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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

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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 6

Site-specific deletion of LepR disrupts basal LH levels in female mice.

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Site-specific deletion of LepR disrupts basal LH levels in female mice.
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(A) Bilateral injections of TAT-Cre protein into the OVLT/MEPO prevented P-STAT3 45 minutes following peripheral leptin injection in the preoptic region (POA) of Leprfl/fl, but not in Lepr+/+, littermates. However, leptin was still able to induce P-STAT3 in caudal areas of the hypothalamus, such as the ARH and PMv, in TAT-CrePOA Leprfl/fl mice. Scale bar: 200 μm. (B) Body weight did not differ between TAT-CrePOA Lepr+/+ and TAT-CrePOA Leprfl/fl mice. (C) Lack of leptin signaling in the OVLT/MEPO resulted in higher uterine weight in TAT-CrePOA Leprfl/fl mice when compared with that of TAT-Cre–injected wild-type littermates. (D) Strikingly, basal levels of LH were increased in females lacking LepR signaling in the preoptic region when compared with those of wild-type mice injected with TAT-Cre. When injected with leptin, TAT-CrePOA Leprfl/fl mice were unable to respond further with a rise in LH levels. Scale bar: 50 μm. *P < 0.05.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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