Abstract
Although the VGF derived peptide TLQP-21 stimulates gonadotropin-releasing hormone (GnRH) and gonadotropin secretion, available data on VGF peptides and reproduction are limited. We used antibodies specific for the two ends of the VGF precursor, and for two VGF derived peptides namely TLQP and PGH, to be used in immunohistochemistry and enzyme-linked immunosorbent assay complemented with gel chromatography. In cycling female rats, VGF C-/N-terminus and PGH peptide antibodies selectively labelled neurones containing either GnRH, or kisspeptin (VGF N-terminus only), pituitary gonadotrophs and lactotrophs, or oocytes (PGH peptides only). Conversely, TLQP peptides were restricted to somatostatin neurones, gonadotrophs, and ovarian granulosa, interstitial and theca cells. TLQP levels were highest, especially in plasma and ovary, with several molecular forms shown in chromatography including one compatible with TLQP-21. Among the cycle phases, TLQP levels were higher during metestrus-diestrus in median eminence and pituitary, while increased in the ovary and decreased in plasma during proestrus. VGF N- and C-terminus peptides also showed modulations over the estrous cycle, in median eminence, pituitary and plasma, while PGH peptides did not. In ovariectomised rats, plasmatic TLQP peptide levels showed distinct reduction suggestive of a major origin from the ovary, while the estrogen-progesterone treatment modulated VGF C-terminus and TLQP peptides in the hypothalamus-pituitary complex. In in vitro hypothalamus, TLQP-21 stimulated release of growth hormone releasing hormone but not of somatostatin. In conclusion, various VGF peptides may regulate the hypothalamus-pituitary complex via specific neuroendocrine mechanisms while TLQP peptides may act at further, multiple levels via endocrine mechanisms involving the ovary.
Highlights
The VGF gene product, and/or its derived peptides, appear to be involved in reproduction since vgf null mice were sexually immature and almost completely infertile [1]
VGF peptide immunolocalisation Immunoreactive VGF peptides were revealed in multiple areas of the reproductive axis as hypothalamus, including the preoptic area (POA) and median eminence, as well as in hypophyseal and ovarian cells (Fig. 2 and 3)
Products derived from the C-terminal domain of VGF have been studied in some detail [11,12] and the major molecular form/s we found in hypothalamus and pituitary may represent socalled VGF18 and 20
Summary
The VGF gene product, and/or its derived peptides, appear to be involved in reproduction since vgf null mice were sexually immature and almost completely infertile [1]. The 66 kDa VGF precursor [1,2,3,4,5,6] is composed of 617 or 615 amino acid residues (in rat or human, respectively), and gives rise to several low molecular weight VGF peptides which are abundant in multiple brain regions, peripheral neurones, and certain endocrine and neuroendocrine cell populations [7,8,9,10,11,12,13]. We addressed the localisation and changes of VGF peptides in the female rat reproductive axis in connection with the estrous cycle, as well as after ovariectomy Their presence and modulation in plasma was outlined in parallel, as a clue to their possible endocrine significance. In view of its selective distribution in the hypothalamus, the ability of the TLQP-21 peptide to release somatostatin or growth-hormonereleasing hormone (GHRH) was tested in vitro
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