Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus
Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus
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DOI：
10.1038/35078085
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发表时间：
2001-05-24
期刊：
影响因子：
64.8
通讯作者：
Low, MJ
中科院分区：
文献类型：
--
作者：
Cowley, MA;Smart, JL;Low, MJ
对瘦素缺乏的人和类似的Lep（ob）/Lep（ob）小鼠给予瘦素（1），有效地减少了食欲过盛和肥胖（2，3）。但普通肥胖与瘦素升高有关，这表明肥胖的人对这种脂肪细胞激素有抵抗力。除了调节长期能量平衡外，瘦素还迅速影响神经元活动（4-6）。下丘脑弓状核中的前阿黑皮素（POMC）和神经肽-Y型神经元（7）都是瘦素受体表达的主要位点，也是强效神经肽调节剂黑皮质素和神经肽Y的来源，它们对摄食和代谢产生相反的作用（8，9）。因此，这些神经元是表征瘦素作用和瘦素抵抗机制的理想选择;然而，它们的弥散分布使它们难以研究。在这里，我们报告POMC神经元，我们确定了有针对性的表达绿色荧光蛋白在转基因小鼠的电生理记录。瘦素通过两种机制增加促食欲POMC神经元的动作电位频率：通过非特异性阳离子通道的去极化;和减少局部促食欲神经肽-Y/GABA（γ-氨基丁酸）神经元的抑制。此外，我们表明，黑皮质素肽对这个电路有自抑制作用。在我们的研究结果的基础上，我们提出了一个整合模型的瘦素行动和神经元结构在弓状核的下丘脑。
The administration of leptin(1) to leptin-deficient humans, and the analogous Lep(ob)/Lep(ob) mice, effectively reduces hyperphagia and obesity(2,3). But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone. In addition to regulating long-term energy balance, leptin also rapidly affects neuronal activity(4-6). Proopiomelanocortin (POMC) and neuropeptide-Y types of neurons in the arcuate nucleus of the hypothalamus(7) are both principal sites of leptin receptor expression and the source of potent neuropeptide modulators, melanocortins and neuropeptide Y, which exert opposing effects on feeding and metabolism(8,9). These neurons are therefore ideal for characterizing leptin action and the mechanism of leptin resistance; however, their diffuse distribution makes them difficult to study. Here we report electrophysiological recordings on POMC neurons, which we identified by targeted expression of green fluorescent protein in transgenic mice. Leptin increases the frequency of action potentials in the anorexigenic POMC neurons by two mechanisms: depolarization through a nonspecific cation channel; and reduced inhibition by local orexigenic neuropeptide-Y/GABA (gamma -aminobutyric acid) neurons. Furthermore, we show that melanocortin peptides have an autoinhibitory effect on this circuit. On the basis of our results, we propose an integrated model of leptin action and neuronal architecture in the arcuate nucleus of the hypothalamus.