Inhibition of adipocyte differentiation by Nur77, Nurr1, and Nor1.
Inhibition of adipocyte differentiation by Nur77, Nurr1, and Nor1.
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DOI：
10.1210/me.2008-0161
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发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Tontonoz P
中科院分区：
文献类型：
--
作者：
Chao LC;Bensinger SJ;Villanueva CJ;Wroblewski K;Tontonoz P
核受体NR 4A亚组的成员参与胰岛素敏感组织如肝脏和骨骼肌中葡萄糖和脂质代谢的调节。然而，它们在脂肪细胞中的功能还没有很好的定义。先前的研究已经报道，这些受体在用成脂鸡尾酒处理3 T3-L1前脂肪细胞后迅速上调。我们发现，尽管3 T3-L1细胞中的Nur 77表达被cAMP激动剂急性诱导，但它不被其他成脂刺激物诱导，如PPARγ配体，也不在3 T3-F442 A前脂肪细胞分化过程中诱导，这表明Nur 77诱导不是前脂肪细胞分化的必然特征。我们进一步证明了拮抗分化的炎症信号，如TNFα和脂多糖，在体外和体内均急性诱导Nur 77表达。我们还表明，NR 4A在脂肪组织中的表达是响应于禁食/再喂养。将NR 4A受体（Nur 77、Nurr 1和NOR 1）中的每一种逆转录病毒转导到3 T3-L1或3 T3-F442 A前脂肪细胞中有效地抑制脂肪生成。有趣的是，NR 4A介导的脂肪形成抑制不能通过PPARγ过表达或激活来挽救。表达Nur 77的前脂肪细胞的转录谱导致间隙连接蛋白α 1（Gja 1）和tolloid样1（Tll 1）被鉴定为Nur 77响应基因。值得注意的是，在3 T3-L1前脂肪细胞中Gja 1或Tll 1的逆转录病毒表达也抑制脂肪细胞分化，暗示这些基因是Nur 77对脂肪形成的作用的潜在介质。最后，我们发现Nur 77表达抑制前脂肪细胞的有丝分裂克隆扩增，提供了Nur 77可能抑制脂肪形成的额外机制。
Members of the NR4A subgroup of nuclear receptors have been implicated in the regulation of glucose and lipid metabolism in insulin-sensitive tissues such as liver and skeletal muscle. However, their function in adipocytes is not well defined. Previous studies have reported that these receptors are rapidly upregulated following treatment of 3T3-L1 preadipocytes with an adipogenic cocktail. We show here that although Nur77 expression is acutely induced by cAMP agonists in 3T3-L1 cells, it is not induced by other adipogenic stimuli, such as PPARγ ligands, nor is it induced during the differentiation of 3T3-F442A preadipocytes, suggesting that Nur77 induction is not an obligatory feature of preadipocyte differentiation. We further demonstrate that inflammatory signals that antagonize differentiation, such as TNFα and lipopolysaccharide, acutely induce Nur77 expression both in vitro and in vivo. We also show that NR4A expression in adipose tissue is responsive to fasting/refeeding. Retroviral transduction of each of the NR4A receptors (Nur77, Nurr1 and NOR1) into either 3T3-L1 or 3T3-F442A preadipocytes potently inhibits adipogenesis. Interestingly, NR4A-mediated inhibition of adipogenesis cannot not be rescued by PPARγ overexpression or activation. Transcriptional profiling of Nur77-expressing preadipocytes led to the identification of gap-junction protein alpha 1 (Gja1) and tolloid-like 1 (Tll1) as Nur77-responsive genes. Remarkably, retroviral expression of either Gja1 or Tll1 in 3T3-L1 preadipocytes also inhibited adipocyte differentiation, implicating these genes as potential mediators of Nur77’s effects on adipogenesis. Finally, we show that Nur77 expression inhibits mitotic clonal expansion of preadipocytes, providing an additional mechanism by which Nur77 may inhibit adipogenesis.
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