REVIEW Role of adenoviruses in obesity Jameson D. Voss 1 *, Richard L. Atkinson 2,3 and Nikhil V. Dhurandhar 4 1 Epidemiology Consult Division, United States Air Force School of Aerospace Medicine, Wright-Patterson AFB, OH, USA 2 Virginia Obesity Research Institute, Richmond, VA, USA 3 Virginia Commonwealth University, Richmond, VA, USA 4 Department of Nutrition Sciences, Texas Tech University, Lubbock, TX, USA SUMMARY 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 ad- iposity 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 ad- ipocytes. 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. Copyright © 2015 John Wiley & Sons, Ltd. Received: 26 May 2015; Revised: 13 July 2015; Accepted: 15 July 2015 INTRODUCTION Adenoviridae are a large family of viruses with seven human species (A–G) that include over 60 subtypes, many of which are known to cause hu- man disease such as conjunctivitis, respiratory disease, and/or gastrointestinal disease. The meta- bolic effects of adenoviruses have gained more interest since the 1990s when SMAM1 was shown to cause adiposity in chickens and antibody to SMAM1 was associated with human obesity [1,2]. Since then, the metabolic effects of a total of nine adenoviruses have been investigated in cells, animal studies, and/or in human epidemiologic studies. Because of several recent publications in- vestigating additional subtypes (Ad8 and Ad9) and identifying novel associations (Ad5 and Ad31), there are currently no reviews that provide a panoptic view of the relationship between all investigated adenoviruses and obesity. Thus, we sought to review and synthesize the current evidence. We also discuss the E4-ORF1 protein of Adenovirus 36 (Ad36), sometimes referred to as a dUTPase. This protein is necessary and sufficient for the adipogenic effect of Ad36 [3], so we com- pare overall amino acid homology of this protein among adenoviruses. Finally, we discuss directions for future research including candidate serotypes and the implications for research design. The nine adenoviruses that have been investi- gated for metabolic effects thus far include four species D types (Ad8, Ad9, Ad36, and Ad37), two species C types (Ad2 and Ad5), one species A type (Ad31), and two non-human adenoviruses (chick embryo lethal orphan virus and SMAM1) (Table 1). ADENOVIRUS SPECIES D Adenovirus 36 was the first human adenovirus to be associated with human adiposity and has the *Correspondence author: J. D. Voss, Epidemiology Consult Division, United States Air Force School of Aerospace Medicine, 2510 Fifth Street, Building 840, Wright-Patterson AFB, OH, 45433, USA. E-mail: jameson.voss@us.af.mil Rev. Med. Virol. 2015; 25: 379–387. Published online 9 September 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/rmv.1852 Reviews in Medical Virology Copyright © 2015 John Wiley & Sons, Ltd.