Specific physiological roles for signal transducer and activator of transcription 3 in leptin receptor-expressing neurons
Specific physiological roles for signal transducer and activator of transcription 3 in leptin receptor-expressing neurons
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DOI：
10.1210/me.2007-0389
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发表时间：
2008-03-01
影响因子：
--
通讯作者：
Xu, Allison W.
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文献类型：
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作者：
Piper, Merisa L.;Unger, Elizabeth K.;Xu, Allison W.
瘦素是一种脂肪源性激素，对能量平衡和神经内分泌功能发挥多效性作用。瘦素或其受体[瘦素受体，亚型B（LepRb）]缺陷的小鼠表现出严重的肥胖、不育和线性生长降低。瘦素与其受体结合触发多种信号传导途径，包括信号转导和转录激活因子3（Stat 3）、磷脂酰肌醇-3-激酶和ERK。大量的研究集中在这些信号通路如何介导不同的瘦素功能。含有不能进行Stat 3信号传导的突变型LepRb的小鼠肥胖，但仍能生育，线性生长增强。相比之下，在Nestin-Cre的全脑中Stat 3的缺失导致不育和线性生长下降，以及肥胖。Nestin介导的缺失的额外表型可以反映Stat 3在非LepRb神经元中的作用或LepRb神经元中不依赖于瘦素的Stat 3作用。为了解决这一矛盾，并获得更多的了解Stat 3的代谢作用，我们已经产生了小鼠，其中Stat 3被破坏，特别是在LepRb神经元后，瘦素受体表达的发病。我们发现，突变小鼠表现出严重的肥胖与增加线性增长和正常的生育能力。此外，这些动物的血糖控制受损与其肥胖程度相关。这些结果表明，LepRb神经元中的Stat 3不调节线性生长或生育力。这些结果进一步表明，瘦素对生长和繁殖的影响是由其他信号通路介导的，而Stat 3介导的这些功能的控制是独立于瘦素和LepRb神经元介导的。
Leptin is a fat-derived hormone that exerts pleiotropic effects on energy balance and neuroendocrine functions. Mice defective in leptin or its receptor [leptin receptor, isoform b (LepRb)] exhibit profound obesity, infertility, and reduced linear growth. Leptin binding to its receptor triggers multiple signaling pathways, including signal transducer and activator of transcription 3 (Stat 3), phosphatidylinositol-3-kinase, and ERK. A considerable amount of effort has been focused on how these signaling pathways mediate diverse leptin functions. Mice containing a mutant LepRb incapable of Stat3 signaling are obese but remain fertile with enhanced linear growth. In contrast, deletion of Stat3 in the whole brain with Nestin-Cre results in infertility and decreased linear growth, in addition to obesity. The additional phenotypes of the Nestin-mediated deletion could reflect Stat3 action in non-LepRb neurons or leptin-independent Stat3 actions in LepRb neurons. To resolve this discrepancy and to gain more insight into the metabolic actions of Stat3, we have generated mice in which Stat3 is disrupted specifically in LepRb neurons after the onset of leptin receptor expression. We show that mutant mice exhibit profound obesity with increased linear growth and normal fertility. In addition, impaired glycemic control in these animals correlates with their degree of obesity. These results demonstrate that Stat3 in LepRb neurons does not regulate linear growth or fertility. These results further suggest that leptin's effects on growth and reproduction are mediated by other signaling pathways, and that Stat3-mediated control of these functions is mediated independently of leptin and LepRb neurons.