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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction
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Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction

机译：富含黑色素的激素可直接抑制GnRH神经元并阻断kisepteptin活化，将能量平衡与生殖联系起来

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摘要

A link between energy balance and reproduction is critical for the survival of all species. Energy-consuming reproductive processes need to be aborted in the face of a negative energy balance, yet knowledge of the pathways mediating this link remains limited. Fasting and food restriction that inhibit fertility also upregulate the hypothalamic melanin-concentrating hormone (MCH) system that promotes feeding and decreases energy expenditure; MCH knockout mice are lean and have a higher metabolism but remain fertile. MCH also modulates sleep, drug abuse behavior, and mood, and MCH receptor antagonists are currently being developed as antiobesity and antidepressant drugs. Despite the clinical implications of MCH, the direct postsynaptic effects of MCH have never been reported in CNS neurons. Using patch-clamp recordings in brain slices from multiple lines of trans-genic GFP mice, we demonstrate a strong inhibitory effect of MCH on an exclusive population of septal vGluT2-GnRH neurons that is activated by the puberty-triggering and preovulatory luteinizing hormone surge-mediating peptide, kisspeptin. MCH has no effect on kisspeptin-insensitive GnRH, vGluT2, cholinergic, or GABAergic neurons located within the same nucleus. The inhibitory effects of MCH are reproducible and nondesensitizing and are mediated via a direct postsynaptic Ba~(2+)-sensitive K~+ channel mechanism involving the MCHR1 receptor. MCH immunoreactive fibers are in close proximity to vGluT2-GFP and GnRH-GFP neurons. Importantly, MCH blocks the excitatory effect of kisspeptin on vGluT2-GnRH neurons. Considering the role of MCH in regulating energy balance and of GnRH and kisspeptin in triggering puberty and maintaining fertility, MCH may provide a critical link between energy balance and reproduction directly at the level of the kisspeptin-activated vGluT2-GnRH neuron.
机译：能量平衡与繁殖之间的联系对于所有物种的生存至关重要。面对负面的能量平衡，需要中止耗能的生殖过程，但是对介导这种联系的途径的知识仍然有限。禁食和限制生育的食物限制也下丘脑黑色素浓缩激素（MCH）系统上调，从而促进进食并减少能量消耗； MCH基因敲除小鼠是苗条的，具有较高的新陈代谢，但仍能繁殖。 MCH还可以调节睡眠，药物滥用行为和情绪，MCH受体拮抗剂目前正在开发为抗肥胖和抗抑郁药。尽管MCH具有临床意义，但尚未在中枢神经系统神经元中报道过MCH的直接突触后作用。在多行转基因GFP小鼠的大脑切片中使用膜片钳记录，我们证明了MCH对隔室vGluT2-GnRH神经元的独家种群具有强烈的抑制作用，该种群被青春期触发和排卵前促黄体激素激增所激活。介导肽，kisepteptin。 MCH对位于同一核内的对吻肽素不敏感的GnRH，vGluT2，胆碱能或GABA能神经元没有影响。 MCH的抑制作用是可再现的且不脱敏的，并且通过涉及MCHR1受体的直接突触后Ba〜（2+）敏感K〜+通道机制介导。 MCH免疫反应性纤维非常靠近vGluT2-GFP和GnRH-GFP神经元。重要的是，MCH阻断了kisepteptin对vGluT2-GnRH神经元的兴奋作用。考虑到MCH在调节能量平衡中的作用以及GnRH和Kisspeptin在触发青春期和维持生育力中的作用，MCH可能直接在KissPeptin激活的vGluT2-GnRH神经元水平上提供能量平衡与生殖之间的关键联系。

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  • 作者

    Min Wu; Iryna Dumalska; Elena Morozova; Anthony van den Pol; Meenakshi Alreja;

  • 作者单位

    Departments of Psychiatry, Yale University School of Medicine and the Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT 06508;

    Departments of Psychiatry, Yale University School of Medicine and the Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT 06508;

    Departments of Psychiatry, Yale University School of Medicine and the Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT 06508;

    Departments of Neurosurgery, Yale University School of Medicine and the Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT 06508;

    Departments of Psychiatry, Yale University School of Medicine and the Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT 06508 Departments of Neurobiology, Yale University School of Medicine and the Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT 06508;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    fertility; gonadotropins; HPG axis; obesity; starvation;

    机译：生育能力促性腺激素HPG轴;肥胖;饥饿;

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