The role of SOCS-3 in leptin signaling and leptin resistance
The role of SOCS-3 in leptin signaling and leptin resistance
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DOI：
10.1074/jbc.274.42.30059
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发表时间：
1999-10-15
影响因子：
4.8
通讯作者：
Flier, JS
中科院分区：
文献类型：
--
作者：
Bjorbæk, C;El-Haschimi, K;Flier, JS
我们先前证实瘦素诱导下丘脑中SOCS-3 mRNA的表达。此外，转染数据表明SOCS-3是瘦素信号传导的抑制剂。然而，关于瘦素对SOCS-3表达的调节以及SOCS-3抑制瘦素作用的机制知之甚少。我们在此表明，在稳定表达长型瘦素受体（CHO-OBR 1）的CHO细胞中，瘦素诱导内源性SOCS-3 mRNA的瞬时表达，但不诱导CIS、SOCS-1或SOCS-2 mRNA的瞬时表达。SOCS-3蛋白水平在瘦素处理2-3小时后达到最大，并在20小时保持升高。此外，在瘦素预处理的CHO-OBR 1细胞中，近端瘦素信号传导在预处理后被阻断超过20小时，因此与增加的SOCS-3表达相关。瘦素预处理不影响细胞表面瘦素受体的表达，通过I-125-Peptin结合试验测定。在转染的COS细胞中，SOCS-3的强制表达导致瘦素诱导的JAK 2酪氨酸磷酸化的抑制。最后，JAK 2与来自瘦素处理的COS细胞的裂解物中的SOCS-3共免疫沉淀。这些结果表明，SOCS-3是一个瘦素调节的抑制剂近端瘦素信号在体内。因此，瘦素反应细胞中过量的SOCS-3活性是瘦素抵抗的潜在机制，瘦素抵抗是人类肥胖的特征。
We earlier demonstrated that leptin induces expression of SOCS-3 mRNA in the hypothalamus. Furthermore, transfection data suggest that SOCS-3 is an inhibitor of leptin signaling. However, little is known about the regulation of SOCS-3 expression by leptin and the mechanism by which SOCS-3 inhibits leptin action. We here show that in CHO cells stably expressing the long form of the leptin receptor (CHO-OBRl), leptin induces transient expression of endogenous SOCS-3 mRNA but not of CIS, SOCS-1, or SOCS-2 mRNA. SOCS-3 protein levels were maximal after 2-3 h of leptin treatment and remained elevated at 20 h. Furthermore, in leptin-pretreated CHO-OBRl cells, proximal leptin signaling was blocked for more than 20 h after pretreatment, thus correlating with increased SOCS-3 expression. Leptin pretreatment did not affect cell surface expression of leptin receptors as measured by I-125-Peptin binding assays. In transfected COS cells, forced expression of SOCS-3 results in inhibition of leptin-induced tyrosine phosphorylation of JAK2. Finally, JAK2 co-immunoprecipitates with SOCS-3 in lysates from leptin-treated COS cells. These results suggest that SOCS-3 is a leptin-regulated inhibitor of proximal leptin signaling in vivo. Excessive SOCS-3 activity in leptin-responsive cells is therefore a potential mechanism for leptin resistance, a characteristic feature in human obesity.