Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction.
Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction.
复制标题
黑色素浓缩激素直接抑制 GnRH 神经元并阻止 Kisspeptin 激活，从而将能量平衡与生殖联系起来。
DOI：
10.1073/pnas.0908200106
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发表时间：
2009
影响因子：
11.1
通讯作者：
Alreja,Meenakshi
中科院分区：
文献类型：
--
作者：
Wu,Min;Dumalska,Iryna;Morozova,Elena;vandenPol,Anthony;Alreja,Meenakshi
能量平衡和繁殖之间的联系对所有物种的生存至关重要。面对负能量平衡，需要中止消耗能量的生殖过程，但对调节这种联系的途径的了解仍然有限。抑制生育能力的禁食和食物限制也上调了促进进食和减少能量消耗的下丘脑黑色素浓缩激素（MCH）系统; MCH基因敲除小鼠瘦，代谢更高，但仍能生育。MCH还调节睡眠、药物滥用行为和情绪，并且MCH受体拮抗剂目前正在被开发为抗肥胖和抗抑郁药物。尽管MCH的临床意义，MCH的直接突触后效应从未在CNS神经元中报道。使用膜片钳记录在脑切片从多个线的转基因GFP小鼠，我们证明了一个强大的抑制作用MCH上的一个独家人口的隔vGluT 2-GnRH神经元激活的青春期触发和排卵前促黄体激素浪涌介导肽，kisspeptin。MCH对位于同一核内的kisspeptin不敏感的GnRH、vGluT 2、胆碱能或GABA能神经元无影响。MCH的抑制作用是可重复的和非脱敏的，并且通过涉及MCHR 1受体的直接突触后Ba 2+敏感性K+通道机制介导。MCH免疫反应性纤维与vGluT 2-GFP和GnRH-GFP神经元非常接近。重要的是，MCH阻断kisspeptin对vGluT 2-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vGluT 2-GnRH神经元水平上提供能量平衡和生殖之间的关键联系。
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 transgenic 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 Ba2+-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.