Role of adenoviruses in obesity.

UNLABELLED: Five human adenovirus subtypes, Ad5, Ad9, Ad31, Ad36, and Ad37, and a non-human adenovirus, SMAM1, are linked to increased adiposity in vitro or in vivo. Experimental infection with Ad5, Ad36, and Ad37 produced excess adiposity or weight gain in animals. Ad9 and Ad31 increase fat storage in tissue culture but are not associated with animal or human obesity. Ad36 is the most extensively studied adipogenic adenovirus and is correlated with some measure of overweight/obesity in humans from multiple countries. The correlation is strongest and most consistent in children, but some studies have been negative in both children and adults. About 30% of overweight/obese children and adults and about 15-20% of lean individuals have Ad36 antibodies in epidemiologic studies. The mechanisms of action of Ad36 are due to the early gene 4, open reading frame 1 (E4-ORF1). Blocking E4-ORF1 with siRNA prevents the effects of Ad36, and transfection of lentivirus with E4-ORF1 reproduces the Ad36 effects. Increased adiposity is caused by stimulation of at least three pathways by Ad36. Cell membrane glucose receptors are increased via the Ras pathway, leading to increased intracellular glucose. Fatty acid synthase is increased, which converts the glucose to fatty acids. Finally, peroxisome proliferator-activated receptor-γ is increased, resulting in differentiation of adult stem cells into adipocytes. CONCLUSIONS: several adenoviruses increase adiposity in animals and are associated with obesity in humans. There are critical gaps in the literature needing further investigation including evaluation of other adenovirus subtypes and better research designs to improve the strength of causal inferences.