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In Vitro Stimulation of the Prepubertal Rat Gonadotropin-Releasing Hormone Pulse Generator by Leptin and Neuropeptide Y through Distinct Mechanisms¹

Developmental Neuroendocrinology Unit (M.C.L, E.V, A.G, A.S.P, J.P.B.), Division of Ambulatory Pediatrics and Adolescent Medicine, Department of Pediatrics, University of Liège, C.H.U. Sart Tilman, B-4000 Liège, Belgium; and Ferring Research Institute (J.L.J), Paris 75007, France

Address all correspondence and requests for reprints to: Marie-Christine Lebrethon, M.D., Ph.D., Division of Pediatric and Adolescent Medicine, C.H.U. Sart Tilman, B35, B-4000 Liège, Belgium. E-mail: Marie-Christine.Lebrethon{at}chu.ulg.ac.be

Leptin may act as a negative feedback signal to the brain in the control of appetite through suppression of neuropeptide Y (NPY) secretion and stimulation of cocaine- and amphetamine-regulated transcript (CART), a new anorectic peptide. We aimed at studying whether leptin, NPY, and CART have related effects on the hypothalamic control of the pituitary-gonadal system and the developmental changes in NPY and CART effects. Using retrochiasmatic hypothalamic explants from prepubertal 15-day-old male rats, the GnRH interpulse interval (mean ± SD : 62 ± 5 min) was significantly reduced by 10^-7 M of leptin (46 ± 3.3 min) as well as 10^-7 M of NPY (47 ± 4.4 min) and 10^-6 M of CART (46 ± 2.7 min), whereas the GnRH pulse amplitude was not affected. The stimulatory effects of different NPY receptor agonists [human PYY _3–36, porcine NPY _13–36, human (D-Trp ₃₂) NPY, porcine (Leu ₃₁ Pro ₃₄) NPY, human pancreatic polypeptide (PP)], as well as the absent effects of rat PP were consistent with the involvement of the Y5-receptor subtype in mediation of NPY effects. Incubation with 10^-7 M of a Y5-receptor selective antagonist prevented the effect of NPY (61 ± 4 vs. 46 ± 2 min), whereas leptin and CART effects were not (47 ± 3 vs. 46 ± 3 min and 46 ± 3 vs. 46 ± 2 min, respectively), suggesting that NPY was not involved in leptin and CART effects. Using an anti-CART antiserum (1:1000), the reduction of GnRH interpulse interval caused by leptin was partially prevented (56.2 ± 4 vs. 47.9 ± 3.8 min), whereas the reduction of GnRH interval caused by NPY was not affected (45.9 ± 2.5 vs. 47.8 ± 3.7). The GnRH interpulse interval was decreased by 10^-7 M of NPY at 5 days (72 ± 3.8 vs. 91.9 ± 3.5) as well as at 15 days, whereas such an effect was not observed anymore at 25 and 50 days. Similar effects were observed using 10^-6 M of CART-peptide. Using 10^-6 M of the Y5-receptor antagonist, the GnRH interpulse interval was significantly increased at 15 days (66.6 ± 2.7 min), 25 days (56.5 ± 39.9 min), and 50 days (52.5 vs. 38.2 min), whereas no change was observed at 5 days. Using the anti-CART antiserum, a significant increase of GnRH interpulse interval was observed at 25 days only. In conclusion, the stimulatory effects of leptin and NPY on the frequency of pulsatile GnRH secretion before puberty involve two distinct mechanisms. NPY causes acceleration of GnRH pulsatility via the Y5-receptor subtype, which is not involved in leptin effects while the CART is involved in leptin effects on GnRH secretion but not in NPY effects. The reduction of pulsatility by the Y5 antagonist provides evidence of endogenous NPY involvement in the control of GnRH secretion from the time of onset of puberty.

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