The transcription factor AP-2β causes cell enlargement and insulin resistance in 3T3-L1 adipocytes
The transcription factor AP-2β causes cell enlargement and insulin resistance in 3T3-L1 adipocytes
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DOI：
10.1210/en.2005-1304
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发表时间：
2006-04-01
期刊：
影响因子：
4.8
通讯作者：
Kashiwagi, A
中科院分区：
文献类型：
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作者：
Tao, Y;Maegawa, H;Kashiwagi, A
我们已经报道了激活蛋白-2 β（AP-2 β）转录因子基因变异与2型糖尿病的相关性。该基因以分化阶段依赖性方式优先在3 T3-L1脂肪细胞中表达，初步实验表明，具有疾病易感等位基因的受试者在脂肪组织中的表达比没有易感等位基因的受试者更强。因此，我们在3 T3-L1脂肪细胞中过表达AP-2 β基因，以阐明AP-2 β是否可能通过脂肪细胞功能失调在2型糖尿病的发病机制中发挥关键作用。在过表达AP-2 β的细胞中，甘油三酯的积累伴随着葡萄糖摄取的增加而使细胞大小增加。相反，通过小干扰RNA抑制AP-2 β表达抑制葡萄糖摄取。AP-2 β过表达对葡萄糖摄取的增强作用可被磷脂酶C（PLC）和非典型蛋白激酶C zeta/lambda（PKC zeta/lambda）抑制剂减弱，但不能被磷脂酰肌醇3-激酶（PI 3- K）抑制剂减弱。一致地，我们发现AP-2 β表达激活PLC和非典型PKC，但不激活PI 3- K。此外，PLC γ的过表达增强葡萄糖摄取，并且这种激活被非典型PKC抑制剂抑制，这表明增强的葡萄糖摄取可能是通过PLC和非典型PKC zeta/lambda介导的，而不是PI 3- K。此外，我们观察到Grb 2相关结合物-1（Gab 1）的酪氨酸磷酸化增加及其与PLC γ的相关性，表明Gab 1可能参与AP-2 β诱导的PLC γ激活。最后，发现AP-2 γ过表达与受损的胰岛素信号传导有关。我们认为AP-2 β是产生脂肪细胞肥大的候选基因，可能与肥胖症中观察到的脂肪细胞异常特征有关。
We have reported the association of variations in the activating protein-2 beta (AP-2 beta) transcription factor gene with type 2 diabetes. This gene was preferentially expressed in 3T3-L1 adipocytes in a differentiation stage-dependent manner, and preliminary experiments showed that subjects with the disease-susceptible allele showed stronger expression in adipose tissue than those without the susceptible allele. Thus, we over-expressed the AP-2 beta gene in 3T3-L1 adipocytes to clarify whether AP-2 beta might play a crucial role in the pathogenesis of type 2 diabetes through dysregulation of adipocyte function. In cells overexpressing AP-2 beta, cells increased in size by accumulation of triglycerides accompanied by enhanced glucose uptake. On the contrary, suppression of AP-2 beta expression by small interfering RNA inhibited glucose uptake. Enhancement of glucose uptake by AP-2 beta overexpression was attenuated by inhibitors of phospholipase C ( PLC) and atypical protein kinase C zeta/lambda (PKC zeta/lambda), but not by a phosphatidylinositol 3-kinase (PI3- K) inhibitor. Consistently, we found activation of PLC and atypical PKC, but not PI3- K, by AP-2 beta expression. Furthermore, overexpression of PLC gamma enhanced glucose uptake, and this activation was inhibited by an atypical PKC inhibitor, suggesting that the enhanced glucose uptake may be mediated through PLC and atypical PKC zeta/lambda, but not PI3- K. Moreover, we observed the increased tyrosine phosphorylation of Grb2-associated binder-1 (Gab1) and its association with PLC gamma, indicating that Gab1 may be involved in AP-2 beta-induced PLC gamma activation. Finally, AP-2 gamma overexpression was found to relate to the impaired insulin signaling. We propose that AP-2 beta is a candidate gene for producing adipocyte hypertrophy and may relate to the abnormal characteristics of adipocytes observed in obesity.