Human adenovirus Ad-36 induces adipogenesis via its E4 orf-1 gene
Human adenovirus Ad-36 induces adipogenesis via its E4 orf-1 gene
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DOI：
10.1038/sj.ijo.0803748
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发表时间：
2008-03-01
影响因子：
4.9
通讯作者：
Dhurandhar, N. V.
中科院分区：
文献类型：
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作者：
Rogers, P. M.;Fusinski, K. A.;Dhurandhar, N. V.
目的：了解细胞和细胞外因子对脂肪细胞分化的调节对于更好地管理慢性疾病如肥胖、胰岛素抵抗和脂肪代谢障碍至关重要。用人腺病毒36型（Ad-36）实验感染大鼠可改善胰岛素敏感性并促进脂肪形成，这让人想起噻唑啉二酮类药物的作用。因此，我们研究了Ad-36作为脂肪形成过程的新型调节剂的作用。设计和结果：即使在不存在脂肪形成诱导剂的情况下，Ad-36而不是Ad-2（另一种人腺病毒）感染3 T3-L1前脂肪细胞和人脂肪源性干细胞（hASC），调节跨越整个脂肪形成级联的调节点，包括cAMP的上调，磷脂酰肌醇3-激酶和p38信号传导途径，Wnt 10 b表达下调，CCAAT/增强子结合蛋白-β和过氧化物酶体增殖物激活受体γ 2表达增加，从而导致脂质蓄积。接下来，我们鉴定了病毒的E4开放阅读框（orf）-1基因对于Ad-36诱导的脂肪生成是必要的和充分的。通过RNAi选择性敲低E4 orf-1消除了3 T3-L1细胞和hASC中Ad-36诱导的脂肪形成信号级联。与空载体相比，Ad-36 E4 orf-1在3 T3-L1中的选择性表达可诱导脂肪细胞的分化，而当该蛋白的PDZ结合结构域缺失时，这种诱导作用被取消。
Objective: Understanding the regulation of adipocyte differentiation by cellular and extracellular factors is crucial for better management of chronic conditions such as obesity, insulin resistance and lipodystrophy. Experimental infection of rats with a human adenovirus type 36 (Ad-36) improves insulin sensitivity and promotes adipogenesis, reminiscent of the effect of thiozolinediones. Therefore, we investigated the role of Ad-36 as a novel regulator of the adipogenic process.Design and Results: Even in the absence of adipogenic inducers, infection of 3T3-L1 preadipocytes and human adipose-derived stem cells (hASC) by Ad-36, but not Ad-2 that is another human adenovirus, modulated regulatory points that spanned the entire adipogenic cascade ranging from the upregulation of cAMP, phosphatidylinositol 3-kinase and p38 signaling pathways, downregulation of Wnt10b expression, and increased expression of CCAAT/enhancer binding protein-beta and peroxisome proliferator-activated receptor gamma 2 and consequential lipid accumulation. Next, we identified that E4 open reading frame (orf)-1 gene of the virus is necessary and sufficient for Ad-36-induced adipogenesis. Selective knockdown of E4 orf-1 by RNAi abrogated Ad-36-induced adipogenic signaling cascade in 3T3-L1 cells and hASC. Compared to the null vector, selective expression of Ad-36 E4 orf-1 in 3T3-L1 induced adipogenesis, which was abrogated when the PDZ-binding domain of the protein was deleted.Conclusion: Thus, Ad-36 E4 orf-1 is a novel inducer of rodent and human adipocyte differentiation process.