RFamide-related peptide-3 (RFRP-3) neurons have been shown to inhibit gonadotropin-releasing hormone (GnRH) neuronal activity and hence reproduction in birds and eutherian mammals. They have also been proposed to have a direct hypophysiotropic effect on pituitary gonadotropin release. We used a new RFRP-3 antibody to characterize the cell body distribution and fiber projections of RFRP-3 neurons in the adult female brushtail possum brain. RFRP-3-immunoreactive cell bodies were found scattered within the dorsomedial hypothalamus and the dorsomedial half of the ventromedial hypothalamus, while GnRH neurons were observed scattered rostrocaudally along the lateral septum, rostral to the medial septum. There was a significant 2-fold increase in the RFRP-3 cell body number during the nonbreeding season (summer) compared to the breeding season (winter). Immunoreactive RFRP-3 fibers were distributed throughout the thalamus, preoptic area, and hypothalamus. Very few fibers were observed in the median eminence, especially in the external zone. Intraperitoneal injection of the retrograde tracer Fluoro-Gold resulted in the labeling of 40% of hypophysiotropic tuberoinfundibular dopaminergic (tyrosine hydroxylase-positive) neurons; however, <10% of zona incerta dopaminergic neurons (which are not hypophysiotropic) or RFRP-3 neurons were labeled with this tracer. These observations suggest that RFRP-3 exhibits a seasonal fluctuation in cell numbers, as seen in sheep and birds, which is consistent with an increased inhibitory tone during the nonbreeding season. The lack of RFRP-3 fibers in the median eminence and of Fluoro-Gold uptake from the periphery imply that the actions of this peptide occur primarily centrally rather than at the anterior pituitary gland.
Leptin, a permissive hormonal regulator of fertility, provides information about the body's energy reserves to the hypothalamic gonadotrophin-releasing hormone (GnRH) neuronal system that drives reproduction. Leptin does not directly act on GnRH neurones, and the neuronal pathways that it uses remain unclear. RFamide-related peptide-3 (RFRP-3) neurones project to GnRH neurones and primarily inhibit their activity. We tested whether leptin could act via RFRP-3 neurones to potentially modulate GnRH activity. First, the effects of leptin deficiency or high-fat diet-induced obesity on RFRP-3 cell numbers and gene expression were assessed in male and female mice. There was no significant difference in Rfrp mRNA levels or RFRP-3-immunoreactive cell counts in wild-type versus leptin-deficient ob/ob animals, or in low-fat versus high-fat diet fed wild-type mice. Second, the presence of leptin-induced signalling in RFRP-3 neurones was examined in male and female wild-type mice and rats. Dual label immunohistochemistry revealed leptin-induced phosphorylated signal transducer and activator of transcription-3 in close proximity to RFRP-3 neurones, although there was very little (2-13%) colocalisation and no significant differences between vehicle and leptin-treated animals. Furthermore, we were unable to detect leptin receptor mRNA in a semi-purified RFRP-3 cell preparation. Because GABA neurones form critical leptin-responsive GnRH inputs, we also determined whether RFRP-3 and GABA cells were colocalised. No such colocalisation was detected. These results support the concept that leptin has little or no effects on RFRP-3 neurones, and that these neurones are unlikely to be an important neuronal pathway for the metabolic regulation of fertility by leptin.
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