Original Article
International Journal of Obesity (2008) 32, 397–406; doi:10.1038/sj.ijo.0803748; published online 6 November 2007
Human adenovirus Ad-36 induces adipogenesis via its E4 orf-1 gene
P M Rogers1,3, K A Fusinski2,3, M A Rathod1,2,3, S A Loiler1, M Pasarica1, M K Shaw2, G Kilroy1, G M Sutton1, E J McAllister1, N Mashtalir1, J M Gimble1, T C Holland2 and N V Dhurandhar1
- 1Department of Infections and Obesity, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
- 2Wayne State University, Detroit, MI, USA
Correspondence: Dr NV Dhurandhar, Department of Infections and Obesity, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70808, USA. E-mail: nikhil.dhurandhar@pbrc.edu
3These authors contributed equally to this work.
Received 21 May 2007; Revised 22 July 2007; Accepted 17 August 2007; Published online 6 November 2007.
Abstract
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-
and peroxisome proliferator-activated receptor 
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.
Keywords:
adiposity, infectobesity, infection, stem cells, 3T3-L1, preadipocytes
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