Rogers P M, Fusinski K A, Rathod M A, Loiler S A, Pasarica M, Shaw M K, Kilroy G, Sutton G M, McAllister E J, Mashtalir N, Gimble J M, Holland T C, Dhurandhar N V
Department of Infections and Obesity, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808, USA.
Int J Obes (Lond). 2008 Mar;32(3):397-406. doi: 10.1038/sj.ijo.0803748. Epub 2007 Nov 6.
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.
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 gamma2 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.
Thus, Ad-36 E4 orf-1 is a novel inducer of rodent and human adipocyte differentiation process.
了解细胞和细胞外因子对脂肪细胞分化的调节作用，对于更好地管理肥胖、胰岛素抵抗和脂肪营养不良等慢性疾病至关重要。用人36型腺病毒（Ad-36）对大鼠进行实验性感染可改善胰岛素敏感性并促进脂肪生成，这与噻唑烷二酮类药物的作用相似。因此，我们研究了Ad-36作为脂肪生成过程新型调节因子的作用。
即使在没有脂肪生成诱导剂的情况下，Ad-36感染3T3-L1前脂肪细胞和人脂肪来源干细胞（hASC），而非另一种人腺病毒Ad-2，可调节整个脂肪生成级联反应的调控点，包括cAMP、磷脂酰肌醇3激酶和p38信号通路的上调、Wnt10b表达的下调以及CCAAT/增强子结合蛋白β和过氧化物酶体增殖物激活受体γ2表达的增加以及随之而来的脂质积累。接下来，我们确定病毒的E4开放阅读框（orf）-1基因对于Ad-36诱导的脂肪生成是必要且充分的。通过RNAi选择性敲低E4 orf-1可消除3T3-L1细胞和hASC中Ad-36诱导的脂肪生成信号级联反应。与空载体相比，在3T3-L1中选择性表达Ad-36 E4 orf-1可诱导脂肪生成，当该蛋白的PDZ结合结构域缺失时，脂肪生成被消除。
因此，Ad-36 E4 orf-1是啮齿动物和人类脂肪细胞分化过程的新型诱导剂。
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