Piper Merisa L, Unger Elizabeth K, Myers Martin G, Xu Allison W
Diabetes Center, University of California San Francisco, San Francisco, California 94143, USA.
Mol Endocrinol. 2008 Mar;22(3):751-9. doi: 10.1210/me.2007-0389. Epub 2007 Dec 20.
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.
瘦素是一种由脂肪产生的激素，对能量平衡和神经内分泌功能具有多效性作用。瘦素或其受体[瘦素受体，异构体b（LepRb）]缺陷的小鼠表现出严重肥胖、不育和线性生长减缓。瘦素与其受体结合会触发多种信号通路，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。大量研究致力于探讨这些信号通路如何介导瘦素的多种功能。含有无法进行Stat3信号传导的突变型LepRb的小鼠肥胖，但仍可生育且线性生长增强。相反，用Nestin-Cre在全脑敲除Stat3除了导致肥胖外，还会导致不育和线性生长减缓。Nestin介导的敲除所产生的额外表型可能反映了Stat3在非LepRb神经元中的作用或LepRb神经元中不依赖瘦素的Stat3作用。为了解决这一差异并更深入了解Stat3的代谢作用，我们构建了在瘦素受体表达开始后Stat3在LepRb神经元中特异性缺失的小鼠。我们发现突变小鼠表现出严重肥胖，线性生长增加且生育能力正常。此外，这些动物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Stat3不调节线性生长或生育能力。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，并且Stat3对这些功能的控制独立于瘦素和LepRb神经元介导。
