Role of the hypothalamus in ghrelin effects on reproduction: sperm function and sexual behavior in male mice

in Reproduction
Authors:
María Belén PorettiInstituto de Investigaciones en Ciencias de la Salud (INICSA, CONICET- UNC), CONICET and Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Argentina
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden

Search for other papers by María Belén Poretti in
Current site
Google Scholar
PubMedClose
,
Santiago BianconiInstituto de Investigaciones en Ciencias de la Salud (INICSA, CONICET- UNC), CONICET and Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Argentina
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden

Search for other papers by Santiago Bianconi in
Current site
Google Scholar
PubMedClose
,
Eugenia LuqueInstituto de Investigaciones en Ciencias de la Salud (INICSA, CONICET- UNC), CONICET and Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Argentina

Search for other papers by Eugenia Luque in
Current site
Google Scholar
PubMedClose
,
Ana Carolina MartiniInstituto de Investigaciones en Ciencias de la Salud (INICSA, CONICET- UNC), CONICET and Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Argentina

Search for other papers by Ana Carolina Martini in
Current site
Google Scholar
PubMedClose
,
Laura VincentiInstituto de Investigaciones en Ciencias de la Salud (INICSA, CONICET- UNC), CONICET and Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Argentina

Search for other papers by Laura Vincenti in
Current site
Google Scholar
PubMedClose
,
Veronica CantarelliInstituto de Investigaciones en Ciencias de la Salud (INICSA, CONICET- UNC), CONICET and Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Argentina

Search for other papers by Veronica Cantarelli in
Current site
Google Scholar
PubMedClose
,
Pedro TorresInstituto de Investigaciones en Ciencias de la Salud (INICSA, CONICET- UNC), CONICET and Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Argentina

Search for other papers by Pedro Torres in
Current site
Google Scholar
PubMedClose
,
Marina PonzioInstituto de Investigaciones en Ciencias de la Salud (INICSA, CONICET- UNC), CONICET and Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Argentina

Search for other papers by Marina Ponzio in
Current site
Google Scholar
PubMedClose
,
Helgi B SchiöthFunctional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden

Search for other papers by Helgi B Schiöth in
Current site
Google Scholar
PubMedClose
, and
Valeria Paola CarliniInstituto de Investigaciones en Ciencias de la Salud (INICSA, CONICET- UNC), CONICET and Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Argentina
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden

Search for other papers by Valeria Paola Carlini in
Current site
Google Scholar
PubMedClose
https://orcid.org/0000-0001-9933-2678
View More View Less

Correspondence should be addressed to V P Carlini; Email: v.carlini@fcm.unc.edu.ar
DOI:
https://doi.org/10.1530/REP-22-0098
Volume/Issue:
Volume 165: Issue 1
Page Range:
123–134
Article Type:
Research Article
Online Publication Date:
07 Dec 2022
Copyright:
© Society for Reproduction and Fertility 2023
Restricted access

USD  $0.01
USD  $0.01

USD  $0.01
USD  $0.01

USD  $0.01
USD  $0.01

USD  $0.01
USD  $0.01

USD  $0.01
USD  $0.01

USD  $0.01
USD  $0.01

USD  $0.01
USD  $0.01

USD  $1.00
USD  $1.00

In brief

Ghrelin signals to the hypothalamus inhibit reproduction during times of food scarcity. In this study, we demonstrate that ghrelin impairs sperm quality in male mice.

Abstract

Ghrelin (GHRL) is an orexigenic peptide that has been investigated as one of the signals responsible for the reproductive performance of mammals under fluctuating metabolic conditions. Central GHRL administration impairs spermatogenesis in mice by regulating the hypothalamic–pituitary–gonadal axis function. In the present study, the hypothalamus role as a mediator of GHRL effects on sperm fertilizing capacity and male sexual behavior was evaluated. After 42 days of hypothalamic GHRL infusion or artificial cerebrospinal fluid, in vitro and in vivo sperm fertilizing capacity, testicular α-tubulin, speriolin gene expression and spermatic α-tubulin protein were evaluated. Hypothalamic expression of genes Kiss1, Gpr54 and Gnrh was also studied. The second group of animals was infused with one time only GHRL or artificial cerebrospinal fluid into the hypothalamus to evaluate the effects on sexual behavior. Results demonstrated that chronic GHRL administration to male mice significantly increased the percentages of pre-implantation embryo loss and the number of post-implantation embryo loss. In relation to the gene expression, our results show a relative decrease of Kiss1, Gpr54 and Spatc1. Although no significant differences were observed in the quantitative expression of α-tubulin protein, qualitative changes in its expression pattern were observed. In addition, a dual effect on sexual behavior was observed: 40% of the treated animals showed a significant reduction in the number of mounts and intromissions, while a 60% showed a significant decrease in ejaculation latency vs control animals. In conclusion, our results provide evidence that central GHRL administration possibly induces failure in embryo development and/or implantation in the females mated with treated males, possibly because of a negative effect in the α-tubulin pattern.

Supplementary Materials

Reproduction is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 76 76 6
PDF Downloads 96 96 6

 

  • Collapse
  • Expand
Print ISSN:
1470-1626
Online ISSN:
1741-7899

  • Adekunbi DA, Li XF, Lass G, Shetty K, Adegoke OA, Yeo SH, Colledge WH, Lightman SL & O'byrne KT 2018 Kisspeptin neurones in the posterodorsal medial amygdala modulate sexual partner preference and anxiety in male mice. Journal of Neuroendocrinology 30 e12572. (https://doi.org/10.1111/jne.12572)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Agmo A 1999 Sexual motivation–an inquiry into events determining the occurrence of sexual behavior. Behavioural Brain Research 105 129–150. (https://doi.org/10.1016/s0166-4328(9900088-1)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Agmo A 2002 Copulation-contingent aversive conditioning and sexual incentive motivation in male rats: evidence for a two-stage process of sexual behavior. Physiology and Behavior 77 425–435. (https://doi.org/10.1016/s0031-9384(0200874-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Babaei-Balderlou F & Khazali H 2016 Effects of ghrelin on sexual behavior and luteinizing hormone beta-subunit gene expression in male rats. Journal of Reproduction and Infertility 17 88–96.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Balthazart J, Absil P, Gerard M, Appeltants D & Ball GF 1998 Appetitive and consummatory male sexual behavior in Japanese quail are differentially regulated by subregions of the preoptic medial nucleus. Journal of Neuroscience 18 6512–6527. (https://doi.org/10.1523/JNEUROSCI.18-16-06512.1998)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bertoldi ML, Luque EM, Carlini VP, Vincenti LM, Stutz G, Santillan ME, Ruiz RD, Fiol de Cuneo M & Martini AC 2011 Inhibitory effects of ghrelin on sexual behavior: role of the peptide in the receptivity reduction induced by food restriction in mice. Hormone and Metabolic Research 43 494–499. (https://doi.org/10.1055/s-0031-1277228)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Castellano JM, Navarro VM, Fernandez-Fernandez R, Nogueiras R, Tovar S, Roa J, Vazquez MJ, Vigo E, Casanueva FF & Aguilar E et al.2005 Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology 146 3917–3925. (https://doi.org/10.1210/en.2005-0337)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Clermont Y, Oko R & Hermo L 1990 Immunocytochemical localization of proteins utilized in the formation of outer dense fibers and fibrous sheath in rat spermatids: an electron microscope study. Anatomical Record 227 447–457. (https://doi.org/10.1002/ar.1092270408)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dvořáková K, Moore HD, Šebková N & Paleček J 2005 Cytoskeleton localization in the sperm head prior to fertilization. Reproduction 130 61–69. (https://doi.org/10.1530/rep.1.00549)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Eddy EM 1998 Regulation of gene expression during spermatogenesis. Seminars in Cell and Developmental Biology 9 451–457. (https://doi.org/10.1006/scdb.1998.0201)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fernandez-Fernandez R, Martini AC, Navarro VM, Castellano JM, Dieguez C, Aguilar E, Pinilla L & Tena-Sempere M 2006 Novel signals for the integration of energy balance and reproduction. Molecular and Cellular Endocrinology 254–255 127–132. (https://doi.org/10.1016/j.mce.2006.04.026)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ferraz MR, Ferraz MM & Santos R 2001 How REM sleep deprivation and amantadine affects male rat sexual behavior. Pharmacology, Biochemistry, and Behavior 69 325–332. (https://doi.org/10.1016/s0091-3057(0100508-1)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fourest-Lieuvin A, Peris L, Gache V, Garcia-Saez I, Juillan-Binard C, Lantez V & Job D 2006 Microtubule regulation in mitosis: tubulin phosphorylation by the cyclin-dependent kinase Cdk1. Molecular Biology of the Cell 17 1041–1050. (https://doi.org/10.1091/mbc.e05-07-0621)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fraser LR 1993 In vitro capacitation and fertilization. Methods in Enzymology 225 239–253. (https://doi.org/10.1016/0076-6879(9325016-u)

  • Garcia MC, Lopez M, Alvarez CV, Casanueva F, Tena-Sempere M & Dieguez C 2007 Role of ghrelin in reproduction. Reproduction 133 531–540. (https://doi.org/10.1530/REP-06-0249)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Goode BL, Drubin DG & Barnes G 2000 Functional cooperation between the microtubule and actin cytoskeletons. Current Opinion in Cell Biology 12 63–71. (https://doi.org/10.1016/s0955-0674(9900058-7)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Goto M, O'brien DA & Eddy EM 2010 Speriolin is a novel human and mouse sperm centrosome protein. Human Reproduction 25 1884–1894. (https://doi.org/10.1093/humrep/deq138)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gottsch ML, Cunningham MJ, Smith JT, Popa SM, Acohido BV, Crowley WF, Seminara S, Clifton DK & Steiner RA 2004 A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology 145 4073–4077. (https://doi.org/10.1210/en.2004-0431)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hill JW, Elmquist JK & Elias CF 2008 Hypothalamic pathways linking energy balance and reproduction. American Journal of Physiology. Endocrinology and Metabolism 294 E827–E832. (https://doi.org/10.1152/ajpendo.00670.2007)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Howes SC, Alushin GM, Shida T, Nachury MV & Nogales E 2014 Effects of tubulin acetylation and tubulin acetyltransferase binding on microtubule structure. Molecular Biology of the Cell 25 257–266. (https://doi.org/10.1091/mbc.E13-07-0387)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hull EM & Dominguez JM 2007 Sexual behavior in male rodents . Hormones and Behavior 52 45–55. (https://doi.org/10.1016/j.yhbeh.2007.03.030)

  • Hull EM & Dominguez JM 2019 Neuroendocrine regulation of male sexual behavior. Comprehensive Physiology 9 1383–1410. (https://doi.org/10.1002/cphy.c180018)

  • Hull EM & Rodríguez-Manzo G 2009 Male sexual behavior. In Hormones, Brain and Behavior, 3rd ed. Pfaff DW, AP Arnold, Etgen AM, SE Fahrbach, RT Rubin Eds.: Elsevier Academic Press, pp. 5–65. (https://doi.org/10.1016/B978-008088783-8.00001-2)

    • Search Google Scholar
    • Export Citation

  • Hull EM, Wood RI & Mckenna KE 2006 The neurobiology of male sexual behavior. In Neill J, Pfaff DEds. The Physiology of Reproduction, pp. 1729–1824. (https://doi.org/10.1016/B978-012515400-0/50038-5)

    • Search Google Scholar
    • Export Citation

  • Jodar M, Sendler E & Krawetz SA 2016 The protein and transcript profiles of human semen. Cell and Tissue Research 363 85–96. (https://doi.org/10.1007/s00441-015-2237-1)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jordan MA & Wilson L 2004 Microtubules as a target for anticancer drugs. Nature Reviews. Cancer 4 253–265. (https://doi.org/10.1038/nrc1317)

  • Kalebic N, Martinez C, Perlas E, Hublitz P, Bilbao-Cortes D, Fiedorczuk K, Andolfo A & Heppenstall PA 2013 Tubulin acetyltransferase alphaTAT1 destabilizes microtubules independently of its acetylation activity. Molecular and Cellular Biology 33 1114–1123. (https://doi.org/10.1128/MCB.01044-12)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kim J, Kwon JT, Jeong, J, Kim J, Hong SH, Kim J, Park ZY, Chung KH, Eddy EM & Cho C 2018 SPATC1L maintains the integrity of the sperm head-tail junction. EMBO Reports 19. (https://doi.org/10.15252/embr.201845991)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H & Kangawa K 1999 Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402 656–660. (https://doi.org/10.1038/45230)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kojima M, Hosoda H, Matsuo H & Kangawa K 2001 Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends in Endocrinology and Metabolism 12 118–122. (https://doi.org/10.1016/s1043-2760(0000362-3)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kojima M & Kangawa K 2005 Ghrelin: structure and function. Physiological Reviews 85 495–522. (https://doi.org/10.1152/physrev.00012.2004)

  • Kondo Y & Sachs BD 2002 Disparate effects of small medial amygdala lesions on noncontact erection, copulation, and partner preference. Physiology and Behavior 76 443–447. (https://doi.org/10.1016/s0031-9384(0200682-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kumar N & Singh AK 2015 Trends of male factor infertility, an important cause of infertility: a review of literature. Journal of Human Reproductive Sciences 8 191–196. (https://doi.org/10.4103/0974-1208.170370)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Luque EM, Torres PJ, De Loredo N, Vincenti LM, Stutz G, Santillan ME, Ruiz RD, De Cuneo MF & Martini AC 2014 Role of ghrelin in fertilization, early embryo development, and implantation periods. Reproduction 148 159–167. (https://doi.org/10.1530/REP-14-0129)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ma X & Sayeski PP 2007 Identification of tubulin as a substrate of Jak2 tyrosine kinase and its role in Jak2-dependent signaling. Biochemistry 46 7153–7162. (https://doi.org/10.1021/bi700101n)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Martini AC, Fiol de Cuneo M, Ruiz RD, Ponce AA & Lacuara JL 2000 In vitro parthenogenesis of mouse oocytes under several experimental conditions. Zygote 8 45–49. (https://doi.org/10.1017/s0967199400000812)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Munro CJ & Lasley BL 1988 Non-radiometric methods for immunoassay of steroid hormones. Progress in Clinical and Biological Research 285 289–329.

  • Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K & Matsukura S 2001 A role for ghrelin in the central regulation of feeding. Nature 409 194–198. (https://doi.org/10.1038/35051587)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nirschl JJ, Magiera MM, Lazarus JE, Janke C & Holzbaur EL 2016 Alpha-tubulin Tyrosination and CLIP-170 Phosphorylation Regulate the Initiation of Dynein-Driven Transport in Neurons. Cell Reports 14 2637–2652. (https://doi.org/10.1016/j.celrep.2016.02.046)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Paxinos G & Franklin KBJ 2007 The Mouse Brain in Stereotaxic Coordinates. Amsterdam: Elsevier Science.

  • Poretti MB, Frautschi C, Luque E, Bianconi S, Martini AC, Stutz G, Vincenti L, Santillan ME, Ponzio M & Schioth HB et al.2018 Reproductive performance of male mice after hypothalamic ghrelin administration. Reproduction 156 121–132. (https://doi.org/10.1530/REP-17-0535)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Poretti MB, Rask-Andersen M, Kumar P, Rubiales de Barioglio S, Fiol De Cuneo M, Schioth HB & Carlini VP 2015 Ghrelin effects expression of several genes associated with depression-like behavior. Progress in Neuro-Psychopharmacology and Biological Psychiatry 56 227–234. (https://doi.org/10.1016/j.pnpbp.2014.09.012)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Puechagut PB, Martini AC, Stutz G, Santillán ME, Luque EM, De Cuneo MF, Ruiz RD & Vincenti LM 2012 Reproductive performance and fertility in male and female adult mice chronically treated with hexarelin. Reproduction, Fertility, and Development 24 451–460. (https://doi.org/10.1071/RD11009)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Schatten H & Sun QY 2009 The role of centrosomes in mammalian fertilization and its significance for ICSI. Molecular Human Reproduction 15 531–538. (https://doi.org/10.1093/molehr/gap049)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Slomiany BL & Slomiany A 2016 Helicobacter pylori-induced changes in microtubule dynamics conferred by alpha-tubulin phosphorylation on Ser/Tyr mediate gastric mucosal secretion of matrix metalloproteinase-9 (MMP-9) and its modulation by ghrelin. Inflammopharmacology 24 197–205. (https://doi.org/10.1007/s10787-016-0278-z)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tena-Sempere M 2006 GPR54 and kisspeptin in reproduction. Human Reproduction Update 12 631–639. (https://doi.org/10.1093/humupd/dml023)

  • Tena-Sempere M 2007 Ghrelin as a pleotrophic modulator of gonadal function and reproduction. Nature Clinical Practice. Endocrinology and Metabolism 4 666–674. (https://doi.org/10.1038/ncpendmet1003)

    • Search Google Scholar
    • Export Citation

  • Tena-Sempere M 2008 Ghrelin and reproduction: ghrelin as novel regulator of the gonadotropic axis. Vitamins and Hormones 77 285–300. (https://doi.org/10.1016/S0083-6729(0677012-1)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tschöp M, Smiley DL & Heiman ML 2000 Ghrelin induces adiposity in rodents. Nature 407 908–913. (https://doi.org/10.1038/35038090)

  • Vandesompele J, de Preter K, Pattyn F, Poppe B, Van Roy N, de Paepe A & Speleman F 2002 Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biology 3 RESEARCH0034. (https://doi.org/10.1186/gb-2002-3-7-research0034)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA & Bloom SR 2001 Ghrelin enhances appetite and increases food intake in humans. Journal of Clinical Endocrinology and Metabolism 86 5992. (https://doi.org/10.1210/jcem.86.12.8111)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yelian FD & Dukelow WR 1992 Effects of a DNA-specific fluorochrome, Hoechst 33258, on mouse sperm motility and fertilizing capacity. Andrologia 24 167–170. (https://doi.org/10.1111/j.1439-0272.1992.tb02632.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang QX, Zhang XY, Zhang ZM, Lu W, Liu L, Li G, Cai ZM, Gui YT & Chang C 2012 Identification of testosterone-/androgen receptor-regulated genes in mouse Sertoli cells. Asian Journal of Andrology 14 294–300. (https://doi.org/10.1038/aja.2011.94)

    • PubMed
    • Search Google Scholar
    • Export Citation