快速感知 L-亮氨酸：人类和鼠下丘脑神经元的神经化学和机制见解。
Rapid sensing of l-leucine by human and murine hypothalamic neurons: Neurochemical and mechanistic insights.
机构信息
MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 OQQ, UK.
MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 OQQ, UK.
出版信息
Mol Metab. 2018 Apr;10:14-27. doi: 10.1016/j.molmet.2018.01.021. Epub 2018 Feb 7.
OBJECTIVE
Dietary proteins are sensed by hypothalamic neurons and strongly influence multiple aspects of metabolic health, including appetite, weight gain, and adiposity. However, little is known about the mechanisms by which hypothalamic neural circuits controlling behavior and metabolism sense protein availability. The aim of this study is to characterize how neurons from the mediobasal hypothalamus respond to a signal of protein availability: the amino acid l-leucine.
METHODS
We used primary cultures of post-weaning murine mediobasal hypothalamic neurons, hypothalamic neurons derived from human induced pluripotent stem cells, and calcium imaging to characterize rapid neuronal responses to physiological changes in extracellular l-Leucine concentration.
RESULTS
A neurochemically diverse subset of both mouse and human hypothalamic neurons responded rapidly to l-leucine. Consistent with l-leucine's anorexigenic role, we found that 25% of mouse MBH POMC neurons were activated by l-leucine. 10% of MBH NPY neurons were inhibited by l-leucine, and leucine rapidly reduced AGRP secretion, providing a mechanism for the rapid leucine-induced inhibition of foraging behavior in rodents. Surprisingly, none of the candidate mechanisms previously implicated in hypothalamic leucine sensing (K channels, mTORC1 signaling, amino-acid decarboxylation) were involved in the acute activity changes produced by l-leucine. Instead, our data indicate that leucine-induced neuronal activation involves a plasma membrane Ca channel, whereas leucine-induced neuronal inhibition is mediated by inhibition of a store-operated Ca current.
CONCLUSIONS
A subset of neurons in the mediobasal hypothalamus rapidly respond to physiological changes in extracellular leucine concentration. Leucine can produce both increases and decreases in neuronal Ca concentrations in a neurochemically-diverse group of neurons, including some POMC and NPY/AGRP neurons. Our data reveal that leucine can signal through novel mechanisms to rapidly affect neuronal activity.
目的
膳食蛋白质被下丘脑神经元感知，并强烈影响代谢健康的多个方面，包括食欲、体重增加和肥胖。然而，人们对控制行为和代谢的下丘脑神经回路感知蛋白质可用性的机制知之甚少。本研究旨在描述中脑基下丘脑神经元如何响应蛋白质可用性的信号：氨基酸 l-亮氨酸。
方法
我们使用了断奶后鼠中脑基下丘脑神经元的原代培养物、源自人类诱导多能干细胞的下丘脑神经元以及钙成像技术，来描述快速神经元对细胞外 l-亮氨酸浓度生理变化的反应。
结果
在鼠和人下丘脑神经元中，一个神经化学多样化的子集对 l-亮氨酸迅速做出反应。与 l-亮氨酸的厌食作用一致，我们发现 25%的鼠 MBH POMC 神经元被 l-亮氨酸激活。10%的 MBH NPY 神经元被 l-亮氨酸抑制，亮氨酸迅速减少 AGRP 分泌，为亮氨酸快速抑制啮齿动物觅食行为提供了一种机制。令人惊讶的是，以前涉及下丘脑亮氨酸感应的候选机制（K 通道、mTORC1 信号、氨基酸脱羧作用）都没有参与 l-亮氨酸产生的急性活性变化。相反，我们的数据表明，亮氨酸诱导的神经元激活涉及质膜 Ca 通道，而亮氨酸诱导的神经元抑制是通过抑制储存操作的 Ca 电流介导的。
结论
中脑基下丘脑的一部分神经元对细胞外亮氨酸浓度的生理变化迅速做出反应。亮氨酸可以在一个神经化学多样化的神经元群体中产生神经元 Ca 浓度的增加和减少，包括一些 POMC 和 NPY/AGRP 神经元。我们的数据揭示了亮氨酸可以通过新的机制快速信号传递，从而迅速影响神经元活性。
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