Deficiency in the Nuclear Factor E2-related Factor-2 Transcription Factor Results in Impaired Adipogenesis and Protects against Diet-induced Obesity
Deficiency in the Nuclear Factor E2-related Factor-2 Transcription Factor Results in Impaired Adipogenesis and Protects against Diet-induced Obesity
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DOI：
10.1074/jbc.m109.093955
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发表时间：
2010-03-19
影响因子：
4.8
通讯作者：
Chan, Jefferson Y.
中科院分区：
文献类型：
--
作者：
Pi, Jingbo;Leung, Laura;Chan, Jefferson Y.
核因子 E2 相关因子 2 (Nrf2) 是一种 cap-n-collar 碱性亮氨酸拉链 (CNC-bZIP) 转录因子，被认为是 II 期解毒和抗氧化基因表达的主要调节因子，并且在参与外源代谢的组织（包括肝脏和肾脏）中强烈表达。 Nrf2 在脂肪组织中也大量表达；然而，Nrf2 在脂肪细胞生物学中的确切功能尚不清楚。在当前的研究中，我们表明，靶向敲除小鼠中的 Nrf2 可减少脂肪组织质量，促进小脂肪细胞的形成，并防止高脂肪饮食引起的体重增加和肥胖。在小鼠胚胎成纤维细胞、3T3-L1 细胞和人皮下前脂肪细胞中，Nrf2 的选择性缺陷会损害脂肪细胞的分化。 Nrf2 缺乏还会导致脂肪细胞分化过程中过氧化物酶体增殖物激活受体 γ (PPAR γ)、CCAAT 增强子结合蛋白 α (C/EBP α) 及其下游靶标的表达降低。相反，通过稳定敲低 Nrf2 的负调节因子 Keap1 来激活 3T3-L1 细胞中的 Nrf2，增强并加速激素诱导的脂肪细胞分化。 Nrf2 的转染会刺激 Ppar gamma 启动子活性，Keap1 的稳定敲低会增强 3T3-L1 细胞中 PPAR gamma 的表达。此外，染色质免疫沉淀研究表明，Nrf2 与 Ppar gamma 启动子中 Nrf2 的共有结合位点相关。这些发现表明，Nrf2 除了参与解毒和抗氧化途径之外，还具有新的生物学作用，并将 Nrf2 置于有限的转录因子网络中，通过调节 PPAR γ 的表达来控制脂肪细胞分化。
Nuclear factor E2-related factor 2 (Nrf2) is a cap-n-collar basic leucine zipper (CNC-bZIP) transcription factor that is well established as a master regulator of phase II detoxification and antioxidant gene expression and is strongly expressed in tissues involved in xenobiotic metabolism including liver and kidney. Nrf2 is also abundantly expressed in adipose tissue; however, the exact function of Nrf2 in adipocyte biology is unclear. In the current study we show that targeted knock-out of Nrf2 in mice decreases adipose tissue mass, promotes formation of small adipocytes, and protects against weight gain and obesity otherwise induced by a high fat diet. In mouse embryonic fibroblasts, 3T3-L1 cells, and human subcutaneous preadipocytes, selective deficiency of Nrf2 impairs adipocyte differentiation. Deficiency of Nrf2 also leads to decreased expression of peroxisome proliferator-activated receptor gamma (PPAR gamma), CCAAT enhancer-binding protein alpha (C/EBP alpha), and their downstream targets during adipocyte differentiation. Conversely, activation of Nrf2 in 3T3-L1 cells by stable knockdown of its negative regulator Keap1 enhances and accelerates hormone-induced adipocyte differentiation. Transfection of Nrf2 stimulates Ppar gamma promoter activity, and stable knockdown of Keap1 enhances PPAR gamma expression in 3T3-L1 cells. In addition, chromatin immunoprecipitation studies show that Nrf2 associates with consensus binding sites for Nrf2 in the Ppar gamma promoter. These findings demonstrate a novel biologic role for Nrf2 beyond its participation in detoxification and antioxidant pathways and place Nrf2 within the limited network of transcription factors that control adipocyte differentiation by regulating expression of PPAR gamma.