Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction
Nicole Bellefontaine, … , Sebastien G. Bouret, Vincent Prevot
Nicole Bellefontaine, … , Sebastien G. Bouret, Vincent Prevot
Published May 8, 2014
Citation Information: J Clin Invest. 2014;124(6):2550-2559. https://doi.org/10.1172/JCI65928.
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Research Article

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

Nicole Bellefontaine, Konstantina Chachlaki, Jyoti Parkash, Charlotte Vanacker, William Colledge, Xavier d’Anglemont de Tassigny, John Garthwaite, Sebastien G. Bouret, Vincent Prevot

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Figure 4

A deficiency in NO signaling renders leptin unable to induce puberty in Lepob/ob mice.

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A deficiency in NO signaling renders leptin unable to induce puberty in ...
(A) Nos1–/– Lepob/ob mice displayed a lower body weight than Nos1+/+ Lepob/ob littermates prior to the leptin regimen, although both groups lost weight with leptin treatment. (B) Nos1–/– Lepob/ob mice never underwent first vaginal estrus. ND, not detected. (C) No difference in body weight was observed between Lepob/ob mice infused with either vehicle or l-NAME, although both groups responded to leptin with a decrease in body weight. (D) The Lepob/ob mice treated chronically with l-NAME never demonstrated first vaginal estrus. (E) Blockade of nNOS in Lepob/ob mice, either by genetic or pharmacologic means, resulted in a lack of estrous cyclicity, while this was corrected in control mice. C, cornified (estrus); N, nucleated (proestrus); L, lymphocytic (diestrus). (F) Blockade of nNOS in Lepob/ob mice leads to nondetectable levels of LH. Nos1+/+ Lepob/ob and Nos1–/– Lep+/+ mice showed partial to full surge-like LH levels following exposure to male odor. (G) Ovarian sections from Nos1+/+ Lepob/ob mice with no leptin treatment, following 28 days of leptin treatment, and Nos1–/– Lepob/ob mice, following 28 days of leptin treatment. Note the presence of corpora lutea (CL) in Nos1+/+ Lepob/ob mice treated with leptin. Scale bar: 100 μm. AF, atretic follicles; i.c., intracranial.