Rapid sensing of l-leucine by human and murine hypothalamic neurons: Neurochemical and mechanistic insights.
Rapid sensing of l-leucine by human and murine hypothalamic neurons: Neurochemical and mechanistic insights.
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DOI：
10.1016/j.molmet.2018.01.021
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发表时间：
2018-04
影响因子：
8.1
通讯作者：
Blouet C
中科院分区：
文献类型：
--
作者：
Heeley N;Kirwan P;Darwish T;Arnaud M;Evans ML;Merkle FT;Reimann F;Gribble FM;Blouet C
饮食蛋白质由下丘脑神经元感知，强烈影响代谢健康的多个方面，包括食欲、体重增加和肥胖症。然而，人们对下丘脑神经回路控制行为和新陈代谢感知蛋白质可用性的机制知之甚少。这项研究的目的是描述下丘脑内侧基底核的神经元对蛋白质可获得性的信号：氨基酸L-亮氨酸的反应。我们使用断奶后小鼠下丘脑内侧基底部神经元的原代培养，人类诱导的多能干细胞来源的下丘脑神经元，以及钙成像来表征神经元对细胞外L-亮氨酸浓度生理变化的快速反应。小鼠和人类下丘脑神经元中神经化学成分不同的子集对L亮氨酸的反应迅速。与L亮氨酸的厌食作用一致，我们发现L亮氨酸激活了25%的小鼠MBH POMC神经元。L亮氨酸可抑制10%的MBHNPY神经元，且亮氨酸可迅速抑制AGRP的分泌，为亮氨酸快速抑制啮齿类动物的觅食行为提供了机制。令人惊讶的是，先前涉及下丘脑亮氨酸感知的候选机制(KATP通道、mTORC1信号、氨基酸脱羧基)都没有参与L-亮氨酸引起的急性活动变化。相反，我们的数据表明，亮氨酸诱导的神经元激活涉及质膜钙通道，而亮氨酸诱导的神经元抑制是通过抑制储存操作的钙电流来介导的。下丘脑内侧基底区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。亮氨酸可以引起神经元内钙离子浓度的升高和降低，包括一些POMC和NPY/AGRP神经元。我们的数据显示，亮氨酸可以通过新的机制发出信号，迅速影响神经元的活动。一组神经化学成分各异的小鼠和人类下丘脑神经元迅速感觉到L亮氨酸并对其做出反应。亮氨酸可以通过独特和新颖的钙信号机制产生神经元激活或神经元抑制。亮氨酸激活25%的ARH POMC神经元。亮氨酸抑制10%ARH NPY/AGRP神经元，减少下丘脑内侧基底脑片AGRP的分泌。
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. 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. 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 (KATP 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 Ca2+ channel, whereas leucine-induced neuronal inhibition is mediated by inhibition of a store-operated Ca2+ current. 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 Ca2+ 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. A neurochemically diverse group of mouse and human hypothalamic neurons rapidly sense and respond to l-leucine. Leucine can produce neuronal activation or neuronal inhibition via distinct and novel Ca2+ signaling mechanisms. Leucine activates 25% ARH POMC neurons. Leucine inhibits 10% ARH NPY/AGRP neurons and reduces AGRP secretion from fasted mediobasal hypothalamic slices.
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影响因子：
7.7
作者：
Henry FE;Sugino K;Tozer A;Branco T;Sternson SM
通讯作者：
Sternson SM
影响因子：
56.9
作者：
Cota, D;Proulx, K;Seeley, RJ
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Seeley, RJ
影响因子：
14.8
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Brewer, Gregory J.;Torricelli, John R.
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Torricelli, John R.
影响因子：
7.3
作者：
ASHFORD, MLJ;BODEN, PR;TREHERNE, JM
通讯作者：
TREHERNE, JM
影响因子：
6.9
作者：
Huang, Xin;Hancock, Dale P.;Simpson, Stephen J.
通讯作者：
Simpson, Stephen J.