title: Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction.
abstract: The transition to puberty and adult fertility both require a minimum level of energy availability. The adipocyte-derived hormone leptin signals the long-term status of peripheral energy stores and serves as a key metabolic messenger to the neuroendocrine reproductive axis. Humans and mice lacking leptin or its receptor fail to complete puberty and are infertile. Restoration of leptin levels in these individuals promotes sexual maturation, which requires the pulsatile, coordinated delivery of gonadotropin-releasing hormone to the pituitary and the resulting surge of luteinizing hormone (LH); however, the neural circuits that control the leptin-mediated induction of the reproductive axis are not fully understood. Here, we found that leptin coordinated fertility by acting on neurons in the preoptic region of the hypothalamus and inducing the synthesis of the freely diffusible volume-based transmitter NO, through the activation of neuronal NO synthase (nNOS) in these neurons. The deletion of the gene encoding nNOS or its pharmacological inhibition in the preoptic region blunted the stimulatory action of exogenous leptin on LH secretion and prevented the restoration of fertility in leptin-deficient female mice by leptin treatment. Together, these data indicate that leptin plays a central role in regulating the hypothalamo-pituitary-gonadal axis in vivo through the activation of nNOS in neurons of the preoptic region.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bellefontaine
authors.forename: Konstantina
authors.initials: K
authors.lastname: Chachlaki
authors.forename: Jyoti
authors.initials: J
authors.lastname: Parkash
authors.forename: Charlotte
authors.initials: C
authors.lastname: Vanacker
authors.forename: William
authors.initials: W
authors.lastname: Colledge
authors.forename: Xavier
authors.initials: X
authors.lastname: d'Anglemont de Tassigny
authors.forename: John
authors.initials: J
authors.lastname: Garthwaite
authors.forename: Sebastien G
authors.initials: SG
authors.lastname: Bouret
authors.forename: Vincent
authors.initials: V
authors.lastname: Prevot
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D059648:Kisspeptins / Q000378:metabolism; D020738:Leptin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011301:Preoptic Area / Q000378:metabolism / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D000074502:Receptors, Kisspeptin-1; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012098:Reproduction / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C492248:Kiss1r protein, mouse; D059648:Kisspeptins; D020738:Leptin; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D009569:Nitric Oxide; D007986:Luteinizing Hormone; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse