Is Obesity Caused by an Adenovirus?

Nikhil V Dhurandhar


Expert Rev Anti Infect Ther. 2012;10(5):521-524. 

Abstract and Introduction


Is obesity, a condition traditionally linked with nutrition and physical activity, a relevant or important topic for an infectious diseases journal? A few decades ago, infection was not considered relevant to cancer, but now the roles of human papilloma-virus, hepatitis viruses and Helicobacter pylori infections in various cancers are under aggressive investigation. Similar to the early stages of infection–cancer research, emerging evidence now indicates a role for certain infections at least in a subtype of obesity. This offers an excellent opportunity for the field of infectious diseases to extend expertise to an unacquainted discipline. Over the last 30 years, nearly a dozen microbes have been causatively or correlatively linked with animal or human obesity (reviewed in).[1] These adipogenic microbes include viruses, bacteria, parasites, gut microflora and scrapie agents. This offers a potential opportunity to impact obesity by designing effective prevention or treatment strategies against adipogenic pathogens, or by modulating the gut microflora, which are not considered pathogens under normal conditions. Such an approach could be particularly significant considering the sharp increase in obesity prevalence in recent years and the intractable nature of the condition. WHO has declared obesity as a 'global epidemic'.[2] Obesity is not merely a cosmetic issue, but a serious medical condition, with serious health consequences, including a shortened life span.[3,4] Effective action is urgently needed to counter the health and economic consequences of obesity at the individual and societal level. However, effective strategies for obesity prevention or treatment at the community level are unavailable despite considerable research. Dietary restraint and increased physical activity are the cornerstones of weight-loss treatment or long-term maintenance. This approach is successful in very few individuals in clinical studies, and disappointingly ineffective for a large majority, and is particularly ineffective in free-living populations. Although pharmacotherapy or surgery for weight loss show some promise, the accompanying undesirable effects have restricted their widespread application.

Despite its multifactorial etiology,[5] conventional obesity treatment or pre-vention strategies offer a blanket approach, mostly irrespective of the cause. Effective cause-specific treatment or prevention strategies could be developed if the precise contribution of various factors to obesity is identified. If certain infections contribute to obesity, prevention or treatment approaches for such a subgroup of obesity could differ from extensive and long-term lifestyle changes. Nonetheless, identifying adipogenic microbes and determining their causative role in human adiposity is challenging.

Among the known adipogenic pathogens, some induce obesity in animal models, whereas others are associated with human obesity.[1] Adenoviruses are the only infective agents reported to be linked with adiposity in both experimental animal models and naturally infected humans, which make them promising candidates for investigating their role in human obesity. SMAM-1, an avian virus, is the first adenovirus reported to increase adiposity and the first virus reported to be associated with human obesity.[6,7] Adenovirus Ad-36 is the first human virus reported to cause obesity in animals.[8–11] Ad-36 is also associated with human obesity.[1] Reports about the adipogenic role of additional human adenoviruses, Ad-5 and Ad-37, followed.[12,13] Thankfully, commonly prevalent human adenoviruses Ad-2 and Ad-31, and avian adenovirus chick embryo lethal orphan are not adipogenic.[9,12] Since the first report about the adipogenic properties of adenovirus SMAM-1 in 1990, approximately 60 publications in PubMed address the role of adenoviruses in obesity. Of these, approximately 45 were published in the last 5 years, indicating a growing interest in this area. Overall, researchers are more aware of infections as potential contributors to obesity.[14] In 2009, the NIH/National Institute of Diabetes, and Digestive and Kidney Diseases organized a symposium titled 'Non-traditional Risk Factors for Obesity', which covered the topic of obesity of infectious origin. Despite the attention, the crucial question – whether viruses in general and adenoviruses in particular cause obesity – is only partially answered.

For conceptual and practical reasons, unequivocally determining the causative role of a viral infection in human obesity would be a significant milestone. The relative preponderance of information about the adipogenic role of adenoviruses in general, and Ad-36 in particular, allows the assessment of progress, challenges and limitations in conclusively determining the contribution of virus infections to human obesity. Human adenoviruses are DNA viruses and have over 50 subtypes, linked to upper respiratory tract infections, conjunctivitis or GI tract symptoms. Ad-36 was first isolated in the late 1970s in Germany, from the fecal sample of a girl suffering from enteritis.[15] This is the only information available to postulate a GI-related role for Ad-36 and a possible feco–oral route of transfection. Substantial evidence exists to conclude that Ad-36 induces obesity in animals. Experimental infection of chickens, mice, rats and marmosets with Ad-36 increases adiposity,[8–11,16] which is not explained by food intake. In agreement with Koch's postulate, blood obtained from an Ad-36-infected animal shows viremia and induces obesity in another animal receiving that blood intravenously.[8] Up to threefold greater weight gain and 60% increase in adipose tissue is observed in Ad-36-infected animals as compared with uninfected controls, but the response seems to vary with the host species. Animals excrete Ad-36 in feces for up to 2 months postinfection[11] and the virus seems to quickly reach multiple organs, including the liver, spleen, kidney, brain and, surprisingly, the adipose tissue.[17] The amount of Ad-36 DNA present in the adipose tissue significantly correlates with adipose tissue mass of that animal,[8] which led the way to discovering the role of adipocyte differentiation as a potential mechanism for Ad-36-induced obesity.[18–22] MCP-1 and E4orf1, appear to be the required host and viral factors, respectively, for Ad-36-induced adiposity.[23,24] Ad-36 infection produces a distinctive phenotype, albeit with some host species-specific variation.

Excessive adiposity is linked with deterioration in glycemic control, and increased amount of circulating and hepatic stores of lipids. Ad-36 improves high-fat diet-induced hyperglycemia and hepatic steatosis, and reduces serum cholesterol and triglyceride levels, despite the adiposity it induces.[8–11,16] Findings from several studies indicate that via its E4orf1 gene, Ad-36 induces adipogenic commitment, proliferation and lipid accumulation in adipocyte progenitors, and also increases cellular glucose and lipid uptake.[16,18–20,22–27] Collectively, these effects appear to explain adipose tissue expansion and a paradoxical clearance of lipids and glucose levels from the circulation induced by Ad-36. Although further information is welcome, evidence to date certainly argues in favor of a definite adipogenic role for Ad-36 in animals. Determining the adipogenic role of Ad-36 in humans, on the other hand, is as complex as it is important.

Experimentally infecting humans with Ad-36 and determining the effect on their adiposity can conclusively determine the role of Ad-36 in human obesity. However, ethical reasons preclude experimental infection of humans with Ad-36, and the evidence will have to remain indirect. Natural Ad-36 infection in humans is associated with obesity. With the exception of two studies, multiple studies from the USA, Italy and South Korea have reported a significant association of natural Ad-36 infection with obesity in children and adults (reviewed in[1]). Human twins who were discordant for Ad-36 seropositivity showed that Ad-36-positive co-twins were significantly heavier and fatter as compared with their antibody-negative counterparts.[28] Furthermore, natural Ad-36 infection in humans is associated with a phenotype similar to that induced by experimental Ad-36 infection in animal models, which suggests causality. Ad-36 DNA is present in human adipose tissue and those carrying Ad-36 DNA in adipose tissue have greater adipogenesis potential.[19] Also, natural Ad-36 infection is associated with lower serum lipids, better glycemic profile and lower liver fat in humans.[16,28–31] Although these reports are highly suggestive of the causative role of Ad-36, they are associations. Given the cardinal rule in epidemiology that 'an association does not prove causation', additional convincing evidence is required. The insidious onset of obesity further complicates the matter. It is hard to retrospectively track an infectious episode that initiated the development of obesity a while ago. Moreover, multiple factors ranging from genetics to biology and behavior may contribute to obesity in an individual and they may vary between individuals, making it difficult to isolate the relative contribution of any single factor. Therefore, the question of whether Ad-36 contributes to human obesity has remained incompletely answered, although we seem to be progressing in the right direction.

Longitudinal studies may help settle this question to a large extent. A longitudinal study in rhesus monkeys showed that natural Ad-36 infection was associated with a 15% increase in body weight and a 29% drop in serum cholesterol levels.[11] Such studies with a long-term follow-up of changes in adiposity and other phenotypes associated with natural Ad-36 infection are required in humans.

If indeed Ad-36 contributes to human obesity, it may influence obesity treatment or prevention approaches and encourage the search for additional adipogenic pathogens. If Ad-36 infection persists long term and continues to promote obesity in an individual, an effective obesity treatment will have to include anti-Ad-36 therapeutics. On the other hand, if it is a 'hit-and-run' type of event, which perpetuates obesity long after the virus has ceased to be active in a host, a preventive approach, such as vaccination, may be suitable. Obviously, such a vaccine would only eliminate or attenuate the risk of the obesity due to that specific pathogen, and not due to other contributory factors. Nevertheless, at least for a subgroup of population, this obesity prevention approach could be far simpler and more effective than the current conventional approach. After all, smallpox eradication was achieved with a vaccine, not by lifestyle modification.


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