SEMINAR: Induction of fertile ovulation and puberty advancement by a new kisspeptin analog

The Seminar: The neuropeptide kisspeptin and its receptor, KiSS1R, govern the reproductive timeline of mammals. Previous studies pointed to their central role to maintain fertility by triggering puberty onset and promoting ovulation by stimulating gonadotrophin-releasing hormone (GnRH) secretion. However, the extremely short half-life of kisspeptin limits its use outside an experimental setting. To overcome this limitation we designed kisspeptin analogs with improved resistance to degradation and reduced renal excretion. The best analog, C6, induced a dose-dependent and long-lasting increase on LH and FSH plasma concentration. To explore potential applications in reproduction management C6 was injected to progestogen primed ewe and compared to PMSG treatment. The synchronization of LH surge obtained with a single bolus intramuscular injection of 15 nmol/ewe of C6 was superior to that induced by PMSG administration. Furthermore, using the same protocol either in the breeding or in the non-breeding season, C6 administration triggered ovulation that produced healthy corpora lutea as shown by progesterone increase starting from 3 days after treatment. In an additional experiment performed during the breeding season we showed that ovulations were fertile as demonstrated by the delivery of healthy lambs at term. Preliminary experiments in goats during the breeding season using a similar protocol produced similar results. Puberty control is another important requirement in livestock management. To assess if C6 could modulate puberty onset we used the mouse, which has the advantage of short time to puberty allowing for rapid testing. In prepubertal female mice daily injections (0.15 nmol/mouse) for five days significantly advanced vaginal opening and first estrus, confirming the potential for this application. To summarize C6 has a potent and long-lasting action in different species. Its ability to trigger ovulation and advance puberty onset demonstrate that kisspeptin analogs may find application in the management of livestock reproduction by, for example, substituting the use of PMSG to synchronize ovulations. Additional experiments are ongoing to establish if in the non-breeding season it would be possible to induce fertile ovulation without progestogen priming. This will definitively represent a breakthrough in livestock reproduction management.

The Speaker: My story with kisspeptin started in 2008 when I performed my PhD studies under the supervision of Alain Caraty and Christine Briant at the French National Institute for Agricultural Research (INRA). During that period, I first explored the localization of kisspeptin neurons and theirs interactions with GnRH neuronal system in equine hypothalamus. Using kisspeptin administration I also explored the possibility to trigger ovulation in mares under different physiological conditions. This work allowed me to obtain my PhD with full honors in 2012. Passionate by this research subject I continued my work on kisspeptin and extended to RFRP-3 during my post-doctorate in the team of Massimiliano Beltramo always at the INRA. My present research on kisspeptin focuses on evaluating the possibility to manage livestock reproduction with kisspeptin analogs. By working in collaboration with a group of peptide chemists of the CNRS I take part in the development of a drug discovery program to generate kisspeptin analogs. This effort has already lead to the identification of an analog holding strong promise for development of field applications.