The Significance of Leptin Signals to Neonatal Somatotropes and Gonadotropes

瘦素信号对新生儿生长激素和促性腺激素的意义

• 批准号: 8294398
• 负责人: GWEN V CHILDS
• 金额: $ 28.06万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294398
• 关键词: Ablation; Address; Adipocytes; Adult; Affect; Age; Alleles; Amenorrhea; Animals; Anterior Pituitary Gland; Appearance; Birth; Body Composition; Body Weight decreased; Cells; Child; Competence; Complement; Data; Defect; Desire for food; Development; Eating Disorders; Embryo; Endocrine; Energy Intake; Energy Metabolism; Exons; Fatty acid glycerol esters; Fertility; Fetus; Gene Deletion; Glucose; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Growth; Health; Hormones; Human; Hypothalamic structure; Infertility; Insulin; Insulin-Like Growth Factor I; Knock-out; Leptin; Link; Luteinizing Hormone; Maintenance; Metabolic; Modeling; Mus; Mutant Strains Mice; Mutate; Mutation; Neonatal; Neurons; Neuropeptides; Nutritional status; Obesity; Organ; Physiologic pulse; Pituitary Gland; Play; Population; Puberty; Rattus; Relative (related person); Reproduction; Reproductive system; Rodent; Role; Running; Second Pregnancy Trimester; Serum; Signal Transduction; Site; Somatotrope Cell; Somatotropin; Somatotropin-Releasing Hormone; Technology; Testing; Time; Transgenes; Uncertainty; Unplanned pregnancy; Woman; cell type; cost; excessive exercise; fetal; functional hypothalamic amenorrhea; growth hormone-releasing hormone receptor; hypothalamic pituitary gonadal axis; leptin receptor; men; mouse model; mutant; neuropeptide Y; novel; nutrition; pituitary gonadal axis; postnatal; prepuberty; promoter; recombinase; reproductive; reproductive development; reproductive function; reproductive hormone; response; restoration; vpr Genes

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.

描述（由申请人提供）：脂肪细胞瘦素被认为是正常繁殖的“许可”；然而，其确切作用尚不确定。在人类中，血清瘦素水平在妊娠中期达到峰值，就在生长激素和促性腺激素群体出现和扩张之前。在啮齿类动物中，瘦素水平在新生儿发育期（相当于人类的妊娠中期）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。这项研究正在探索的新假设是，瘦素可能通过在发育早期支持生长激素和促性腺激素的发育，充当生殖功能的早期产后调节剂。促性腺激素和生长激素表达瘦素受体 (Ob-R) 的数据支持了这一点。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均减少。瘦素或 Ob-R 突变的人类无法生育，而 Ob-R 突变的人类则无法正常生长。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已确立的作用，从而促进对下丘脑刺激的正常反应。这种作用可能在神经肽脉冲成熟之前发挥作用。我们的假设将用小鼠模型进行检验，其中 Ob-R 在生长激素或促性腺激素群体中被选择性地消除或截短。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 整体敲除的小鼠或大鼠中观察到的混杂效应。细胞特异性删除 Ob-R 基因 (Lepr) 的突变小鼠将通过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) 驱动的 Cre 重组酶转基因的杂交创始人产生。 -GFP-Cre），小鼠携带 Ob-R 基因，两侧为 loxP 序列（“floxed”）。目标 1 研究将测试消除生长激素中的 Ob-R 对生长激素的产后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。目标 2 研究将测试删除促性腺激素中的 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。两组研究还将调查瘦素在产后催乳素发育、青春期时机、生育力、生殖器官发育以及对性腺类固醇的生长激素或促性腺激素反应中的作用。这些研究将首次集中关注瘦素受体对促性腺激素或生长激素以及生长激素子集的重要性。公众健康相关性：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，瘦素水平会在促性腺激素和生长激素（垂体前叶细胞，产生生殖必需激素）数量增加并在 10-15 天时达到成人水平之前上升。这项研究将检验这样的假设：出生后瘦素水平的升高会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，该提案解决了瘦素如何影响垂体水平的生殖能力的重要问题。