The Significance of Leptin Signals to Neonatal Somatotropes and Gonadotropes

描述(申请人提供)：脂肪细胞瘦素一直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达到峰值，恰好在生长激素和促性腺激素出现和扩大之前。在啮齿动物中，在新生儿发育期(相当于人类的中期妊娠)，瘦素水平也有类似的上升，其峰值与生长激素和促性腺激素出生后扩张的时间相匹配。这项研究中探索的新假设是，瘦素可能通过支持促生长激素和促性腺激素的早期发育来作为出生后早期生殖功能的调节因子。数据显示促性腺激素和促生长激素细胞表达瘦素受体(Ob-R)，这一点得到了支持。此外，在缺乏瘦素或Ob-R的突变大鼠或小鼠中，这两种细胞类型的数量都减少了。有瘦素或Ob-R突变的人是不育的，那些Ob-R突变的人不能正常生长。我们假设，瘦素在垂体中的作用是对其在下丘脑的作用的补充，它通过刺激生长激素和促性腺激素的扩张，从而促进对下丘脑刺激的正常反应。这种作用可能会在神经肽脉冲成熟之前发挥作用。我们的假设将在小鼠模型中得到验证，在小鼠模型中，Ob-R在促生长激素或促性腺激素群体中被选择性地消融或截断。这种方法将一次隔离Ob-R对一种细胞类型的影响，从而消除在具有全局Ob-R基因敲除的小鼠或大鼠中看到的混杂效应。携带由大鼠生长激素启动子(rGHp-Cre)或大鼠促黄体激素-2启动子(rLH2p-GFP-Cre)驱动的Cre-重组酶转基因的创建者与携带Ob-R基因的小鼠(侧翼有loxP序列)杂交，将产生Ob-R基因(Lepr)细胞特异性缺失的突变小鼠。目的1研究切除生长激素受体(Ob-R)对生长激素释放激素(GHRH)和胰岛素样生长因子-1(IGF-1)的影响。目的研究促性腺激素释放激素(GnRH)和神经肽Y(NPY)对促性腺激素释放激素(GnRH)和神经肽Y(NPY)的影响。这两组研究还将调查瘦素在催乳素的出生后发育、青春期的时间、生育能力、生殖器官的发育以及促生长激素或促性腺激素对性腺类固醇的反应中的作用。这些研究将首次提供瘦素受体对促性腺激素或生长激素以及生长激素的一个子集的重要性的集中观点。与公众健康相关：瘦素是一种由脂肪产生的激素，在调节能量摄入和支出方面发挥着关键作用。出生后，瘦素水平在促性腺激素和生长激素之前上升，生长激素是脑下垂体前叶的细胞，产生生殖所需的激素，数量增加，在10-15天时达到成年水平。这项研究将检验这样一种假设，即出生后瘦素水平的上升促进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，这项建议解决了瘦素如何在脑下垂体水平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.