Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion
Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion
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DOI：
10.1210/en.2007-1132
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发表时间：
2008-04-01
期刊：
影响因子：
4.8
通讯作者：
Chua, Streamson C.
中科院分区：
文献类型：
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作者：
de Wall, Esther Van;Leshan, Rebecca;Chua, Streamson C.
弓状核内存在两种已知类型的瘦素反应神经元：刺鼠基因相关肽 (AgRP)/神经肽 Y (NPY) 神经元和阿片黑皮素原 (POMC) 神经元。通过删除小鼠 AgRP/NPY 和/或 POMC 神经元中的瘦素受体基因 (Lepr)，我们检查了这些神经元对瘦素作用的多个和组合贡献。单独删除 AgRP 和 POMC 神经元中的 Lepr 会增加体重和肥胖，并且同时删除两个神经元（A + P LEPR-KO 小鼠）进一步增加了这些指标。年轻（围断奶）A + P LEPR-KO 小鼠表现出食欲亢进和能量消耗减少，体重增加增加，甘油三酯氧化减少，脂肪积累增加。然而有趣的是，许多这些异常在成年动物中减弱，高剂量的瘦素部分抑制了 A+P LEPR-KO 小鼠的食物摄入。尽管有轻度高胰岛素血症，A + P LEPR-KO 小鼠仍表现出正常的葡萄糖耐量和生育能力。因此，AgRP/NPY 和 POMC 神经元各自在瘦素调节的能量稳态方面发挥着重要作用，成年小鼠的高瘦素水平减轻了这些神经元中瘦素反应性对能量平衡组成部分的重要性，表明存在其他瘦素调节途径，部分补偿了 POMC 和 AgRP/NPY 神经元瘦素作用的缺乏。
Two known types of leptin-responsive neurons reside within the arcuate nucleus: the agouti gene-related peptide (AgRP)/neuropeptide Y (NPY) neuron and the proopiomelanocortin (POMC) neuron. By deleting the leptin receptor gene (Lepr) specifically in AgRP/NPY and/or POMC neurons of mice, we examined the several and combined contributions of these neurons to leptin action. Body weight and adiposity were increased by Lepr deletion from AgRP and POMC neurons individually, and simultaneous deletion in both neurons (A + P LEPR-KO mice) further increased these measures. Young (periweaning) A + P LEPR-KO mice exhibit hyperphagia and decreased energy expenditure, with increased weight gain, oxidative sparing of triglycerides, and increased fat accumulation. Interestingly, however, many of these abnormalities were attenuated in adult animals, and high doses of leptin partially suppress food intake in the A + P LEPR-KO mice. Although mildly hyperinsulinemic, the A + P LEPR-KO mice displayed normal glucose tolerance and fertility. Thus, AgRP/NPY and POMC neurons each play mandatory roles in aspects of leptin-regulated energy homeostasis, high leptin levels in adult mice mitigate the importance of leptin-responsiveness in these neurons for components of energy balance, suggesting the presence of other leptin-regulated pathways that partially compensate for the lack of leptin action on the POMC and AgRP/NPY neurons.