the Kisspeptin Antagonist, Peptide 234, Reveales Regulatory Mechanisms of Reproductive Functions and Energy Balance By Kisspeptin and RF9, a Selective Antagonist of RF-Amide Related Peptide Receptors, in Female Rats

Presentation Number: LBF-089
Date of Presentation: March 6th, 2015

Haluk Kelestimur*, Zafer Sahin, Sinan Canpolat and Mete Ozcan
Firat University Medical School, Elazig, Turkey


There is growing evidence that RFamide-related peptides (RFRPs) show their effects on reproductive functions by modulating kisspeptin/GPR54 signaling system. Our previous experiment (1) shows that GnIH treatment attenuates kisspeptin-10-induced GnRH release in GT1-7 cells. Combined injection of kisspeptin-10 and the antagonist of RFRP receptor, RF9, modestly increased the responses to kisspeptin alone (2). The above data strongly suggest the possibility of interactions between kisspeptins and RFRPs in the control of the HPG axis. Therefore, it is proposed that it is the dynamic balance and interplay between these two sets of factors that drives the function of the reproductive system. The aim of this study was to determine the modulatory effects of peptide 234 (p234) (an antagonist of GPR54 receptors) on kisspeptin and RF9 (an RFamide-related peptide antagonist) - induced changes in reproductive functions and energy balance in female rats.  Female Sprague-Dawley rats were weaned on post natal day (pnd) 21. The animals were intracerebroventricularly cannulated under general anesthesia on pnd 23. Groups of female rats were injected with kisspeptin, RF9, p234, kisspeptin plus p234 or RF9 plus p234, daily. Kisspeptin and RF9 elicited significant elevations of circulating LH levels. Coadministrations of kisspeptin or RF9 with p234 decreased LH levels significantly. The use of p234 alone did not cause any significant change in LH secretion. Kisspeptin or  RF9 alone advanced vaginal opening (VO), which was delayed by administration of kisspeptin antagonist alone. In the rats given kisspeptin plus p234 or RF9 plus peptide 234, VO was not different from control rats.   Kisspeptin decreased both food intake and body weight while RF9 decreased only food intake without affecting body weight. The effects of both kisspeptin and RF9 on energy balance were also reversed by central administration of p234. In conclusion, kisspeptin antagonist, p234, modulates the effects of not only kisspeptin but also RF9 on reproductive functions and energy balance, and therefore RF9 seems to exert its effects on reproductive functions and energy balance by means of GPR54 signaling the same as kisspeptin in the female rats. The understanding of the effects of kisspeptin and RFRP-3 antagonists will provide new therapeutic approaches to treat some hormone-dependent reproductive and metabolic disorders such as precocious puberty and obesity, respectively.


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