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Diabetes Publish Ahead of Print published online ahead of print July 3, 2008
DOI: 10.2337/db07-1311
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Original Research

Metabolically Favorable Remodeling of Human Adipose Tissue by Human Adenovirus Ad-36

Pamela M. Rogers2, Nazar Mashtalir2, Miloni A. Rathod1, Olga Dubuisson2, Zhong Wang2, Kumar Dasuri2, Scott Babin2, Alok Gupta2, Nathan Markward2, William T. Cefalu2, and Nikhil V. Dhurandhar2

1Department of Nutrition, Wayne State University, Detroit, MI 48202
2Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808

Objectives: Experimental infection of rats with a human adenovirus type 36 (Ad-36) promotes adipogenesis and improves insulin sensitivity in a manner reminiscent of the pharmacologic effect of thiozolinediones. To exploit the potential of the viral proteins as therapeutic target for treating insulin resistance, this study investigated the ability of Ad-36 to induce metabolically favorable changes in human adipose tissue.

Research Design and Methods: We determined if Ad-36 increases glucose uptake in human adipose tissue explants. Cell signaling pathways targeted by Ad-36 to increase glucose uptake were determined in the explants and human adipose derived stem cells (hASC). Ad-2, a non-adipogenic human adenovirus was used as a negative control. As a proof of concept, non-diabetic and diabetic humans were screened for the presence of Ad-36 antibodies to ascertain if natural Ad-36 infection predicted improved glycemic control.

Results: Ad-36 increased glucose uptake by adipose tissue explants obtained from non-diabetic and diabetic subjects. Without insulin stimulation, Ad-36 up-regulated expressions of several pro-adipogenic genes, adiponectin and fatty-acid-synthase (FAS), and reduced the expression of inflammatory cytokine – macrophage-chemoattractant-protein-1 (MCP-1), in a phosphotidyl-inositol 3-kinase (PI3K) dependent manner. In turn, the activation of PI3K by Ad-36 was independent of insulin receptor signaling, but dependent on Ras signaling recruited by Ad-36. Ad-2 was non-adipogenic and did not increase glucose uptake. Natural Ad-36 infection in non-diabetic and diabetic human subjects was associated with significantly lower fasting glucose levels and HbA1c, respectively.

Conclusion: Ad-36 proteins may provide novel therapeutic targets that remodel human adipose tissue to a more metabolically favorable profile.

Correspondence: nikhil.dhurandhar{at}pbrc.edu

Key Words: Infectobesity • insulin resistance • adipose tissue • metabolic remodeling • glucose uptake • Ad-36


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