Tropic Roles for Leptin in the Maturation of Somatotropes

项目摘要/摘要 新陈代谢健康严重依赖脂肪因子瘦素的趋向性作用，瘦素负责编程 下丘脑在围产期发育过程中接收正常代谢信号。垂体前叶 促生长激素依赖于瘦素的正常代谢功能，然而，瘦素的发育时机 这种瘦素依赖性和潜在的机制代表了我们对瘦素更广泛的作用的认识上的差距。 这项应用的总体目标是确定新生儿瘦素激增对 促生长激素成熟。我们的第一个假设表明，正常的促生长激素成熟是依赖于 围产期瘦素信号及早期瘦素信号缺失对成人促生长激素的影响 功能。我们的第二个假设认为，瘦素通过效应器调节生长激素。 转录因子POU1F1/PIT1的转录调控途径 蛋白质、武藏(MSI)和调节microRNAs(MiRNAs)。两个目标将检验这些假设： 目的1研究将确定瘦素信号的丢失如何影响新生儿的成熟。 成人的生长激素及其代谢功能。我们将研究婴儿的新生儿发育 瘦素信号被删除的动物模型中的促生长激素：1)在促生长激素之后- 选择性消融Lepr外显子1；2)在瘦素激增期间被瘦素拮抗剂阻断或3)被 产妇营养不良。我们将在营养不良的动物身上替换新生的瘦素来检验这一假说 早期瘦素信号对新生儿生长激素的成熟及其正常功能至关重要。 成年人。目的2研究将确定瘦素调节生长激素的潜在机制。 这些研究将使用纯化的生长激素群体来确定瘦素的作用是否由 减弱MSI介导的Pou1f1、TSH和PRL mRNAs抑制的信号通路。我们还将研究 MiRNA介导的GH和GHRHR mRNAs的抑制，并将采用无偏见的方法来识别 其他新的瘦素依赖机制控制促生长激素成熟。这一贡献是 因为它解决了瘦素在预防高血压中的重要性这一全球性问题 母亲营养不良引起的代谢功能障碍，占全球疾病总数的11% 负担，最终导致35%的儿童死亡。拟议的研究在概念上是创新的，因为它 扩大了我们对瘦素作用的理解，包括已知的脑垂体前叶细胞 重要的代谢感受器，并介绍了瘦素的新调节途径，并利用方法学 生长激素的纯化研究进展。这项工作的预期结果是：(1)调查结果 将使该领域充分了解瘦素在促生长激素成熟和功能中的促生长作用，以及(2)这项工作 将提供有关瘦素的作用机制的信息，这些机制可能是针对治疗的预防 早期瘦素缺乏引起的严重代谢功能障碍。

PROJECT SUMMARY/ABSTRACT Metabolic health is critically dependent on tropic actions by the adipokine leptin, which programs the hypothalamus during perinatal development to receive normal metabolic signals. Anterior pituitary somatotropes are dependent on leptin for normal metabolic functions, however, the developmental timing of this leptin dependency and underlying mechanisms represent a gap in our knowledge of leptin's broader roles. The overall objective of this application is to ascertain the importance of the neonatal surge of leptin to somatotrope maturation. Our first hypothesis states that normal somatotrope maturation is dependent on perinatal leptin signals and that lack of early leptin signals alters adult somatotrope functions. Our second hypothesis states that leptin regulates somatotropes through effector pathways involving the POU1F1/PIT1 transcription factor, the mRNA translational control protein, Musashi (MSI) and regulatory microRNAs (miRNAs). Two aims will test these hypotheses: Aim 1 studies will determine how the loss of leptin signals impacts neonatal maturation of somatotropes and their metabolic functions in the adult. We will study the neonatal development of somatotropes in animal models in which leptin signals are either: 1) deleted following the somatotrope- selective ablation of Lepr exon 1; 2) blocked by a leptin antagonist during the leptin surge or 3) attenuated by maternal undernutrition. We will replace neonatal leptin in the undernourished animals to test the hypothesis that early leptin signaling is vital for neonatal maturation of somatotropes and their normal function in the adult. Aim 2 studies will identify mechanisms underlying the leptin regulation of somatotropes. These studies will use purified populations of somatotropes to determine if leptin's actions are mediated by signaling pathways that attenuate MSI-mediated repression of Pou1f1, Tsh, and Prl mRNAs. We will also study miRNA-mediated repression of Gh and Ghrhr mRNAs and will employ unbiased approaches to identify additional novel leptin-dependent mechanisms controlling somatotrope maturation. This contribution is significant because it addresses the global problem of the importance of leptin in the prevention of the metabolic dysfunction caused by maternal undernutrition, which contributes to 11% of the total global disease burden, ultimately leading to 35% of child deaths. The proposed research is conceptually innovative because it broadens our understanding of leptin actions to include cells in the anterior pituitary that are known to be important metabolic sensors, and introduces novel regulatory pathways for leptin and utilizes methodological advancements in the purification of somatotropes. The expected outcomes of the work are that (1) the findings will fully inform the field about leptin's tropic role in somatotrope maturation and function and (2) this work will provide information about mechanisms of leptin's action that may be targeted therapeutically to prevent the severe metabolic dysfunction caused by early leptin deficiency.