BACKGROUND AND AIMS: Kisspeptins (Kps) are structurally related peptides involved in the upstream regulation of the hypothalamic-pituitary-gonadal (HPG) axis. Their precursor is posttranslationally processed into peptides of various lengths. The forms considered to result from endogenous processing are the longest with 54 or 52 amino acids in humans or rodents, respectively. However, the shortest functional Kp consists of only the 10 amino acids at the C-terminal of the long forms. In this study, we used various mouse, rat and human Kps to assess the effect of peptide length and administration route on the activation of the HPG axis. METHODS: Male Wistar rats (n=4–8) received an intraperitoneal (ip; 150 nmol/kg) injection of mouse (m) Kp-10, -13, -14, -16, -52, rat (r) Kp-16, human (h) Kp-16, -54 or vehicle, or an intracerebroventricular (icv; 8 nmol/kg) injection of mKp10, mKp52, hKp54 or vehicle. After 45 min, we measured plasma concentrations of testosterone (T) and luteinizing hormone (LH) with radioimmunoassay and enzyme-linked immunosorbent assay, respectively, as well as expression of the immediate early gene c-Fos in gonadotropinreleasing hormone (GnRH) neurons with immunohistochemistry. RESULTS: Ip injections of mKp10, -16, -52, rKp16, hKp16 and -54 significantly increased T levels. hKp54 also produced a significant increase in LH levels, whereas shorter forms had no significant effect. Similarly, only hKp54 increased c-Fos in GnRH neurons in the vicinity of the organum vasculosum of the lamina terminalis (OVLT) including the anteroventral periventricular nucleus (AVPV). Icv injections of mKp10, mKp52 and hKp54 caused T and LH increases for mKp10 only. All three peptides produced significant GnRH neuron activation in the OVLT, the medial septum and the AVPV. CONCLUSIONS: This study demonstrated that the amino acid sequences of kisspeptins and their administration route are determining factors for the mechanisms by which they affect GnRH neurons and the HPG axis.
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