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


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.
Rogers
Pamela M
PM
Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA.
Mashtalir
Nazar
N
Rathod
Miloni A
MA
Dubuisson
Olga
O
Wang
Zhong
Z
Dasuri
Kumar
K
Babin
Scott
S
Gupta
Alok
A
Markward
Nathan
N
Cefalu
William T
WT
Dhurandhar
Nikhil V
NV
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000258:Adenovirus Infections, Human / Q000378:metabolism*; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D000328:Adult; D000914:Antibodies, Viral / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy; D005947:Glucose / Q000493:pharmacokinetics; D006801:Humans; D015187:Lipectomy; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D046509:Tissue Culture Techniques; D018631:ras Proteins / Q000378:metabolism
D000914:Antibodies, Viral; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D018631:ras Proteins; D005947:Glucose