Leptin Regulation of Gonadotrope Gonadotropin-Releasing Hormone Receptors As a Metabolic Checkpoint and Gateway to Reproductive Competence.
Leptin Regulation of Gonadotrope Gonadotropin-Releasing Hormone Receptors As a Metabolic Checkpoint and Gateway to Reproductive Competence.
复制标题
DOI：
10.3389/fendo.2017.00367
复制
发表时间：
2017
影响因子：
5.2
通讯作者：
Childs GV
中科院分区：
文献类型：
--
作者：
Odle AK;Akhter N;Syed MM;Allensworth-James ML;Beneš H;Melgar Castillo AI;MacNicol MC;MacNicol AM;Childs GV
脂肪因子瘦素向大脑，特别是下丘脑发出身体营养状况的信号。然而，瘦素受体（LEPRs）可以在整个身体和大脑中找到，包括垂体。已知瘦素允许生殖，不能产生瘦素（Lep/Lep）的小鼠是不育的。许多研究已经确定瘦素对下丘脑生殖的调节。然而，LEPR存在于下丘脑-垂体-性腺轴的所有水平。我们以前已经表明，删除LEPR的信号部分，特别是在促性腺激素损害雌性小鼠的生育能力。我们最近的研究已经将这种调节靶向于促性腺激素释放激素受体（GnRHR）表达的控制。这里提出的假设有两个方面：（1）垂体GnRHR水平的周期性调节为控制生殖轴建立了一个目标代谢检查点，（2）调节生殖轴的代谢信号传导需要多个检查点。在这里，我们强调和探讨下丘脑和垂体之间的关系，就调节GnRHR。我们提出的原始数据加强了这些假设，并建立在我们以前的研究基础上。我们发现，我们可以通过删除所有的LEPR亚型，特别是在促性腺激素导致不孕症的雌性小鼠的70%。我们的研究结果牵连激活素亚基（InhBa）mRNA作为一个潜在的瘦素在促性腺激素的目标。我们进一步显示促性腺激素特异性上调GnRHR蛋白（但不是mRNA水平）瘦素刺激后。为了尝试和理解这种转录后调控，我们测试了可能与Gnrhr mRNA结合的候选miRNA（通过计算机分析鉴定）。我们在促性腺激素Lepr缺失的女性中显示这些miRNA之一的显著上调。这里提供的证据，结合我们以前的工作，奠定了基础的促性腺激素的代谢调节转录后控制。我们讨论了可能的机制，包括miRNA调控和RNA结合蛋白Musashi的参与。我们还证明了这种调节可能是至关重要的动态重构的促性腺激素在骑自行车的女性。最后，我们提出，下丘脑和垂体的瘦素受体是至关重要的身体的能力，以延迟或减缓生殖期间的低营养。
The adipokine leptin signals the body’s nutritional status to the brain, and particularly, the hypothalamus. However, leptin receptors (LEPRs) can be found all throughout the body and brain, including the pituitary. It is known that leptin is permissive for reproduction, and mice that cannot produce leptin (Lep/Lep) are infertile. Many studies have pinpointed leptin’s regulation of reproduction to the hypothalamus. However, LEPRs exist at all levels of the hypothalamic–pituitary–gonadal axis. We have previously shown that deleting the signaling portion of the LEPR specifically in gonadotropes impairs fertility in female mice. Our recent studies have targeted this regulation to the control of gonadotropin releasing hormone receptor (GnRHR) expression. The hypotheses presented here are twofold: (1) cyclic regulation of pituitary GnRHR levels sets up a target metabolic checkpoint for control of the reproductive axis and (2) multiple checkpoints are required for the metabolic signaling that regulates the reproductive axis. Here, we emphasize and explore the relationship between the hypothalamus and the pituitary with regard to the regulation of GnRHR. The original data we present strengthen these hypotheses and build on our previous studies. We show that we can cause infertility in 70% of female mice by deleting all isoforms of LEPR specifically in gonadotropes. Our findings implicate activin subunit (InhBa) mRNA as a potential leptin target in gonadotropes. We further show gonadotrope-specific upregulation of GnRHR protein (but not mRNA levels) following leptin stimulation. In order to try and understand this post-transcriptional regulation, we tested candidate miRNAs (identified with in silico analysis) that may be binding the Gnrhr mRNA. We show significant upregulation of one of these miRNAs in our gonadotrope-Lepr-null females. The evidence provided here, combined with our previous work, lay the foundation for metabolically regulated post-transcriptional control of the gonadotrope. We discuss possible mechanisms, including miRNA regulation and the involvement of the RNA binding protein, Musashi. We also demonstrate how this regulation may be vital for the dynamic remodeling of gonadotropes in the cycling female. Finally, we propose that the leptin receptivity of both the hypothalamus and the pituitary are vital for the body’s ability to delay or slow reproduction during periods of low nutrition.
登录
查看更多内容
影响因子：
4.8
作者：
Barash, IA;Cheung, CC;Steiner, RA
通讯作者：
Steiner, RA
影响因子：
4.8
作者：
Bronson, FH
通讯作者：
Bronson, FH
影响因子：
4.8
作者：
Akhter, Noor;CarlLee, Tyler;Childs, Gwen V.
通讯作者：
Childs, Gwen V.
影响因子：
56.9
作者：
Bouret, SG;Draper, SJ;Simerly, RB
通讯作者：
Simerly, RB
影响因子：
4.6
作者：
Ayrout, Mohsen;Simon, Violaine;Chauvin, Stephanie
通讯作者：
Chauvin, Stephanie