Metabolically Favorable Remodeling of Human Adipose Tissue by Human Adenovirus Type 36

Metabolically Favorable Remodeling of Human Adipose Tissue by Human Adenovirus Type 36 Pamela M. Rogers 1 , Nazar Mashtalir 1 , Miloni A. Rathod 2 , Olga Dubuisson 1 , Zhong Wang 1 , Kumar Dasuri 1 , Scott Babin 1 , Alok Gupta 1 , Nathan Markward 1 , William T. Cefalu 1 and Nikhil V. Dhurandhar 1 1 Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 2 Department of Nutrition, Wayne State University, Detroit, Michigan Corresponding author: Nikhil V. Dhurandhar, nikhil.dhurandhar{at}pbrc.edu Abstract OBJECTIVE— Experimental infection of rats with 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 a 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 whether 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. Ad-2, a nonadipogenic human adenovirus, was used as a negative control. As a proof of concept, nondiabetic and diabetic subjects 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 nondiabetic and diabetic subjects. Without insulin stimulation, Ad-36 upregulated expressions of several proadipogenic genes, adiponectin, and fatty acid synthase and reduced the expression of inflammatory cytokine macrophage chemoattractant protein-1 in a phosphotidylinositol 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 nonadipogenic and did not increase glucose uptake. Natural Ad-36 infection in nondiabetic and diabetic subjects was associated with significantly lower fasting glucose levels and A1C, respectively. CONCLUSIONS— Ad-36 proteins may provide novel therapeutic targets that remodel human adipose tissue to a more metabolically favorable profile. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 3 July 2008. Readers may use this article as long as the