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

Abstract

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.