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Virus-Induced Obesity in Humans

Recognizing that a particular adenovirus can cause obesity changes perceptions about this condition and strategies for dealing with it

Richard L. Atkinson
AUTHOR PROFILE: Atkinson: a Focus on Virus-induced Obesity and No Plans To Retire

SUMMARY
Infecting animals, including rodents and nonhuman primates, with human adenovirus 36 (Adv36) leads many of them to develop obesity.

Adv36 infection is found in about 30% of obese human adults; among children, obesity correlates with Adv36 infection even more strongly than among adults.

Adv36 infects humans and animals transiently, but viral DNA persists for extended periods, altering host metabolism and responses to stimuli or treatment.

A single Adv36 gene appears responsible for disrupting host physiology and causing obesity.

New government policies and scientific and treatment strategies are needed to address virus-induced obesity.


In 1998, offıcials of the World Health Organization (WHO) declared a global epidemic of obesity, recognizing the steady rise in its prevalence in both developed and developing countries since about 1980. Obesity, defıned as a body mass index (BMI in kg/m2) value of at least 30, doubled among US adults from 1980 to 2000, and tripled in children in the United States and other countries, including England, China, Thailand, and Korea. In women, the prevalence of obesity in Albania, Jordan, Panama, Paraguay, and South Africa is equal to or greater than that in the United States. Although some experts point to increased food intake, including of fast foods, and decreased activity, these factors do not explain the rise of obesity in developing countries.

Instead, this abrupt shift in the global prevalence of obesity appears to fıt the pattern of an infectious epidemic. Several events during the late 1970s appear to be consistent with this hypothesis. For example, soon after commercial chicken growers in Mumbai, India, noted increased deaths among their flocks, an Indian microbiologist identifıed an adenovirus, SMAM-1, that was infecting chickens and lowering immune functions, thus enabling other infectious agents to kill a higher percentage of chickens than usual. Moreover, when infected with SMAM-1, chickens developed increased body fat. Subsequent experiments in which chickens were deliberately infected with SMAM-1 reproduced the obesity seen when they were naturally infected. Meanwhile, some humans developed antibodies to this chicken virus.

Separately in 1978, scientists isolated adenovirus 36 (Adv36) from humans. Later, analysis revealed that this virus has fewer DNA sequences in common with the other approximately 50 human adenoviruses. Moreover, antibodies that recognize Adv36 do not cross-react with more than 40 other human adenoviruses that were tested. These fındings led scientists at the University of Wisconsin to speculate that Adv36 arose from SMAM-1 and that it not only infects humans but also can make them obese. Although not proved, other studies in humans and experiments in animals lend support to this hypothesis.

Adv36 Induces Obesity in Animals

Adv36, which infects humans, also infects other animal species, including chickens and mice, increasing body fat and lowering serum cholesterol and triglycerides (Table 1). Whenatkt1 infected, total body fat and fat inside the abdominal cavity (visceral fat) increases from 50 to 100% in chickens and mice over a period of weeks to months. The animals gain fat without changes in diet and activity. Mice infected with Adv36 easily pass the virus when in contact with uninfected mice.

Adv36 also infects monkeys, leading to increases in body weight through buildup of fat. In one study, investigators at the University of Wisconsin collected blood from 15 monkeys over 7 years, and then tested stored serum for antibodies against Adv36. Nearly half the monkeys had antibodies at the start, and the others developed them during the study through naturally occurring infection. Once antibodies appeared in blood, body weight began to rise in all the monkeys while serum cholesterol levels fell.

In another set of experiments, monkeys were inoculated intranasally with Adv36 and compared to uninfected animals over a 7-month period. The infected monkeys gained four times as much weight and increased body fat by 60% more than did uninfected animals. Serum cholesterol decreased signifıcantly in infected animals but did not change in the uninfected animals. Although live virus was recovered during the fırst 2 weeks after infection (and from feces 2 months after infection), at 7 months it could no longer be isolated from any of them. However, Adv36DNA was still found in brain, lung, liver, muscle, and adipose tissue. Thus, Adv36 DNA persists in tissues for long periods and might be responsible for chronic changes in biochemistry and physiology among infected animals.

Adv36 leads to obesity in 60-70% of infected chickens and mice, but in 100% of infected monkeys. Similarly, the paradoxical effect of Adv36 reducing serum lipid levels is seen broadly among infected rodents, chickens, and monkeys.

Adv36 also Induces Obesity in Humans

Adv36 viral infections in adult humans strongly correlated with obesity and lowered serum cholesterol and triglyceride levels, resembling changes seen in Adv36-infected animals. Among 500 adults in three U.S. cities, Adv36 infected 30% of obese adults but only 11% of nonobese adults. Infected individuals were on average 9 BMI units heavier than were the uninfected (P< 0.001), while serum cholesterol was 34 mg/dl lower in infected individuals, the same decrease seen in monkeys.

The percent of Adv36 infection among obese adults varies from 6% in the Netherlands and Belgium to 65% in Italy, but averages about 30% in most countries. The correlation between obesity and infection was not seen in adults in the Netherlands or among military personnel in San Diego, Calif. The overall prevalence of infection was 37% among military personnel, but higher among black and Hispanic people compared to whites. Unlike animals, serum lipids vary in humans among different studies.

It is diffıcult to explain some of these inconsistencies. One possibility is that when the Adv36 strain began infecting humans about 1980, the fırst populations that were infected and obese stood out from others. With time, however, more people were infected, earlier infected individuals stopped gaining weight, and antibody levels in some long-infected individuals fell. In Korea, for example, the prevalence of Adv36 antibodies in obese individuals is slightly higher but not statistically different from those in normal or overweight subjects.

atkt2However, the correlation between Adv36 infection and obesity is consistently high among children (Table 2). The prevalence of this infection ranges from 22 to 30% in obese children but from 7 to 14% in nonobese children. Among children in San Diego, for example, Adv36 infection prevalence was 22% among the obese compared to 7% among nonobese children, and infected obese children weighed 16 kg more than uninfected children. Meanwhile, the prevalence of Adv36 infection among obese children in Korea is 30%, but only 14% among nonobese children. The patterns of serum lipids in infected children in Korea differ from those among infected U.S. adults. These differences might arise from a variety of factors, including age, race, geography, diet, and duration of infection.

How Adv36 Infects Mammals and Acts Directly on Cells

Adv36 follows a typical adenovirus pattern of events, causing mainly upper respiratory but also sometimes gastrointestinal symptoms. Adv36 was fırst isolated from a stool specimen from a diabetic child in Germany who had acute diarrhea. Although the strain can be isolated from their feces, Adv36-infected animals, including monkeys, do not develop diarrhea. Individuals become infected with Adv36 after being exposed to droplets from other infected individuals who are coughing or sneezing, and infection may also occur via fecal-oral transmission. From cough droplets, the virus invades the upper respiratory epithelium, and its DNA enters cells and migrates to the nucleus to replicate without being incorporated into host DNA. Early viral genes disable host cell apoptosis, ensuring viral DNA replication.

atkt3The host epithelial cells die, releasing viral particles into the blood and they infect other tissues. Although Adv36 invades differentiated cells of multiple organs, it does not replicate or, if so, only slowly. However, in differentiated cells, viral DNA turns on transcription factors and enzymes that produce obesity (Table 3).

After infecting fat cells or preadipocytes in vitro, Adv36 increases the rate of differentiation and accumulation of lipid. Its major targets appear to be phosphatidylinositol 3-kinase (PI3K) and Ras pathways, triggering an increase of glucose receptors in the cell membrane, thereby enabling cells to take up increased levels of glucose. Adv36 also increases production of fatty acid synthase (FAS), a key enzyme in the pathway in which glucose is converted to fatty acids. Increasing cellular glucose and FAS leads to increased fat within fat cells. Adv36 also induces peroxisome proliferator-activated receptors (PPAR), leading to differentiation of adult stem cells within adipose tissue and resulting in higher numbers of fat cells.

Adv36 infects other cell types in vitro, leading to similar changes in muscle, liver, and breast cells as well as in primary adult human stem cells derived from adipose tissue. When monkeys are infected with Adv36, viralDNAis found in brain, lung, liver, muscle, and adipose tissue. After 7 months, viral DNA can be found but live virus can no longer be recovered from such sites in animals.

When Adv36 infects cells in vitro, there are changes in cytokines, including increased expression of IL-1
α, IL-6, IL-11, interferon, and adiponectin, which in vivo can improve insulin sensitivity and lower serum glucose. The virus lowers leptin expression and secretion in fat cells, which may contribute to obesity in vivo.

The E4orf1 gene of Adv36 is crucial for mediating all its cellular and molecular effects. Blocking the E4orf1 gene also blocks fat-inducing effects. Further, inserting this gene into another virus makes it capable of stimulating fat formation. The Adv36 E4orf1 gene has less homology to those of other adenoviruses, apparently accounting for differences in metabolism in infected cells and individuals.

Adv36 Infections: Broader Implications

Adv36 infections occur naturally in large numbers of humans and other species, and the virus alters various molecular, biochemical, physiological, and clinical characteristics of cells and organisms that it infects. For investigators working with everything from specifıc cell types to humans, the possibility of unsuspected Adv36 infection is of concern because it may alter experimental variables. For clinicians, Adv36 infections may alter responses of patients to drugs or other treatments. For example, because Adv36 increases glucose uptake and improves insulin sensitivity, it might alter a diabetic patient's response to antidiabetic drugs and lead to hypoglycemia. Another study showed weight loss on a reduced-calorie diet was greater in individuals with Adv36 infection.

Having an infectious agent responsible for obesity forces all of us to reconsider this condition, which is widely held to be self-inflicted through inappropriate diet and activity levels. Health insurance providers typically limit their coverage for treating this condition, some employers will not hire the obese, while others insist that they enroll in weight reduction programs or pay higher rates for health insurance. These attitudes need to change with the knowledge that anyone susceptible to the Adv36 virus might develop obesity. Meanwhile, additional research is needed to better understand this virus and how to prevent and treat infections that might account for part of the worldwide obesity epidemic that began during the 1980s.

Richard L. Atkinson is Director, Obetech Obesity Research Center and Clinical Professor, Department of Pathology, Virginia Commonwealth University Richmond, Va. Financial Disclosure: The author is the owner of Obetech, LLC. This company provides assays for adenoviruses that produce obesity and has several patents in the area of virus-induced obesity.

Suggested Reading

Atkinson, R. L., N. V. Dhurandhar, D. B. Allison, R. L. Bowen, B. A. Israel, J. B. Albu, and A. S. Augustus.
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Dhurandhar, N. V., B. A. Israel, J. M. Kolesar, G. F. Mayhew, M. E. Cook, and R. L. Atkinson. 2000. Increased adiposity in animals due to a human virus. Int. J. Obesity Related Metabolic Disorders 24:989-996.

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