Transcription factor AP-2β inhibits expression and secretion of leptin, an insulin-sensitizing hormone, in 3T3-L1 adipocytes
Transcription factor AP-2β inhibits expression and secretion of leptin, an insulin-sensitizing hormone, in 3T3-L1 adipocytes
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DOI：
10.1038/ijo.2009.295
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发表时间：
2010-04-01
影响因子：
4.9
通讯作者：
Maegawa, H.
中科院分区：
文献类型：
--
作者：
Fuke, T.;Yoshizaki, T.;Maegawa, H.
背景：我们之前报道过激活蛋白-2 β (AP-2 β)转录因子基因与2型糖尿病之间的关联。该基因优先在脂肪组织中表达，具有AP-2 β疾病易感等位基因的受试者在脂肪组织中的AP-2 β表达强于没有易感等位基因的受试者。此外，AP-2b的过表达导致3T3-L1脂肪细胞脂质积累并诱导胰岛素抵抗。结果：我们发现在3T3-L1脂肪细胞中AP-2 β的过表达降低了瘦素启动子活性，从而降低了信使RNA （mRNA）和蛋白质的表达和分泌。此外，通过rna干扰抑制内源性AP-2 β增加了瘦素mRNA和蛋白的表达。在体外和体内，电泳迁移率和染色质免疫沉淀分析显示AP-2 β与瘦素启动子区域的特异性结合。此外，相对于转录起始位点，位于|34和| 42之间的AP-2结合位点的定点突变消除了AP-2 β的抑制作用。我们的研究结果清楚地表明，AP-2 β通过结合启动子直接抑制胰岛素致敏激素瘦素的表达。结论：AP-2 β通过与其启动子区直接相互作用调节瘦素的表达。国际肥胖杂志（2010）34,670-678；doi: 10.1038 / ijo.2009.295;2010年1月12日在线发布
Background: We have previously reported an association between the activator protein-2 beta (AP-2 beta) transcription factor gene and type 2 diabetes. This gene is preferentially expressed in adipose tissue, and subjects with a disease-susceptible allele of AP-2 beta showed stronger AP-2 beta expression in adipose tissue than those without the susceptible allele. Furthermore, overexpression of AP-2b led to lipid accumulation and induced insulin resistance in 3T3-L1 adipocytes.Result: We found that overexpression of AP-2 beta in 3T3-L1 adipocytes decreased the promoter activity of leptin, and subsequently decreased both messenger RNA (mRNA) and protein expression and secretion. Furthermore, knockdown of endogenous AP-2 beta by RNA-interference increased mRNA and protein expression of leptin. Electrophoretic mobility shift and chromatin immunoprecipitation assays revealed specific binding of AP-2 beta to leptin promoter regions in vitro and in vivo. In addition, site-directed mutagenesis of the AP-2-binding site located between position | 34 and | 42 relative to the transcription start site abolished the inhibitory effect of AP-2 beta. Our results clearly showed that AP-2 beta directly inhibited insulin-sensitizing hormone leptin expression by binding to its promoter.Conclusion: AP-2 beta modulated the expression of leptin through direct interaction with its promoter region. International Journal of Obesity (2010) 34, 670-678; doi: 10.1038/ijo.2009.295; published online 12 January 2010