Metabolically favorable remodeling of human adipose tissue by human adenovirus type 36

Pamela M. Rogers, Nazar Mashtalir, Miloni A. Rathod, Olga Dubuisson, Zhong Wang, Kumar Dasuri, Scott Babin, Alok Gupta, Nathan Markward, William T. Cefalu, Nikhil V. Dhurandhar

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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.

Original languageEnglish
Pages (from-to)2321-2331
Number of pages11
JournalDiabetes
Volume57
Issue number9
DOIs
StatePublished - Sep 2008

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    Rogers, P. M., Mashtalir, N., Rathod, M. A., Dubuisson, O., Wang, Z., Dasuri, K., Babin, S., Gupta, A., Markward, N., Cefalu, W. T., & Dhurandhar, N. V. (2008). Metabolically favorable remodeling of human adipose tissue by human adenovirus type 36. Diabetes, 57(9), 2321-2331. https://doi.org/10.2337/db07-1311