Modulation of neuropeptide Y expression in adult mice does not affect feeding.
Modulation of neuropeptide Y expression in adult mice does not affect feeding.
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DOI：
10.1073/pnas.0509240102
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发表时间：
2005-12
影响因子：
11.1
通讯作者：
Linda Ste Marie;S. Luquet;T. Cole;R. Palmiter
中科院分区：
文献类型：
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作者：
Linda Ste Marie;S. Luquet;T. Cole;R. Palmiter
尽管有许多实验表明，对啮齿动物的神经肽Y（NPY）的施用刺激了喂养和肥胖，而急性干扰NPY信号传导会破坏喂养并促进体重减轻，但NPY-NULL小鼠基本上具有正常体重调节。这些相互矛盾的观察结果表明，在发育过程中慢性缺乏NPY可能会导致补偿性变化，在没有NPY的情况下对食物摄入和能量消耗的调节正常化。为了测试这一想法，我们使用基因靶向将强力霉素（DOX）调节的盒式引入NPY基因座，以表达NPY直到给出小鼠DOX，以阻止转录。与野生型小鼠相比，带有这种构建体的成年小鼠表达了大约4倍的NPY mRNA，在使用DOX治疗后3天内，该构建体降至对照值的20％。 NPY蛋白也下降了大约20倍，但大约5天的半衰期长期存在。这些操纵的生物学有效性通过表明NPY的过表达受到保护侵害的NPY的过表达。长期表达NPY的小鼠体重正常，对这些小鼠的DOX给药并不能抑制喂养。此外，这些小鼠在快速后的重新响应是正常的。我们得出的结论是，如果对NPY水平的变化有补偿，那么它发生在DOX处理所需的时间以消耗NPY水平的时间内。这些观察结果表明，NPY信号传导的药理抑制不太可能对体重产生长期影响。
Despite numerous experiments showing that administration of neuropeptide Y (NPY) to rodents stimulates feeding and obesity, whereas acute interference with NPY signaling disrupts feeding and promotes weight loss, NPY-null mice have essentially normal body weight regulation. These conflicting observations suggest that chronic lack of NPY during development may lead to compensatory changes that normalize regulation of food intake and energy expenditure in the absence of NPY. To test this idea, we used gene targeting to introduce a doxycycline (Dox)-regulated cassette into the Npy locus, such that NPY would be expressed until the mice were given Dox, which blocks transcription. Compared with wild-type mice, adult mice bearing this construct expressed approximately 4-fold more Npy mRNA, which fell to approximately 20% of control values within 3 days after treatment with Dox. NPY protein also fell approximately 20-fold, but the half-life of approximately 5 days was surprisingly long. The biological effectiveness of these manipulations was demonstrated by showing that overexpression of NPY protected against kainate-induced seizures. Mice chronically overexpressing NPY had normal body weight, and administration of Dox to these mice did not suppress feeding. Furthermore, the refeeding response of these mice after a fast was normal. We conclude that, if there is compensation for changes in NPY levels, then it occurs within the time it takes for Dox treatment to deplete NPY levels. These observations suggest that pharmacological inhibition of NPY signaling is unlikely to have long-lasting effects on body weight.