Defective STAT signaling by the leptin receptor in diabetic mice
Defective STAT signaling by the leptin receptor in diabetic mice
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DOI：
10.1073/pnas.93.13.6231
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发表时间：
1996-06-25
影响因子：
11.1
通讯作者：
Skoda, RC
中科院分区：
文献类型：
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作者：
Ghilardi, N;Ziegler, S;Skoda, RC
瘦素及其受体——肥胖受体（OB - R）构成了一个调节体重的重要信号系统。OB - R mRNA的剪接变体所编码的蛋白质在其细胞质结构域的长度上有所不同。我们克隆了一种在野生型瘦素受体中优先在下丘脑表达的长异构体，并表明它可以激活信号转导子和转录激活子（STAT）-3、STAT - 5和STAT - 6。糖尿病（db）小鼠的OB - R基因内的一个点突变产生了一个新的剪接供体位点，该位点显著降低了这种长异构体在纯合db/db小鼠中的表达。相比之下，一种具有较短细胞质结构域的OB - R蛋白在db/db小鼠和野生型小鼠中均存在。我们表明这种短异构体无法激活STAT通路。这些数据进一步证明了OB - R中的突变导致了db/db表型，并确定了三种STAT蛋白作为瘦素抗肥胖作用的潜在介质。
Leptin and its receptor, obese receptor (OB-R), comprise an important signaling system for the regulation of body weight, Splice variants of OB-R mRNA encode proteins that differ in the length of their cytoplasmic domains, We cloned a long isoform of the wild-type leptin receptor that is preferentially expressed in the hypothalamus and show that it can activate signal transducers and activators of transcription (STAT)-3, STAT-5, and STAT-6. A point mutation within the OB-R gene of diabetic (db) mice generates a new splice donor site that dramatically reduces expression of this long isoform in homozygous db/db mice. In contrast, an OB-R protein with a shorter cytoplasmic domain is present in both db/db and wild-type mice, We show that this short isoform is unable to activate the STAT pathway, These data provide further evidence that the mutation in OB-R causes the db/db phenotype and identify three STAT proteins as potential mediators of the anti-obesity effects of leptin.