Leptin effects on pulsatile gonadotropin releasing hormone secretion from the adult rat hypothalamus and interaction with cocaine and amphetamine regulated transcript peptide and neuropeptide Y
Introduction
Alteration in energy balance may influence reproductive function in many species. Food restriction can alter adult reproductive function [1], [2] and delay the timing of pubertal onset [3], [4] by suppression of luteinizing hormone (LH) secretion. Many studies showed that leptin, a key regulator of food intake and energy balance, may play a regulatory role in the hypothalamic–pituitary–gonadal axis. In female ob/ob mice, leptin administration increased basal LH levels and restored fertility [5], [6], [7]. Other experiments have demonstrated that intracerebroventricular (i.c.v.) injection of leptin antiserum led to a decrease in LH pulsatility and an impairment of reproductive function [8].
Neuropeptide (NPY) and, more recently, the cocaine and amphetamine regulated transcript (CART) were shown to be involved in the mechanisms of leptin action on food intake. The hypothalamic transcripts of NPY, a potent stimulator of food intake, were increased by food restriction [9] and reduced by i.c.v. administration of leptin [10], [11]. Leptin administration to obese (ob/ob) mice stimulated the mRNA expression of CART, a hypothalamic inhibitor of food intake [12]. Therefore, it appeared interesting to study whether NPY and CART could be involved in leptin effects on the hypothalamic–pituitary–gonadal system.
Discrepant stimulatory and inhibitory effects of NPY on sexual maturation and reproduction were observed depending on species, steroidal environment [13], site of NPY administration in the brain [14] and chronic [15], [16], [17] versus acute pattern of infusion [18]. CART effects on the reproductive axis were unknown till we reported very recently a study of pulsatile GnRH secretion from hypothalamic explants of prepubertal male and female rats [19]. The frequency of GnRH pulsatility was stimulated by leptin. CART was likely to mediate such an effect. Using the same paradigm, NPY was found to accelerate GnRH pulsatility through the Y5-receptor subtype which appeared to be not involved in mediation of leptin effects [20]. Here, we used hypothalamic explants from adult male rats and female rats at different phases of the estrus cycle. We aimed at studying the effects of leptin and the possible mediating role of NPY and CART in the regulation of frequency and amplitude of pulsatile GnRH secretion.
Section snippets
Animals
Male and female Wistar rats were used. They were housed in temperature and light-controlled conditions (22°C, lights on between 07:00 and 19:00) with water and standard rat pellet ad libitum. The protocols were approved by the University Committee on animal research.
Hypothalamic explants incubation
The animals were sacrificed by decapitation between 10:00 and 11:00 for all experiments except during the estrous cycle when some experiments were started in the afternoon around 16:00. The retrochiasmatic hypothalamus was rapidly
Pulsatile GnRH secretion at different phases of the estrus cycle
Using hypothalamic explants of adult female rats obtained in the morning as well as in the afternoon (Table 1), the mean GnRH interpulse interval was around 40 min and did not change throughout the estrus cycle. Using explants obtained in the morning, the mean GnRH pulse amplitude did not change significantly throughout the cycle. Using explants obtained in the afternoon, when the preovulatory LH surge is known to occur on proestrus, a significantly increased pulse amplitude was seen on
Discussion
The preovulatory LH surge was known to take place during the afternoon of proestrus [27], [28], [29]. In this study, using explants obtained in the afternoon of the different cycle phases, we showed that the frequency of GnRH pulsatility did not change whereas the amplitude showed about a two fold increase on the afternoon of proestrus. Several in vivo studies showed that GnRH secretion in pituitary stalk plasma was markedly increased at the time of the preovulatory LH surge [30], [31], [32].
Acknowledgements
We would like to thank Dr. Peter Kristensen, Novo Nordisk (Bagsvaerd, Denmark) for the generous gift of purified CART protein and CART antibody. We are grateful to Dr. Graeme Semple, Ferring Research Institute (Chilworth, UK) for synthesis of the Novartis non peptidic Y5- receptor antagonist and Dr. V.D. Ramirez for the generous supply of the anti-GnRH antiserum. This study was supported by the Belgian Fonds de la Recherche Scientifique Médicale (grant 3.4529.97), the Faculty of Medecine at the
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