Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons
Jose Donato Jr., … , Joel K. Elmquist, Carol F. Elias
Jose Donato Jr., … , Joel K. Elmquist, Carol F. Elias
Published December 22, 2010
Citation Information: J Clin Invest. 2011;121(1):355-368. https://doi.org/10.1172/JCI45106.
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Research Article

Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons

Abstract

Studies in humans and rodents indicate that a minimum amount of stored energy is required for normal pubertal development. The adipocyte-derived hormone leptin is a key metabolic signal to the neuroendocrine reproductive axis. Humans and mice lacking leptin or the leptin receptor (LepR) (ob/ob and db/db mice, respectively) are infertile and fail to enter puberty. Leptin administration to leptin-deficient subjects and ob/ob mice induces puberty and restores fertility, but the exact site or sites of leptin action are unclear. Here, we found that genetic deletion of LepR selectively from hypothalamic Kiss1 neurons in mice had no effect on puberty or fertility, indicating that direct leptin signaling in Kiss1 neurons is not required for these processes. However, bilateral lesions of the ventral premammillary nucleus (PMV) of ob/ob mice blunted the ability of exogenous leptin to induce sexual maturation. Moreover, unilateral reexpression of endogenous LepR in PMV neurons was sufficient to induce puberty and improve fertility in female LepR-null mice. This LepR reexpression also normalized the increased hypothalamic GnRH content characteristic of leptin-signaling deficiency. These data suggest that the PMV is a key site for leptin’s permissive action at the onset of puberty and support the hypothesis that the multiple actions of leptin to control metabolism and reproduction are anatomically dissociated.

Authors

Jose Donato Jr., Roberta M. Cravo, Renata Frazão, Laurent Gautron, Michael M. Scott, Jennifer Lachey, Inar A. Castro, Lisandra O. Margatho, Syann Lee, Charlotte Lee, James A. Richardson, Jeffrey Friedman, Streamson Chua Jr., Roberto Coppari, Jeffrey M. Zigman, Joel K. Elmquist, Carol F. Elias

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Figure 3

Bilateral lesions of the PMV-blunted leptin action to induce sexual maturation in ob/ob female mice.

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Bilateral lesions of the PMV-blunted leptin action to induce sexual matu...
(A and B) Survival graph illustrating the time required for PMV-nonlesion and PMV-lesion mice to show copulatory plug in the presence of sexually experienced males. Note that the first PMV-lesion mice showed copulatory plug after 25 days with the male, while about 70% of PMV-nonlesion mice had already copulated following the same period of time. 1 PMV-lesion mouse did not show copulatory plugs until the end of the experiment (6 weeks following the intromission of the male in the cage). (C) Pareto chart of t values of coefficients (df = 8, variable: time for copulatory plug). Number of leptin-induced pSTAT3-ir in the PMV, Arc, and number of Kiss1 neurons in the Arc were assessed using a multivariate model. Note that only lesions of the PMV showed a significant coefficient. (D) Bilateral lesions of the PMV precluded leptin stimulatory effect on LH secretion in ob/ob mice. (E) PMV-lesioned mice showed decreased levels of progesterone. *Statistically different from intact ob/ob mice treated with saline. #Statistically different from PMV-lesion mice treated with leptin. Data are expressed as mean ± SEM.