Multinodal regulation of the arcuate/paraventricular nucleus circuit by leptin
Multinodal regulation of the arcuate/paraventricular nucleus circuit by leptin
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DOI：
10.1073/pnas.1016785108
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发表时间：
2011-01-04
影响因子：
11.1
通讯作者：
Cone, Roger D.
中科院分区：
文献类型：
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作者：
Ghamari-Langroudi, Masoud;Srisai, Dollada;Cone, Roger D.
黑素皮质素-4受体（MC 4 R）是维持能量平衡的关键，下丘脑室旁核（PVN）是MC 4 R作用的关键部位。大多数研究表明，瘦素通过与弓状核或腹内侧下丘脑中的受体结合并调节产物如α-黑素细胞刺激激素（α-MSH）、神经肽Y（NPY）、谷氨酸和GABA从一级神经元释放到MC 4 R PVN细胞上来间接调节PVN神经元。在这里，我们调查的机制，这些神经元的活性调节下各种代谢状态下，通过使用下丘脑切片从转基因MC 4 R-GFP小鼠直接从MC 4 R神经元记录。首先，我们表明，在体内瘦素水平调节紧张性放电率的二阶MC 4 R PVN神经元，与禁食增加放电频率的瘦素依赖的方式。我们还表明，虽然瘦素抑制这些神经元直接在突触后膜，α-MSH和NPY有力地刺激和抑制细胞，分别。因此，在与传统的模型瘦素的行动，MC 4 R PVN神经元的主要控制是不太可能介导的瘦素作用于弓状神经肽Y/刺鼠相关蛋白和proopiomelanocortin神经元。我们还表明，MC 4 R PVN神经元的活性是由MC 4 R的组成性活性控制的，并且受体mRNA的表达和α-MSH敏感性都受到瘦素的刺激。因此，瘦素作用于弓状核/PVN回路以调节能量稳态，其突出机制涉及直接控制MC 4 R PVN神经元中的膜电导和基因表达。
Melanocortin-4 receptor (MC4R) is critical for energy homeostasis, and the paraventricular nucleus of the hypothalamus (PVN) is a key site of MC4R action. Most studies suggest that leptin regulates PVN neurons indirectly, by binding to receptors in the arcuate nucleus or ventromedial hypothalamus and regulating release of products like a-melanocyte-stimulating hormone (alpha-MSH), neuropeptide Y (NPY), glutamate, and GABA from first-order neurons onto the MC4R PVN cells. Here, we investigate mechanisms underlying regulation of activity of these neurons under various metabolic states by using hypothalamic slices from a transgenic MC4R-GFP mouse to record directly from MC4R neurons. First, we show that in vivo leptin levels regulate the tonic firing rate of second-order MC4R PVN neurons, with fasting increasing firing frequency in a leptin-dependent manner. We also show that, although leptin inhibits these neurons directly at the postsynaptic membrane, a-MSH and NPY potently stimulate and inhibit the cells, respectively. Thus, in contrast with the conventional model of leptin action, the primary control of MC4R PVN neurons is unlikely to be mediated by leptin action on arcuate NPY/agouti-related protein and proopiomelanocortin neurons. We also show that the activity of MC4R PVN neurons is controlled by the constitutive activity of the MC4R and that expression of the receptor mRNA and a-MSH sensitivity are both stimulated by leptin. Thus, leptin acts multinodally on arcuate nucleus/PVN circuits to regulate energy homeostasis, with prominent mechanisms involving direct control of both membrane conductances and gene expression in the MC4R PVN neuron.