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Vertebrate reproductive science and technology
RESEARCH ARTICLE

Leptin inhibits basal but not gonadotrophin-stimulated testosterone production in the immature mouse and sheep testis

Muren Herrid A B , Yin Xia A C , Tim O’Shea A and James R. McFarlane A D
+ Author Affiliations
- Author Affiliations

A Centre for Bioactive Discovery in Health and Aging, University of New England, Armidale, NSW 2350, Australia.

B Present address: CSIRO Livestock Industries, Locked Bag 1, Post Office, Armidale, NSW 2350, Australia.

C Present address: Program in Membrane Biology and Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard, Medical School, Boston, MA 02114, USA.

D Corresponding author. Email: jmcfarla@une.edu.au

Reproduction, Fertility and Development 20(4) 519-528 https://doi.org/10.1071/RD07062
Submitted: 3 April 2007  Accepted: 27 January 2008   Published: 11 April 2008

Abstract

The mechanisms whereby leptin regulates testosterone secretion are complex and are likely to involve actions at different levels of the hypothalamus–pituitary–gonadal axis. In the present study, the effect of leptin on testicular steroidogenesis at different developmental stages in mice and sheep was investigated. Testosterone data from testicular slice and Leydig cells of immature and adult mice testes demonstrated that the action of leptin in the regulation of steroidogenesis appears to be dependent on the developmental stage of the testis. Leptin biphasically modulates basal testosterone production in immature testicular slice cultures: at relatively low concentrations (6.25–12.5 ng mL–1) leptin exerts a significant inhibitory effect, but has less of an effect at very low (1.25 ng mL–1) or high concentrations (25 ng mL–1). However, leptin failed to modulate basal testosterone levels in Leydig cell preparations. In contrast with immature testes, leptin was unable to regulate either basal or human chorionic gonadotrophin (10 IU mL–1)-stimulated testosterone production in adult testicular slices or Leydig cell cultures. The age- and concentration-dependent regulation pattern was confirmed using sheep testicular slice culture. Leptin (1.56–25 ng mL–1) significantly inhibited basal testosterone production in the testis from birth to Day 21, but had no effect on Day 27 or older testes. However, the plasma and testicular concentrations of leptin and testosterone data in the ram indicate that such a regulatory effect of leptin on testis steroidogenesis in vitro is unable to efficiently influence testosterone concentrations in vivo. This does not exclude the possibility of a non-competitive mechanism of interaction between leptin and luteinising hormone to regulate testosterone production. Thus, we hypothesise that leptin is not an important independent regulator of testosterone concentration in the normal physiological state. The physiological significance and mechanism of leptin regulation of basal testosterone production are not known; further studies are required to elucidate these important issues.

Additional keyword: postnatal development.


References

Adan, L. , Bussieres, L. , Trivin, C. , Souberbielle, J. C. , and Brauner, R. (1999). Effect of short-term testosterone treatment on leptin concentrations in boys with pubertal delay. Horm. Res. 52, 109–112.
CrossRef | PubMed |

Ahima, R. S. , Prabakaran, D. , Mantzoros, C. , Qu, D. , Lowell, B. , Maratos-Flier, E. , and Flier, J. S. (1996). Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252.
CrossRef | PubMed |

Ahima, R. S. , Prabakaran, D. , and Flier, J. S. (1998). Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J. Clin. Invest. 101, 1020–1027.
CrossRef | PubMed |

Ariyaratne, H. B. , and Chamindrani Mendis-Handagama, S. (2000). Changes in the testis interstitium of Sprague Dawley rats from birth to sexual maturity. Biol. Reprod. 62, 680–690.
CrossRef | PubMed |

Baker, P. J. , Sha, J. A. , McBride, M. W. , Peng, L. , Payne, A. H. , and O’Shaughnessy, P. J. (1999). Expression of 3beta-hydroxysteroid dehydrogenase type I and type VI isoforms in the mouse testis during development. Eur. J. Biochem. 260, 911–917.
CrossRef | PubMed |

Barash, I. A. , Cheung, C. C. , Weigle, D. S. , Ren, H. , Kabigting, E. B. , Kuijper, J. L. , Clifton, D. K. , and Steiner, R. A. (1996). Leptin is a metabolic signal to the reproductive system. Endocrinology 137, 3144–3147.
CrossRef | PubMed |

Barenton, B. , Hochereau-de Reviers, M. T. , Perreau, C. , and Saumande, J. (1983). Changes in testicular gonadotropin receptors and steroid content through postnatal development until puberty in the lamb. Endocrinology 112, 1447–1453.
PubMed |

Blache, D. , Celi, P. , Blackberrv, M. A. , Dynes, R. A. , and Martin, G. B. (2000a). Decrease in voluntary feed intake and pulsatile luteinizing hormone secretion after intracerebroventricular infusion of recombinant bovine leptin in mature male sheep. Reprod. Fertil. Dev. 12, 373–381.
CrossRef | PubMed |

Blache, D. , Tellam, R. L. , Chagas, L. M. , Blackberry, M. A. , Vercoe, P. E. , and Martin, G. B. (2000b). Level of nutrition affects leptin concentrations in plasma and cerebrospinal fluid in sheep. J. Endocrinol. 165, 625–637.
CrossRef | PubMed |

Bravo-Moreno, J. F. , Díaz-Sánchez, V. , Montoya-Flores, J. G. , Lamoyi, E. , Saéz, J. C. , and Pérez-Armendariz, E. M. (2001). Expression of Connexin43 in mouse Leydig, sertoli, and germinal cells at different stages of postnatal development. Anat. Rec. 264, 13–24.
CrossRef | PubMed |

Bronson, F. H. (2001). Puberty in female mice is not associated with increases in either body fat or leptin. Endocrinology 142, 4758–4761.
CrossRef | PubMed |

Caprio, M. , Fabbrini, E. , Ricci, G. , Basciani, S. , and Gnessi, L. , et al. (2003). Ontogenesis of leptin receptor in rat leydig cells. Biol. Reprod. 68, 1199–1207.
CrossRef | PubMed |

Collu, R. , Savoie, S. , Hamel, R. , Gibb, W. , and Ducharme, J. R. (1983). Maturation of the hypothalamic–pituitary–gonadal axis in the male lamb: a review. Psychoneuroendocrinology 8, 213–224.
CrossRef | PubMed |

Devaskar, S. U. , Ollesch, C. , Rajakumar, R. A. , and Rajakumar, P. A. (1997). Developmental changes in ob gene expression and circulating leptin peptide concentrations. Biochem. Biophys. Res. Commun. 238, 44–47.
CrossRef | PubMed |

Erfurth, E. M. , and Ahren, B. (2000). The negative association between serum free testosterone and leptin is dependent on insulin-like growth factor-binding protein 1 in healthy young and middle-aged men. Clin. Endocrinol. 52, 493–498.
CrossRef | PubMed |

Handelsman, D. J. , Spaliviero, J. A. , Simpson, J. M. , Allan, C. M. , and Singh, J. (1999). Spermatogenesis without gonadotropins: maintenance has a lower testosterone threshold than initiation. Endocrinology 140, 3938–3946.
CrossRef | PubMed |

Hedger, M. P. , and Eddy, E. M. (1987). The heterogeneity of isolated adult rat Leydig cells sperated on Percoll density gradients: an immunological, cytochemical and functional analysis. Endocrinology 121, 1824–1838.
PubMed |

Herrid, M. , Nguyen, V. L. , Hinch, G. , and McFarlane, J. R. (2006). Leptin has concentration and stage-dependent effects on embryonic development in vitro. Reproduction 132, 247–256.
CrossRef | PubMed |

Isidori, A. M. , Caprio, M. , Strollo, F. , Moretti, C. , Frajese, G. , Isidori, A. , and Fabbri, A. (1999). Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels. J. Clin. Endocrinol. Metab. 84, 3673–3680.
CrossRef | PubMed |

Jockenhovel, F. , Blum, W. F. , Vogel, E. , Englaro, P. , Muller-Wieland, D. , Reinwein, D. , Rascher, W. , and Krone, W. (1997). Testosterone substitution normalizes elevated serum leptin levels in hypogonadal men. J. Clin. Endocrinol. Metab. 82, 2510–2513.
CrossRef | PubMed |

Kauter, K. , Ball, M. , Kearney, P. , Tellam, R. , and McFarlane, J. R. (2000). Adrenaline, insulin and glucagon do not have acute effects on plasma leptin levels in sheep: development and characterisation of an ovine leptin ELISA. J. Endocrinol. 166, 127–135.
CrossRef | PubMed |

Kerr, J. B. , Robertson, D. M. , and de Kretser, D. M. (1985). Morphological and functional characterization of interstitial cells from mouse testes fractionated on Percoll density gradients. Endocrinology 116, 1030–1043.
PubMed |

Klinefelter, G. R. , and Ewing, L. L. (1987). Effect of luteinizing hormone deprivation in situ on steroidogenesis of rat Leydig cells purified by a multistep procedure. Biol. Reprod. 36, 769–783.
CrossRef | PubMed |

McFarlane, J. R. , de Kretser, D. M. , and Risbridger, G. P. (1994). Stimulatory and inhibitory factors of Leydig cell steroidogenesis are secreted simultaneously by the rat seminiferous tubules and do not affect Leydig cell inhibin production in vitro. Reprod. Fertil. Dev. 6, 693–698.
CrossRef | PubMed |

McFarlane, J. R. , Laslett, A. , de Kretser, D. M. , and Risbridger, G. P. (1996). Evidence that heparin binding autocrine factors modulate testosterone production by the adult rat Leydig cell. Mol. Cell. Endocrinol. 118, 57–63.
CrossRef | PubMed |

Morash, B. , Wilkinson, D. , Murphy, P. , Ur, E. , and Wilkinson, M. (2001). Developmental regulation of leptin gene expression in rat brain and pituitary. Mol. Cell. Endocrinol. 185, 151–159.
CrossRef | PubMed |

Mounzih, K. , Lu, R. , and Chehab, F. F. (1997). Leptin treatment rescues the sterility of genetically obese ob/ob males. Endocrinology 138, 1190–1193.
CrossRef | PubMed |

Mystkowski, P. , and Schwartz, M. W. (2000). Gonadal steroids and energy homeostasis in the leptin era. Nutrition 16, 937–946.
CrossRef | PubMed |

O’Shaughnessy, P. J. , Baker, P. J. , Heikkila, M. , Vainio, S. , and McMahon, A. P. (2000). Localization of 17beta-hydroxysteroid dehydrogenase/17-ketosteroid reductase isoform expression in the developing mouse testis: androstenedione is the major androgen secreted by fetal/neonatal leydig cells. Endocrinology 141, 2631–2637.
CrossRef | PubMed |

Savoie, S. , Polychronakos, C. , Forest, M. G. , Haour, F. , Collu, R. , and Ducharme, J. R. (1981). Perinatal activity of the hypothalamic–pituitary–gonadal axis in the lamb. III. LH, testosterone and prolactin secretory pattern in newborn lambs. Horm. Res. 15, 167–178.
PubMed |

Singh, J. , O’Neill, C. , and Handelsman, D. J. (1995). Induction of spermatogenesis by androgens in gonadotropin-deficient (hpg) mice. Endocrinology 136, 5311–5321.
CrossRef | PubMed |

Syed, V. , Khan, S. A. , and Ritzen, E. M. (1985). Stage-specific inhibition of interstitial cell testosterone secretion by rat seminiferous tubules in vitro. Mol. Cell. Endocrinol. 40, 257–264.
CrossRef | PubMed |

Tena-Sempere, M. , Pinilla, L. , Gonzalez, L. C. , Dieguez, C. , Casanueva, F. F. , and Aguilar, E. (1999). Leptin inhibits testosterone secretion from adult rat testis in vitro. J. Endocrinol. 161, 211–218.
CrossRef | PubMed |

Valenti S., Cesarone A., Foppiani L., Giordano G., and Giusti M. (1998). Effect of recombinat murine leptin administration on percoll-purified rat Leydig cells (Abstract). In ‘IV European Congress of Endocrinology’. pp. OR5–6. (BioScientifica: Bristol.)

Vergouwen, R. P. , Jacobs, S. G. , Huiskamp, R. , Davids, J. A. , and de Rooij, D. G. (1991). Proliferative activity of gonocytes, sertoli cells and interstitial cells during testicular development in mice. J. Reprod. Fertil. 93, 233–243.
PubMed |

Wang, C. , Swerdloff, R. S. , Iranmanesh, A. , Dobs, A. , Snyder, P. J. , Cunningham, G. , Matsumoto, A. M. , Weber, T. , and Berman, N. (2000). Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J. Clin. Endocrinol. Metab. 85, 2839–2853.
CrossRef | PubMed |

Yu, W. H. , Kimura, M. , Walczewska, A. , Karanth, S. , and McCann, S. M. (1997). Role of leptin in hypothalamic-pituitary function. Proc. Natl Acad. Sci. USA 94, 1023–1028.
CrossRef | PubMed |

Yura, S. , Ogawa, Y. , Sagawa, N. , Masuzaki, H. , Itoh, H. , Ebihara, K. , Aizawa-Abe, M. , Fujii, S. , and Nakao, K. (2000). Accelerated puberty and late-onset hypothalamic hypogonadism in female transgenic skinny mice overexpressing leptin. J. Clin. Invest. 105, 749–755.
PubMed |

Zachow, R. J. , Weitsman, S. R. , and Magoffin, D. A. (1999). Leptin impairs the synergistic stimulation by transforming growth factor-beta of follicle-stimulating hormone-dependent aromatase activity and messenger ribonucleic acid expression in rat ovarian granulosa cells. Biol. Reprod. 61, 1104–1109.
CrossRef | PubMed |



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