Objective:

Obesity is a serious public health problem associated with increased morbidity and mortality. Although the causes for obesity are unclear, it seems that environmental, genetic, neural and endocrine factors contribute to its development. However, the rapid global spread of obesity resembles epidemiologically the spread of an infectious disease. Thus far, little consideration has been given to the possibility that the epidemic of obesity could be due to an infectious agent. Seven viruses and a scrapie agent have been implicated in obesity.

Design:

This review evaluates the infectious pathogens and the evidence that these viruses are associated with obesity and concludes that a strong evidence base is emerging that associates certain viruses with obesity.

Conclusion:

More work is however required to elucidate the mechanisms of weight gain after viral infection. In the mean time, discounting viruses as a contributing factor to obesity would deprive us of a potential new avenue of investigating and treating the ever increasing epidemic of obesity.

Introduction

Obesity is a serious public health problem associated with increased morbidity and mortality.¹ Obesity is a clinical condition defined by a body mass index (BMI) over 30 kg/m² and probably represents a common pathway of several conditions with varied aetiologies. The prevalence of obesity has risen dramatically in the last three decades. In the USA, according to the National Health and Nutrition Examination Surveys (NHANES), the percentage of obese adults nearly doubled between NHANES 1976–1980 and NHANES 1999–2002. At present 32% of adult Americans are obese with a further 34% being overweight.² Similar increases are evident throughout the developed world.

Although the causes for obesity are unclear it seems that environmental, genetic, neural and endocrine factors contribute to its development.³ The rapid global spread of obesity resembles epidemiologically the spread of an infectious disease. Surprisingly, little consideration has been given to the possibility that the epidemic of obesity could be due to an infectious agent. However in animals, seven viruses and a scrapie agent have been shown to cause obesity,^{4, 5, 6, 7, 8, 9, 10, 11} and adenoviruses Ad-31 and Ad-9 have been shown to be adipogenic in animal cell cultures.^{11, 12} In humans, small EDRK-rich factor 1A (SMAM-1), an avian adenovirus and adenovirus 36 (Ad-36), a human adenovirus have been associated with obesity.^{13, 14}

The following is a review of the infectious pathogens and the evidence that these viruses are associated with obesity in the order in which the observations were made.

Canine distemper virus

Canine distemper virus (CDV) was the first virus linked to obesity.⁴ CDV is a morbillivirus antigenically related to measles, which infects dogs and a wide range of carnivores. Like all morbilliviruses, CDV is highly contagious, and transmission occurs predominantly via aerosols. In susceptible hosts, acute febrile and multisystemic disease is induced; neuroinvasiveness and severe immunosuppression are hallmarks of CDV infection.¹⁵ Lyons et al.⁴ investigated the pathological consequences of CDV infection on the central nervous system (CNS) of mice. Researchers noticed that an obesity syndrome developed in 26% of the study animals who survived the acute CNS disease. Body weights of obese animals 16–20 weeks after infection were comparable to those reported for genetically obese mice and for mice rendered obese by hypothalamic lesions. The total number of adipocytes in specific fat deposits was greater in obese animals than in their lean littermates. Adipocyte hyperplasia was accompanied by moderate fat cell enlargement and pancreatic islet tissue hyperplasia. The concentrations of catecholamines in forebrain specimens from obese animals were 2–3 times lower than in specimens from uninfected lean controls.⁴ Later studies by Bernard et al.¹⁶ revealed that CDV can target hypothalamic nuclei and lead to an obesity syndrome in the late stages of infection. The long leptin receptor isoform was shown to be specifically downregulated in the hypothalami of CDV obese mice. This may explain the inability of the mice to generate an adequate response to leptin in the brain.¹⁷ Furthermore, the melanin-concentrating hormone precursor (ppMCH) mRNA has been demonstrated to be specifically downregulated using differential display polymerase chain reaction in CDV-infected obese mice.¹⁸ Griffond et al.¹⁹ studied the expression of several hypothalamic neuropeptides both during the acute and late stages of CDV infection in mice. During the acute stage, there was a dramatic decrease of expression of neuropeptide Y, melanin-concentrating hormone (MCH), hypocretin, vasopressin and tachykinins, the magnitude of which seemed to be linked to the viral burden and the individual susceptibility. The effect of the virus varied with the hypothalamic nucleus and neuropeptide involved, suggesting that certain circuits were affected while others remained intact. During the late stage of infection, recovery to the initial hypothalamic levels of peptide expression was seen in a number of lean animals, while some neuropeptidergic systems remained disturbed in mice exhibiting the obese phenotype. Griffond et al.¹⁹ suggested that the CDV-related obesity syndrome more probably results from an array of conditions including individual susceptibility, leptin network alteration, imbalance between hypothalamic matrix degrading proteases and their inhibitors and neuropeptide/neurotransmitter impairments. Currently, no evidence exists to link CDV to human obesity.

Rous-associated virus type 7

Avian leucosis viruses (AVL) are retroviruses that may induce neoplastic growth such as B-cell lymphomas, proliferative disorders such as osteopetrosis and chronic degenerative diseases, such as anaemia and immunosuppresion.⁵ Rous-associated virus 7 (RAV-7) is an AVL that causes an obesity syndrome in chickens.^{5, 20} Carter et al.²¹ discovered that infection of 10-day chicken embryos with RAV-7 resulted in stunting, obesity and hyperlipidemia within 3 weeks after hatching. Histological examination of the liver of infected chickens revealed diffuse panlobular fatty infiltrates while the thyroid and the pancreas were infiltrated with lymphoblastoid cells. An increase in serum triglycerides and cholesterol was also present. Further studies by Carter et al. using the same inoculation procedure revealed that lymphoblastoid infiltration of the thyroid was present as early as 7-days post-hatching and the infected chickens had lower T₃ and T₄ levels than uninfected controls. It was suggested that hypothyroidism caused stunting and obesity, but when RAV-7-infected chickens were treated with T₄ supplements there was some alleviation of symptoms. When adult (4-week old) chickens were inoculated with RAV-7 and observed for 3 weeks, no obesity syndrome was found. The serum levels of triglycerides, cholesterol, glucose, amylase, glutamic pyruvic transaminase and glutamic oxalate transaminase were normal among the infected adult chickens. Surprisingly, there was a decrease in body weight which became significant at 3 weeks post-infection.⁵ AVL infect large segments of the modern poultry industry. AVL are present in commercial chickens and eggs and thus expose humans, especially children, on a consistent basis.²² Serological studies, in the sera of poultry workers and subjects with no occupational exposure, have detected antibodies against p27, p19, p15 and p12 AVL/sarcoma viruses antigens.^{23, 24} Moreover, human viral vaccines (mumps, measles, yellow fever) that are manufactured by growing the vaccine-virus in chicken eggs may carry AVL.^{25, 26}

At present there is no report of RAV-7 human infection and whether humans are susceptible to AVL infection is a matter that requires investigation.²⁶

Borna disease virus

Borna disease (BD) was first described more than 200 years ago in Southern Germany as a fatal neurologic disease of horses and sheep. The viral aetiology of BD was published in 1939 by Zwick.²⁷ Borna disease virus (BDV) is a neurotropic, enveloped, non-segmented, negative-strand RNA virus distinctive in its nuclear localization of replication and transcription.²⁸ It is classified in the new virus family Bornaviridae (Mononegavirales order).²⁹ Natural infection with BDV is a non-purulent acute/subacute encephalitis with a propensity to involve the olfactory and limbic systems, and the brainstem.⁷ Horses and sheep represent the main natural hosts but there are reports of spontaneous BDV infection in cattle, cats, dogs, rabbits, deer, alpacas and various zoo animals (hippopotamus, monkey).³⁰ Neither the reservoir nor the mode of transmission of natural infection is known. It has been suggested that the virus may be transmitted through saliva, nasal or conjuctival secretion because BDV-specific RNA has been found in these secretions.^{31, 32} Reports of BDV nucleic acid and proteins in peripheral blood mononuclear cells also indicate the possibility of haematogenous transmission.³³ Rodents and birds have been proposed as possible BDV reservoirs.^{33, 34}

A link between BDV or a similar agent and human neuropsychiatric disorders has been suggested after seroepidemiological studies revealed a higher BDV seroprevalence among patients with major affective disorders, schizophrenia and obsessive compulsive disorders compared to healthy controls.³⁵ It has been speculated that the limbic system may be a target for BDV.³⁵

The BDV neuropathology after experimental infection is similar to that in natural disease but the inflammatory changes are usually more diffuse.⁷ A number of laboratory animal species are susceptible to BDV infection. Lewis rats are highly susceptible to BDV and are therefore used extensively for studies of BD pathogenesis. The clinical manifestations in Lewis rats infected with BDV range from obesity and fertility problems to behavioural, neurological changes and even paralysis.^{32, 36} Herden et al.³⁷ compared the alterations in the brains of Lewis rats experimentally infected with two BDV strains. When the animals where infected with the isolate BDV-biphasic (BDV-bi) they developed a persistent infection of the CNS with a characteristic biphasic course of the disease. Clinical signs of hyperactivity, aggressiveness and weight loss were noted in the first stage of the disease but later on only apathy was observed. The infection of the rats with the variant BDV-obese (BDV-ob) caused rapid increase of body weight and minimal or absent neurological signs. All rats infected either with BDV-bi or BDV-ob developed a non-purulent meningoencephalitis with mononuclear perivascular and parenchymal infiltrates. The BDV-bi infected animals developed inflammatory lesions in many brain areas (cortex cerebri, thalamus, hippocampus, periventricular regions of the third and fourth ventricles). In rats infected with the strain BDV-ob, inflammatory lesions in the brain were restricted mainly to the septum, hippocampus, ventromedian hypothalamus and amygdala. These areas have also been implicated in appetite control. Furthermore, the expression of neuropeptides implicated in the regulation of energy homoeostasis, in BDV-ob-infected rats, revealed that -MSH expression was reduced in infected animals compared to uninfected controls.^{38, 39} Until now there has been no report of evidence linking BDV to human obesity. The spectrum of BDV pathogenicity in humans has not yet been defined and further molecular, seroepidemiological and clinical studies are required to associate BDV with human obesity.

Scrapie agent

Scrapie is a fatal degenerative disease affecting the CNS of sheep and goats. The clinical symptoms of scrapie develop very slowly; the affected animals usually show behavioural changes, tremor, rubbing and locomotor incoordination that progress to recumbence and death. The infectious agent responsible for scrapie is an abnormal form of a physiological constituent of the cell membrane (prion).⁴⁰ In the laboratory the scrapie agent has been transmitted through inoculation to hamsters, mice, rats, gerbils and some species of monkeys. During clinical scrapie disease body weight decreases for most combinations of scrapie strain and experimental animals.⁴¹ Several authors have reported an increase in food consumption followed by a subsequent increase in animal body weight during the pre-clinical phase of the disease. Outram⁴² reported that ME7 scrapie strain caused an increase in weight starting at 9 weeks, with a peak weight occurring at week 17 in A2G mice injected with the agent. Markovitz et al.⁴³ reported an increase in weight in Swiss mice 130 days after injection with a scrapie strain. All mice positive for scrapie were obese when clinical manifestations of the disease began 20 days later. Carp et al.⁴⁴ reported that certain strains of scrapie agent infecting certain strains of mice produced a significant increase in body weight in the animals. Furthermore, Carp et al.⁴⁵ observed that the scrapie-infected obese mice showed reduced glucose tolerance and adrenalectomy prevented both the increase in weight and the aberrant glucose tolerance. Adrenalectomy had no effect on the course of the neurological scrapie disease. Kim et al.¹⁰ suggested that changes in the hypothalamic–pituitary–adrenal axis played an important role in the development of scrapie-related obesity This theory was supported by the following three findings: (1) the scrapie obesity effect was augmented when the scrapie strain was injected into the hypothalamus of mice; (2) the weight of the adrenals was significantly greater (because of cortical enlargement) in scrapie-infected obese mice than that of uninfected controls; (3) low-scrapie infectivity titres were found in the adrenals of the obese mice indicating that the obesity effect was probably not due to direct action of the scrapie agent on the adrenals. Ye et al.⁴⁶ used electron microscopy to study the pathological changes in the islets of Langerhans in obese 139H-infected hamsters. There were very low abnormal prion protein levels in pancreas, and no amyloid deposits in the islets of Langerhans at the electron microscopy level, suggesting that the prion did not have a direct toxic effect in pancreas but it may have acted as a neurotoxicant altering the hypothalamic neuroendocrine regulation of the pancreas.

Smam-1 virus

SMAM-1 virus was first described by Ajinkya who investigated an epidemic that killed thousands of chickens in India.⁶ SMAM-1 is an avian adenovirus that infects chickens and causes excessive fat accumulation.⁶ Dhurandhar et al.⁶ studied the clinical symptoms of SMAM-1 infection by inoculating the virus into the peritoneum of 3-week-old white leghorn broilers; after 3 weeks the chickens were killed. The infected chickens had increased visceral fat and paradoxically lower levels of serum cholesterol and triglycerides compared with control chickens. The virus's ability to spread was verified by placing a third group of uninoculated chickens in the same room with the inoculated group. The uninoculated cagemates of the infected chickens also developed the syndrome after natural infection of SMAM-1.

To assess whether SMAM-1 could be associated with human obesity, Dhurandhar et al.¹³ screened the serum of 52 obese humans in India, for antibodies against SMAM-1 virus. Ten subjects were tested positive to SMAM-1 antibodies, while 42 subjects did not have antibodies. The SMAM-1-positive group had significantly higher BMI and significantly lower serum cholesterol and triglycerides values compared with the SMAM-1 negative group. These findings suggest that SMAM-1, or a serologically similar human virus may be associated with human obesity.¹³

Human adenoviruses

Adenoviruses are medium-sized, non-enveloped icosahedral viruses containing double-stranded DNA. There are more than 50 immunologically distinct types (six species: A–F) that can cause human infections.⁴⁷ Although epidemiological characteristics of the adenoviruses vary by type, all are transmitted by direct contact, faecal-oral transmission and occasionally water-borne transmission. Adenoviruses most commonly cause respiratory disease but they may cause gastroenteritis, conjunctivitis and cystitis.⁴⁸ The last decade six human adenoviruses have been investigated in relation to obesity.^{8, 9, 11, 12, 14, 49, 50, 51}

Human adenovirus 36

Adenovirus 36 (Ad-36) was the first human adenovirus reported to cause obesity in animals. Dhurandhar et al.⁸ presented the adiposity-promoting effects of Ad-36 first, using two animal models. In four separate experiments chicken and mice were inoculated with Ad-36, while weight-matched groups inoculated with tissue culture media were used as non-infected controls. Animals inoculated with Ad-36 developed a syndrome of increased adipose tissue and paradoxically low levels of serum cholesterol and triglycerides. This syndrome was not seen in chickens inoculated with chick embryo lethal orphan virus an avian adenovirus. Sections of the brain and hypothalamus of Ad-36 inoculated animals after 13 weeks of infection did not show any overt histopathological changes.⁸ These observations from different experiments suggested that Ad-36 may predispose infected animals to obesity and altered serum lipids. Moreover, male Wistar rats when infected with Ad-36 showed significantly greater adiposity and paradoxical improvement in insulin sensitivity compared to uninfected controls.⁵²

Although the adipogenic effects of Ad-36 were demonstrated in chickens and rodents, verification in higher mammals was necessary. For ethical reasons humans could not be infected experimentally with Ad-36 to verify its adipogenic effect directly. In the first study with non-human primates, the presence of spontaneously occurring antibodies to Ad-36 in rhesus monkeys (Macaca mulatta) was observed. Moreover, a significant longitudinal association of positive antibody status with weight gain and plasma cholesterol lowering during the 18 months after viral antibody appearance was discovered.⁴⁹ In the second study, which was a randomized controlled experiment; marmosets inoculated with Ad-36 gained 3 times more weight, with greater fat gain and lower serum cholesterol relative to uninfected controls at 28-week post-inoculation.⁴⁹ It has also been reported in golden Syrian hamsters that the cholesterol-lowering effect of Ad-36 infection is associated with a shift in plasma cholesterol from high-density lipoprotein to low-density lipoprotein cholesterol.⁵³ This deleterious change may increase atherogenic risk even if the total cholesterol appears lower.

To examine the metabolic and molecular mechanism responsible for Ad-36-induced adipogenesis, the effect of the virus on differentiation of 3T3-L1 rodent preadipocyte cells and primary human preadipocytes was examined.⁵⁰ Ad-36 increased the number of differentiated adipocytes among 3T3-L1 cells, elevated the levels of the preadipocyte differentiation-specific enzyme, glycerol 3-phosphate dehydrogenase (GPDH) and increased total cellular lipid content. Also Ad-36 increased GPDH levels in human preadipocytes. The specificity of the effect of Ad-36 was determined by using Ad-2 (the most common human adenovirus) as a control for the in vitro experiments and demonstrating that there was no effect on differentiation by Ad-2.⁵⁰

Subsequent to observing the primary effect of Ad-36 on the preadipocyte differentiation process researchers proceeded to investigate functional modulations in the infected adipocytes.¹² Vangipuram et al.¹² reported that Ad-36 suppressed the expression of leptin mRNA in 3T3-L1 cells by approximately 58 and 52% on days 3 and 5 post-infection respectively. Leptin release was significantly lower and lipid accumulation was significantly greater in the Ad-36- infected 3T3-L1 cells. In rat primary adipocytes, an experiment, with 0, 0.48 or 1.6 nM insulin showed that, Ad-36, compared to non-viral controls, decreased leptin release by 40% but only in the presence of 0.48 and 1.6 nM insulin. In contrast Ad-36 increased glucose uptake by 93% in the absence of insulin, while the increased glucose uptake effect diminished to 18% with 0.48 nM insulin and abolished by 1.6 nM insulin.¹² Furthermore, the adipose tissue of Ad-36-infected rats showed lower leptin mRNA expression, and upregulation of key genes of de novo lipogenesis, such as acetyl Co-A carboxylase-1 and fatty acid synthase, compared to the uninfected controls. These in vitro experiments suggested that Ad-36 downregulates leptin expression and secretion in 3T3-L1 cells, as well as leptin secretion from primary adipocytes. Moreover, there was some experimental evidence that Ad-36 increased de novo lipogenesis in adipocytes. The adipogenic effect of Ad-36 on preadipocytes could be attenuated with an antiviral agent.⁵⁴ A recent abstract by Rogers et al.⁵¹ suggests that differentiation in adipocytes is induced by the open-reading frame E4orf1 of Ad-36, which enhances cAMP and insulin signalling pathways. The upregulation of insulin signalling pathways supports the observed increased insulin sensitivity induced by Ad-36 in rats and greater glucose uptake observed in Ad-36-infected rat primary preadipocytes.¹²

Studies determining the prevalence of Ad-36 antibodies in obese people have been carried out by Atkinson et al.¹⁴ These studies have shown that 30% of obese and 11% of non-obese humans have neutralizing antibodies to Ad-36. Antibody-positive subjects were heavier compared with their antibody-negative counterparts. As expected from the animal studies, serum cholesterol and triglycerides were lower in Ad-36 antibody-positive vs negative subjects.¹⁴ A study of 89 twin pairs revealed that there were 20 monozygotic and six dizygotic twin pairs discordant for antibodies to Ad-36. In the discordant group, the antibody-positive twin had a higher BMI (24.55.2 vs 23.14.5 kg/m², P<0.03) and %body fat (29.69.5 vs 27.59.9%, P<0.04) compared to their antibody negative co-twins.¹⁴

Human adenoviruses Ad-37, Ad-31, Ad-9, Ad-5 and Non-adipogenic Ad-2

After observing the adipogenic effect of Ad-36 in chicken, rodents, non-human primates and cell cultures researchers proceeded to investigate other adenoviruses to assess whether an adipogenic potential is a common trait for all adenoviruses. Whigham et al.¹¹ studied three human viruses in vitro and in vivo: Ad-37 (classified as a species D adenovirus like Ad-36), Ad-31 (species A) and Ad-2 (species C). For the in vivo experiments chickens were inoculated with Ad-37, Ad-31, Ad-2 or media (control) at 3 weeks of age. After another 3.5 weeks chickens were killed and visceral fat, body composition and serum lipids were determined. The Ad-37 group had almost threefold more visceral fat and over twofold more total fat vs the control group. The mean visceral fat and total body fat were not different among control, Ad-31- and Ad-2-infected animals. The average food intake was not different between groups. The study of the serum lipids revealed that the Ad-37 group had a significant increase in serum cholesterol from baseline to death (P<0.01). Ad-37 had significantly decreased serum triglyceride levels at the end of the study compared with all the other groups. In the control, Ad-31 and Ad-2 groups there were no changes in serum cholesterol and triglyceride levels.

For the in vitro experiments 3T3-L1 cells were exposed to Ad-37, Ad-31, Ad-2 and Ad-36. The triglyceride-related Bodipy fluorescence score was measured for each treatment group. All the cells infected with Ad-37, Ad-31 and Ad-36 had more than a twofold higher fluorescence score compared with control cells (P<0.0001 for each group compared with control). Ad-2-infected cells were not different compared to controls. In this study Ad-37 decreased serum triglycerides similar to Ad-36 but instead of a decrease in serum cholesterol, Ad-37 caused a significant increase. These data suggest that at least two different mechanisms are responsible for the increased adiposity and changed serum lipid levels in animals inoculated with Ad-36 and Ad-37. Moreover, the increased differentiation of 3T3-L1 cells caused by adenovirus 31 did not correlate with development of obesity in chickens. This finding suggests that the in vitro assay may not be a good screening test to predict response to human adenoviruses in whole animals.¹¹

Vangipuram et al.¹² studied the effect of species C adenovirus Ad-2 and species D adenoviruses Ad-37, Ad-9, Ad-36 on leptin secretion and lipid accumulation of 3T3-L1 preadipocytes. Human adenovirus Ad-2 did not influence cellular lipid accumulation or leptin release while Ad-37, Ad-9 and Ad-36-infected cells had significantly greater lipid accumulation and lower leptin secretion. To find a possible link between adenoviruses and human obesity Atkinson et al.¹⁴ tested obese and non-obese volunteers for antibodies against Ad-37, Ad-31 and Ad-2 but no association of antibodies with BMI or serum lipids was found. The prevalence of Ad-37 was very low in the population tested and this may have caused a type II statistical error.

Subsequently another human adenovirus has been implicated in obesity. So et al.⁹ evaluated adipose tissue as measured by whole-body 1 H magnetic resonance spectroscopy. They showed that mice treated with Ad-5, a species C human adenovirus, gained significantly more weight compared to controls over a period of 21 weeks. No significant difference in intra-hepatic lipid content or food intake was observed between the two groups. However, the gain in bodyweight was associated with increased deposition of adipose tissue, which more than doubled in the Ad-5-treated compared with control animals.

The results of the experiments using human adenoviruses demonstrate that more than one human adenovirus is capable of producing obesity in animal models but the adipogenic property is not necessarily shared by all human adenoviruses.

Conclusions

Obesity is currently thought of as a lifestyle disease, but two decades ago so was peptic ulcer disease before the groundbreaking work by Warren and Marshall⁵⁵ on Helicobacter pylori. Several viruses have been associated with weight gain in vitro and in vivo. A divergent range of animal species ranging from rodents to canines to primates has been used in well-conducted experiments which have been published in reputable journals. Thus it has been proven that animals became obese when infected with certain viruses. Studies in humans have also shown significant associations that warrant further investigations. However although the principles of weight gain after infection with specific viruses have been demonstrated and some epidemiological evidence in humans have been reported, a plausible mechanism is still awaited. The two most likely mechanisms are either a peripheral effect on fat cell differentiation and storage or a central effect on appetite and energy expenditure. Potential changes in specific areas within the brain involved in appetite control have been suggested. These are not novel concepts nor are they without precedent as Encephalitis lethargica which was described by Constantin von Economo after a viral outbreak in the winter of 1916–1917, a condition where the substantia nigra was damaged with severe reduction in dopamine production, while other brain regions such as the cerebral cortex remained unaffected. Thus it is possible for a virus to affect specific neuronal pathways involved with energy balance without other obviously detrimental effects.

Viruses should thus be considered as a possible contributing factor to obesity as not to do so would deprive us of a potential new avenue of investigating and treating the ever-increasing epidemic of obesity. Moreover the treatment of obese patients infected with the implicated viruses may also change significantly. For the moment, studies to confirm or refute the existing data are required, while further work to unravel the mechanism would persuade more scientists to acknowledge the possibility that certain viruses may cause weight gain.

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