The Significance of Leptin Signals to Neonatal Somatotropes and Gonadotropes

描述（由申请人提供）：脂肪细胞瘦素被认为是正常生殖的“允许”；然而，它的确切作用尚不确定。在人类中，血清瘦素水平在妊娠中期上升到峰值，就在生长激素和促性腺激素出现和扩大之前。在啮齿类动物中，在新生儿发育期间（相当于人类的妊娠中期）瘦素水平也有类似的上升，其峰值与出生后生长激素和促性腺激素的扩张时间相匹配。本研究探索的新假设是，瘦素可能通过支持生长激素和促性腺激素的早期发育，在出生后早期调节生殖功能。数据显示促性腺激素和促生长激素表达瘦素受体（Ob-R），这一点得到了支持。此外，在瘦素或Ob-R缺乏的突变大鼠或小鼠中，两种细胞类型的数量都减少了。瘦素或Ob-R发生突变的人是不育的，而Ob-R发生突变的人不能正常生长。我们假设瘦素在垂体中的作用通过刺激生长激素和促性腺激素的扩张来补充其在下丘脑中的作用，从而促进对下丘脑刺激的正常反应。这一作用可能在神经肽脉冲成熟之前起作用。我们的假设将通过小鼠模型进行验证，其中Ob-R在生长激素或促性腺激素群体中被选择性地切除或截断。这种方法将一次分离Ob-R对一种细胞类型的影响，从而消除在Ob-R全基因敲除的小鼠或大鼠中看到的混淆效应。通过将携带由大鼠生长激素启动子（rGHp-Cre）或大鼠黄体生成素- 2启动子（rLH2p-GFP-Cre）驱动的Cre-重组酶基因的创始人与携带loxP序列（“floxed”）的Ob-R基因的小鼠杂交，可以创建具有细胞特异性Ob-R基因缺失（Lepr）的突变小鼠。目的1研究将测试切除生长激素中Ob-R对出生后生长激素的发育及其对生长激素释放激素（GHRH）和胰岛素样生长因子-1 （IGF-1）的反应的影响。目的2研究将检测去除促性腺激素中Ob-R对促性腺激素出生后发育及其对促性腺激素释放激素（GnRH）和神经肽Y （NPY）的反应的影响。这两组研究还将调查瘦素在出生后发育中的作用，青春期的时间，生育能力，生殖器官的发育，以及对性腺激素的生长激素或促性腺激素反应。这些研究将首次提供瘦素受体对促性腺激素或生长变异性和一部分生长变异性的重要性的集中观点。公共卫生相关性：瘦素是一种由脂肪产生的激素，在调节能量摄入和消耗方面起着关键作用。出生后，瘦素水平在促性腺激素和促生长激素之前上升，促性腺激素和促生长激素是脑垂体前叶的细胞，产生生殖所需的激素，在10-15天时数量增加并达到成人水平。这项研究将验证这样一种假设，即出生后瘦素水平的上升促进了生长激素和促性腺激素数量的早期增加，达到对正常生殖至关重要的水平。因此，这一建议解决了关于瘦素如何在垂体水平上影响生殖能力的重要问题。

DESCRIPTION (provided by applicant): Adipocyte leptin has been considered as "permissive" for normal reproduction; however, its exact role is uncertain. In humans, serum leptin levels rise to a peak by midgestation, just before the appearance and expansion of populations of somatotropes and gonadotropes. In rodents, there is a similar rise in leptin level during the neonatal development period (which is equivalent to midgestation in humans), with a peak that matches the timing of the postnatal expansion in both somatotropes and gonadotropes. The novel hypothesis being explored in this study is that leptin may serve as an early postnatal regulator of reproductive function by supporting somatotrope and gonadotrope development early in their development. This is supported by data showing that gonadotropes and somatotropes express leptin receptors (Ob-R). Furthermore, both cell types are reduced in number in mutant rats or mice that are deficient in leptin or Ob-R. Humans with mutations in leptin or Ob-R are infertile and those who have mutated Ob-R do not grow normally. We hypothesize that leptin's role in the pituitary complements its well established role in the hypothalamus by stimulating an expansion of somatotropes and gonadotropes and thus facilitating normal responses to hypothalamic stimulation. This role may be played before the neuropeptide pulses are mature. Our hypothesis will be tested with mouse models in which Ob-R have been selectively ablated or truncated in either the somatotrope or gonadotrope populations. This approach will isolate the effects of Ob-R on one cell type at a time, thus eliminating confounding effects seen in mice or rats with global Ob-R knockout. Mutant mice with cell-specific deletion of the Ob-R gene (Lepr) will be created by crossing founders carrying the Cre- recombinase transgene driven by the rat growth hormone promoter (rGHp-Cre) or the rat luteinizing hormone- 2 promoter (rLH2p-GFP-Cre) with mice carrying the Ob-R gene flanked by loxP sequences ("floxed"). Aim 1 studies will test the effect of ablating Ob-R in somatotropes on the postnatal development of somatotropes and their responses to growth hormone-releasing hormone (GHRH) and insulin-like growth factor-1 (IGF-1). Aim 2 studies will test the effect of deleting Ob-R in gonadotropes on the postnatal development of gonadotropes and their responses to gonadotropin-releasing hormone (GnRH) and neuropeptide Y (NPY). Both sets of studies will also investigate the role of leptin in the postnatal development of lactotropes, timing of puberty, fertility, development of the reproductive organs, and somatotrope or gonadotrope responses to gonadal steroids. These studies will provide for the first time a focused view of the importance of leptin receptors to either gonadotropes or somatotropes and a subset of somatomamotropes. PUBLIC HEALTH RELEVANCE: Leptin is a hormone produced by fat that plays a key role in regulating energy intake and expenditure. After birth, leptin levels rise just before gonadotropes and somatotropes, cells of the anterior pituitary gland that produce hormones essential for reproduction, grow in number and reach adult levels by age 10-15 days. This study will test the hypothesis that this postnatal rise in leptin levels promotes this early increase in the number of somatotropes and gonadotropes to levels that are vital for normal reproduction. This proposal thus addresses important questions about how leptin can affect reproductive competence at the level of the pituitary.