Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons
Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons
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DOI：
10.1172/jci45106
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发表时间：
2011-01-01
影响因子：
15.9
通讯作者：
Elias, Carol F.
中科院分区：
文献类型：
--
作者：
Donato, Jose, Jr.;Cravo, Roberta M.;Elias, Carol F.
人类和啮齿动物的研究表明，正常的青春期发育需要最少量的储存能量。脂肪细胞衍生的激素瘦素是神经内分泌生殖轴的关键代谢信号。人类和缺乏瘦素或瘦素受体(Lepr)的小鼠(分别为ob/ob和db/db小鼠)不育，无法进入青春期。ob/ob小鼠诱导青春期和恢复生育能力，但确切的瘦素作用部位或部位尚不清楚。我们发现，选择性地从下丘脑Kiss1神经元中缺失Lepr基因对青春期或生育能力没有影响。但ob/ob小鼠双侧腹侧乳头体前核(Pmv)损伤削弱了外源性Leptin诱导性成熟的能力。此外，内源性Leprm pmv神经元的单侧重新表达足以诱导雌性Lepr缺失小鼠的青春期和提高生育力。Lepr的重新表达也使Leptin信号缺乏所特有的下丘脑GnRH含量升高正常化。这些数据表明，PMv是Leptin在青春期开始时允许活动的关键部位，并支持Leptin在解剖分离时控制新陈代谢和生殖的多重作用的假说。
Studies m hum ins 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 m mice had no effect on puberty or fertility, indicating that direct leptin signaling m 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 m PMV neurons was sufficient to induce puberty and improve fertility m 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 at e anatomically dissociated