Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Human adenovirus Ad-36 induces adipogenesis via its E4 orf-1 gene

International Journal of Obesity volume 32, pages 397–406 (2008)Cite this article

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-β and peroxisome proliferator-activated receptor γ2 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Rosen ED, Spiegelman BM . Adipocytes as regulators of energy balance and glucose homeostasis. Nature 2006; 444: 847–853.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rosen ED, MacDougald OA . Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol 2006; 7: 885–896.

    Article  CAS  PubMed  Google Scholar 

  3. Yang X, Jansson PA, Nagaev I, Jack MM, Carvalho E, Sunnerhagen KS et al. Evidence of impaired adipogenesis in insulin resistance. Biochem Biophys Res Commun 2004; 317: 1045–1051.

    Article  CAS  PubMed  Google Scholar 

  4. Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI . Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem 2000; 275: 8456–8460.

    Article  CAS  PubMed  Google Scholar 

  5. Gavrilova O, Marcus-Samuels B, Graham D, Kim JK, Shulman GI, Castle AL et al. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest 2000; 105: 271–278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pajvani UB, Trujillo ME, Combs TP, Iyengar P, Jelicks L, Roth KA et al. Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nat Med 2005; 11: 797–803.

    Article  CAS  PubMed  Google Scholar 

  7. Ranganathan G, Unal R, Pokrovskaya I, Yao-Borengasser A, Phanavanh B, Lecka-Czernik B et al. The lipogenic enzymes DGAT1, FAS, and LPL in adipose tissue: effects of obesity, insulin resistance, and TZD treatment. J Lipid Res 2006; 47: 2444–2450.

    Article  CAS  PubMed  Google Scholar 

  8. de Souza CJ, Eckhardt M, Gagen K, Dong M, Chen W, Laurent D et al. Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance. Diabetes 2001; 50: 1863–1871.

    Article  CAS  PubMed  Google Scholar 

  9. Boden G, Cheung P, Mozzoli M, Fried SK . Effect of thiazolidinediones on glucose and fatty acid metabolism in patients with type 2 diabetes. Metabolism 2003; 52: 753–759.

    Article  CAS  PubMed  Google Scholar 

  10. Bogacka I, Xie H, Bray GA, Smith SR . The effect of pioglitazone on peroxisome proliferator-activated receptor-gamma target genes related to lipid storage in vivo. Diabetes Care 2004; 27: 1660–1667.

    Article  CAS  PubMed  Google Scholar 

  11. Farmer SR . Transcriptional control of adipocyte formation. Cell Metab 2006; 4: 263–273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dhurandhar NV, Israel BA, Kolesar JM, Mayhew G, Cook ME, Atkinson RL . Transmissibility of adenovirus-induced adiposity in a chicken model. Int J Obes Relat Metab Disord 2001; 25: 990–996.

    Article  CAS  PubMed  Google Scholar 

  13. Dhurandhar NV, Israel BA, Kolesar JM, Mayhew GF, Cook ME, Atkinson RL . Increased adiposity in animals due to a human virus. Int J Obes Relat Metab Disord 2000; 24: 989–996.

    Article  CAS  PubMed  Google Scholar 

  14. Dhurandhar NV, Whigham LD, Abbott DH, Schultz-Darken NJ, Israel BA, Bradley SM et al. Human adenovirus Ad-36 promotes weight gain in male rhesus and marmoset monkeys. J Nutr 2002; 132: 3155–3160.

    Article  CAS  PubMed  Google Scholar 

  15. Pasarica M, Shin AC, Yu M, Ou Yang HM, Rathod M, Jen KL et al. Human adenovirus 36 induces adiposity, increases insulin sensitivity, and alters hypothalamic monoamines in rats. Obesity (Silver Spring) 2006; 14: 1905–1913.

    Article  CAS  Google Scholar 

  16. Atkinson RL, Dhurandhar NV, Allison DB, Bowen RL, Israel BA, Albu JB et al. Human adenovirus-36 is associated with increased body weight and paradoxical reduction of serum lipids. Int J Obes (London) 2005; 29: 281–286.

    Article  CAS  Google Scholar 

  17. Vangipuram SD, Sheele J, Atkinson RL, Holland TC, Dhurandhar NV . A human adenovirus enhances preadipocyte differentiation. Obes Res 2004; 12: 770–777.

    Article  CAS  PubMed  Google Scholar 

  18. Frese KK, Lee SS, Thomas DL, Latorre IJ, Weiss RS, Glaunsinger BA et al. Selective PDZ protein-dependent stimulation of phosphatidylinositol 3-kinase by the adenovirus E4-ORF1 oncoprotein. Oncogene 2003; 22: 710–721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sakaue H, Ogawa W, Matsumoto M, Kuroda S, Takata M, Sugimoto T et al. Posttranscriptional control of adipocyte differentiation through activation of phosphoinositide 3-kinase. J Biol Chem 1998; 273: 28945–28952.

    Article  CAS  PubMed  Google Scholar 

  20. Tomiyama K, Nakata H, Sasa H, Arimura S, Nishio E, Watanabe Y . Wortmannin, a specific phosphatidylinositol 3-kinase inhibitor, inhibits adipocytic differentiation of 3T3-L1 cells. Biochem Biophys Res Commun 1995; 212: 263–269.

    Article  CAS  PubMed  Google Scholar 

  21. Whigham LD, Israel BA, Atkinson RL . Adipogenic potential of multiple human adenoviruses in vivo and in vitro in animals. Am J Physiol Regul Integr Comp Physiol 2006; 290: R190–R194.

    Article  CAS  PubMed  Google Scholar 

  22. Green H, Meuth M . An established pre-adipose cell line and its differentiation in culture. Cell 1974; 3: 127–133.

    Article  CAS  PubMed  Google Scholar 

  23. Orlicky DJ, DeGregori J, Schaack J . Construction of stable coxsackievirus and adenovirus receptor-expressing 3T3-L1 cells. J Lipid Res 2001; 42: 910–915.

    CAS  PubMed  Google Scholar 

  24. DeLany JP, Floyd ZE, Zvonic S, Smith A, Gravois A, Reiners E et al. Proteomic analysis of primary cultures of human adipose-derived stem cells: modulation by adipogenesis. Mol Cell Proteomics 2005; 4: 731–740.

    Article  CAS  PubMed  Google Scholar 

  25. Ramirez-Zacarias JL, Castro-Munozledo F, Kuri-Harcuch W . Quantitation of adipose conversion and triglycerides by staining intracytoplasmic lipids with Oil red O. Histochemistry 1992; 97: 493–497.

    Article  CAS  PubMed  Google Scholar 

  26. Engelman JA, Lisanti MP, Scherer PE . Specific inhibitors of p38 mitogen-activated protein kinase block 3T3-L1 adipogenesis. J Biol Chem 1998; 273: 32111–32120.

    Article  CAS  PubMed  Google Scholar 

  27. Schilder RJ, Marden JH . Metabolic syndrome and obesity in an insect. Proc Natl Acad Sci USA 2006; 103: 18805–18809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nourry C, Grant SG, Borg JP . PDZ domain proteins: plug and play!. Sci STKE 2003; 2003: RE7.

    PubMed  Google Scholar 

  29. So PW, Herlihy AH, Bell JD . Adiposity induced by adenovirus 5 inoculation. Int J Obes Relat Metab Disord 2005; 29: 603–606.

    Article  CAS  Google Scholar 

  30. Shen Y, Shenk TE . Viruses and apoptosis. Curr Opin Genet Dev 1995; 5: 105–111.

    Article  CAS  PubMed  Google Scholar 

  31. Frese KK, Latorre IJ, Chung SH, Caruana G, Bernstein A, Jones SN et al. Oncogenic function for the Dlg1 mammalian homolog of the Drosophila discs-large tumor suppressor. EMBO J 2006; 25: 1406–1417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Vangipuram SD, Yu M, Tian J, Stanhope KL, Pasarica M, Havel PJ et al. Adipogenic human adenovirus-36 reduces leptin expression and secretion and increases glucose uptake by fat cells. Int J Obes (London) 2007; 31: 87–96.

    Article  CAS  Google Scholar 

  33. Rajala MS, Rajala RV, Astley RA, Butt AL, Chodosh J . Corneal cell survival in adenovirus type 19 infection requires phosphoinositide 3-kinase/Akt activation. J Virol 2005; 79: 12332–12341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tan PH, Xue SA, Manunta M, Beutelspacher SC, Fazekasova H, Alam AK et al. Effect of vectors on human endothelial cell signal transduction: implications for cardiovascular gene therapy. Arterioscler Thromb Vasc Biol 2006; 26: 462–467.

    Article  CAS  PubMed  Google Scholar 

  35. Kagawa T, Varticovski L, Sai Y, Arias IM . Mechanism by which cAMP activates PI3-kinase and increases bile acid secretion in WIF-B9 cells. Am J Physiol Cell Physiol 2002; 283: C1655–C1666.

    Article  CAS  PubMed  Google Scholar 

  36. Webster CR, Anwer MS . Role of the PI3K/PKB signaling pathway in cAMP-mediated translocation of rat liver Ntcp. Am J Physiol 1999; 277: G1165–G1172.

    CAS  PubMed  Google Scholar 

  37. Yoshizaki T, Maegawa H, Egawa K, Ugi S, Nishio Y, Imamura T et al. Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes. J Biol Chem 2004; 279: 22715–22726.

    Article  CAS  PubMed  Google Scholar 

  38. Schernthaner G, Matthews DR, Charbonnel B, Hanefeld M, Brunetti P . Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double-blind, randomized trial. J Clin Endocrinol Metab 2004; 89: 6068–6076.

    Article  CAS  PubMed  Google Scholar 

  39. Yu JG, Javorschi S, Hevener AL, Kruszynska YT, Norman RA, Sinha M et al. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 2002; 51: 2968–2974.

    Article  CAS  PubMed  Google Scholar 

  40. Garg A . Lipodystrophies. Am J Med 2000; 108: 143–152.

    Article  CAS  PubMed  Google Scholar 

  41. Mallon PW, Cooper DA, Carr A . HIV-associated lipodystrophy. HIV Med 2001; 2: 166–173.

    Article  CAS  PubMed  Google Scholar 

  42. Mallon PW, Wand H, Law M, Miller J, Cooper DA, Carr A . Buffalo hump seen in HIV-associated lipodystrophy is associated with hyperinsulinemia but not dyslipidemia. J Acquir Immune Defic Syndr 2005; 38: 156–162.

    Article  PubMed  Google Scholar 

  43. Carr A, Workman C, Carey D, Rogers G, Martin A, Baker D et al. No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial. Lancet 2004; 363: 429–438.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was partly funded by The William Hardy Endowment for Obesity Research and NIH 1R01 DK066164-01 awarded to NVD, by NIH 5F31 AI061827-01 to KAF and Cell Biology Core Facility of the Clinical Nutrition Research Center of the Pennigton Biomedical Research Center (PBRC) with support from DK072476 to GK and JMG. We thank Dr James Granneman and Dr Todd Leff from Wayne State University for helpful discussions and Susan Newman from PBRC for guidance with qRT-PCR assays. CAR overexpressing 3T3-L1 cells were a gift from Dr David Orlicky, University of Colorado Cancer Center, Denver, CO.

Author information

Author notes

  1. P M Rogers, K A Fusinski and M A Rathod: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Infections and Obesity, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA

    P M Rogers, M A Rathod, S A Loiler, M Pasarica, G Kilroy, G M Sutton, E J McAllister, N Mashtalir, J M Gimble & N V Dhurandhar

  2. Wayne State University, Detroit, MI, USA

    K A Fusinski, M A Rathod, M K Shaw & T C Holland

Authors
  1. P M Rogers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K A Fusinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M A Rathod
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S A Loiler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Pasarica
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M K Shaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G Kilroy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G M Sutton
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. E J McAllister
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. N Mashtalir
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J M Gimble
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. T C Holland
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. N V Dhurandhar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N V Dhurandhar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rogers, P., Fusinski, K., Rathod, M. et al. Human adenovirus Ad-36 induces adipogenesis via its E4 orf-1 gene. Int J Obes 32, 397–406 (2008). https://doi.org/10.1038/sj.ijo.0803748

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0803748

Keywords

This article is cited by

Search

Advanced search

Quick links