Tanzeel HUMA, Farhad ULLA, Farnaz HANIF, Joshua D. RIZAK, Muhammad SHAHAB

Peripheral administration of kisspeptin antagonist does not alter basal plasma testosterone but decreases plasma adiponectin levels in adult male rhesus macaques

Kisspeptin signaling is a potent regulator of the reproductive axis and an elicitor of gonadotropin-releasing hormone secretion. The present study assessed the effect of the peripheral administration of a kisspeptin antagonist (P234) on testosterone secretion in the adult male rhesus monkey. Five monkeys were administered with either P234 (38.8 µg/kg body weight) or a vehicle (0.9% saline). Plasma testosterone and adiponectin levels, as a positive control, were then measured using specific ELISA assays from blood samples collected sequentially at 15-min intervals from 60 min prior to until 360 min after the P234/vehicle injection. In 3 monkeys, the experiment was repeated where the animals received a kisspeptin-10 (50 µg) challenge 30 min after the P234 or vehicle treatment. No effects on basal testosterone levels were found after the systemic administration of P234. Plasma adiponectin levels were found to be briefly decreased by P234. P234 administration was found to suppress kisspeptin-dependent testosterone release and to inhibit kisspeptin-dependent adiponectin release. This suggested that the systemic administration of P234 was effective peripherally. However, the minimal peripheral effects on testosterone secretion in the male macaque suggested that P234 did not cross the blood-brain barrier and blocked the peripheral kisspeptin receptors.

Anahtar Kelimeler:

Kisspeptin, peptide 234, testosterone, rhesus monkey, adiponectin, reproduction

Peripheral administration of kisspeptin antagonist does not alter basal plasma testosterone but decreases plasma adiponectin levels in adult male rhesus macaques

Keywords:

Kisspeptin, peptide 234, testosterone, rhesus monkey, adiponectin, reproduction,

PDF

___

Brailoiu GC, Dun SL, Ohsawa M, Yin D, Yang J, Chang JK, Brailoiu E, Dun NJ (2005). KiSS-1 expression and metastin-like immunoreactivity in the rat brain. J Comp Neurol 481: 314– 329.
Brown RE, Imran SA, Ur E, Wilkinson M (2008). KiSS-1 mRNA in adipose tissue is regulated by sex hormones and food intake. Mol Cell Endocrinol 28: 64–72. de Roux Genin NE, Carel JC, Matsuda F, Chaussain JL, Milgrom E (2003). Hypogonadotropic hypogonadism due to loss of function of the Kiss1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A 100: 10972–10976.
Dhillo WS, Chaudhri OB, Patterson M, Thompson EL, Murphy KG, Badman MK, McGowan BM, Amber V, Patel S, Ghatei MA et al., (2005). Kisspeptin-54 stimulates the hypothalamic- pituitary gonadal axis in human males. J Clin Endocrinol Metab 90: 6609–6615.
Funes S, Hedrick JA, Vassileva G, Markowitz L, Abbondanzo S, Golovko A, Yang S, Monsma FJ, Gustafson EL (2003). The KiSS- 1 receptor GPR54 is essential for the development of the murine reproductive system. Biochem Biophys Res Commun 312: 1357– 1363.
Guerriero KA, Keen KL, Millar RP, Terasawa E (2012). Developmental changes in GnRH release in response to kisspeptin agonist and antagonist in female rhesus monkeys (Macaca mulatta): implication for the mechanism of puberty. Endocrinology 153: 825–836.
Inoue N, Pheng V, Inamoto Y, Uenoyama Y, Tsukamura H, Ichikawa M, Maeda KI (2008). Kisspeptin fibers directly contact with gonadotropin-releasing hormone fibers in the median eminence of female rats. In: Proceedings of the First World Conference on Kisspeptin Signaling in the Brain, Cordoba, Spain, p. 74.
Irfan S, Anees, M, Wahab F, Zaman U, Shahab M, Plant TM (2008). Evidence for a direct intratesticular action of kisspeptin in the adult rhesus monkey (Macaca mulatta). In: Program of the 90th Annual Meeting of the Endocrine Society, San Francisco, CA, USA.
Lee DK, Nguyen T, O’Neill GP, Cheng R, Liu Y, Howard AD, Coulombe N, Tan CP, Tang-Nguyen AT, George SR et al. (1999). Discovery of a receptor related to the galanin receptors. FEBS Lett 446: 103–107.
Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A, Szekeres PG, Sarau HM, Chambers JK, Murdock P et al. (2001). AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem 276: 28969–28975.
Navarro VM, Castellano JM, Fernandez-Fernandez R, Barreiro ML, Roa J, Sanchez-Criado JE, Aguilar E, Dieguez C, Pinilla L, Tena- Sempere M (2004). Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide. Endocrinology 145: 4565–4574.
Oakley AE, Clifton DK, Steiner RA (2009). Kisspeptin signaling in the brain. Endocr Rev 30: 713–743.
Pineda R, Garcia-Galiano D, Roseweir A, Romero A, Sanchez-Garrido MA, Ruiz-Pino F, Morgan K, Pinilla L, Millar RP, Tena-Sempere M (2010). Critical roles of kisspeptins in female puberty and preovulatory gonadotropin surges as revealed by a novel antagonist. Endocrinology 151: 722–730.
Ramaswamy S, Guerriero KA, Gibbs RB, Plant TM (2008). Structural interactions between kisspeptin and GnRH neurons in the mediobasal hypothalamus of the male rhesus monkey (Macaca mulatta) as revealed double immunofluorescence and confocal microscopy. Endocrinology 149: 4387– 4395.
Roseweir AK, Kauffman AS, Smith JT, Guerriero KA, Morgan K, Pielecka-Fortuna J, Pineda R, Gottsch ML, Tena- Sempere M, Moenter SM et al. (2009). Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J Neurosci 29: 3920–3929.
Saez JM (1994). Leydig cells: endocrine, paracrine, and autocrine regulation. Endocr Rev 15: 574–626.
Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG et al. (2003). The GPR54 gene as a regulator of puberty. N Engl J Med 349: 1614–1626.
Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM (2005). Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci U S A 102: 2129–2134.
Simonneaux V, Ansel Revel GF, Klosen P, Pévet P, Mikkelsen DJ (2009). Kisspeptin and the seasonal control of reproduction in hamsters. Peptides 30: 146–153.
Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA (2005a). Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology 146: 3686–3692.
Smith JT, Dungan HM, Stoll EA, Gottsch ML, Braun RE, Eacker SM, Clifton DK, Steiner RA (2005b). Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology 146: 2976–2984.
Tariq A, Pereira A, Smith JT, Loveland K, O’Brien M, Shahab M, Clarke IJ (2010). Kisspeptin and gonadotropin inhibitory hormone (GnIH) in the testis of the non-human primate, Macaca mulatta. In: Proceedings of the Seventh International Congress of Neuroendocrinology, Rouen, France.
Teles MG, Bianco SD, Brito VN, Trarbach EB, Kuohung W, Xu S, Seminara SB, Mendonca BB, Kaiser UB, Latronico AC (2008). A GPR54-activating mutation in a patient with central precocious puberty . N Engl J Med 358: 709–715.
Wahab F, Bano R, Jabeen S, Irfan S, Shahab M (2010). Effect of peripheral kisspeptin administration on adiponectin, leptin, and resistin secretion under fed and fasting conditions in the adult male rhesus monkey (Macaca mulatta). Horm Metab Res 42: 570–574.
Wahab F, Ullah F, Chan Y, Seminara SB, Shahab M (2011). A potential mechanism for fasting-induced suppression of the HPG axis in the adult male rhesus monkey (Macaca mulatta) . Horm Metab Res 43: 81–85.