Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat

https://doi.org/10.1016/j.bbrc.2004.05.185Get rights and content

Abstract

Metastin is a novel peptide that has been isolated from the human placenta as the cognate ligand of the G-protein-coupled receptor OT7T175 (or GPR54). However, its physiological functions have not yet been fully investigated. In the present study, we show that subcutaneous administration of metastin increased the plasma levels of gonadotropins (follicle-stimulating hormone and luteinizing hormone) and induced ovulation in prepubertal female rats that had been pretreated with pregnant mare serum gonadotropin to induce follicle maturation. Furthermore, metastin administration drastically increased the plasma levels of gonadotropins in male rats. This action was abolished by pretreatment with a GnRH antagonist, and was accompanied by induction of c-Fos immunoreactivity in GnRH neurons. These results suggest that s.c. administered metastin induces the release of gonadotropin via activation of the hypothalamic GnRH neurons.

Section snippets

Materials and methods

Materials. Human metastin was synthesized as described previously [15]. PMSG and hCG (Teikoku Hormone MFG, Tokyo, Japan), synthetic GnRH peptide (Peptide Institute, Osaka, Japan), GnRH antagonist Cetrorelix (ANASPEC, San José, USA), DNase I, pancreatin, and 17-β estradiol (Sigma–Aldrich, St. Louis, MO), Collagenase A (Roche Diagnostics, IN, USA), Dulbecco’s modified Eagle’s medium (DMEM without phenol red, Invitrogen, CA, USA), and charcoal/dextran-treated fetal calf serum (FCS) (HyClone, UT,

Gonadotropin-releasing activity and ovulation-inducing activity in prepubertal female rats

Subcutaneous administration of metastin (6.7 nmol/body, or ca. 100 nmol/kg) markedly elevated plasma FSH and LH levels compared to each zero-time level and also compared to saline-treated group at each time point in 25-day-old female rats (Figs. 1A and B). The maximal increase was found 2 h after administration. Saline-treatment did not induce any significant changes in these hormone levels. Under the normal physiological conditions, such an explosive LH release is seen in the LH surge that

Discussion

In the present study, we found that s.c. administered metastin dramatically increased plasma FSH and LH levels in three animal models, untreated and PMSG-primed prepubertal female rats, and adult male rats, suggesting that metastin contributes to the release of gonadotropins in both sexes. Increased plasma LH levels were close to the ‘LH-surge level’ ordinary observed in preovulatory female rats. In fact, metastin administration induced ovulation in PMSG-primed rats, which have preovulatory

Acknowledgements

We are grateful to H. Sawada, T. Kokubo, and T. Itoh for providing the synthetic metastin peptide, and S. Usuki, M. Fujino, Y. Fujisawa, K. Okonogi, C. Kitada, and M. Mori for discussions and encouragement.

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