Obesity has become the number one public health problem
in America.1 Obesity is a complex, multifactorial disease that
involves the interaction of genetic, metabolic, social, behavioral and cultural
factors. In the decade from 1980 to 1990, the number of people with obesity
increased by 30% in the US; the number of obese adults further increased to 61%
between 1991 and 2000.2 The numerous health risks associated with
obesity are well known to the medical community.
The epidemic increase
in obesity, its medical consequences, and the rapidly escalating health care
costs associated with it have prompted a multidisciplinary approach by health
professionals, government, and non-governmental organizations to search for new
methods to control it.3 Such efforts are likely to be facilitated by
a better understanding of the etiology of obesity. Sclafani4
classified the etiology of animal obesity into 9 groups, including obesity of
neural, endocrine, pharmacological, nutritional, environmental, seasonal,
genetic, idiopathic, and viral origin. Of these factors, the viral etiology of
obesity, a relatively recent discovery first noted in 1982,5 has
barely been studied. Over the past 20 years, 8 pathogens have been reported to
cause obesity in animal models.5-11 The relative contribution of
these pathogens to human obesity is not yet clear. Considering the emerging
reports addressing an infectious etiology of several other chronic diseases,12
the contribution of certain infections to the etiology and pathogenesis of
obesity need not be inconceivable. If shown to be relevant to humans, this
relatively novel concept may be potentially important. An adequate
understanding of such pathogens is needed for better management of obesity. A
new perspective about the infectious etiology of this disease may initiate
additional research in the field to assess the contribution of pathogens in
human obesity and its co-morbidities and possibly to prevent or treat the
obesity of infectious origin.
The known obesity-producing infective agents are listed
in Table 1. There are 7 viral pathogens known to cause obesity in animal
models, 4 are either known human pathogens or have been shown to be associated
with human obesity. In addition Chlamydia pneumoniae has been associated
with obesity in humans. In this paper we review the present knowledge in the
field as this may be of importance to those who deal with patients and/or those
who are interested in obesity.
ADENOVIRUS AND OBESITY
Human Adenovirus Type-36
In 2000 we reported
that adenovirus type 36 (Ad-36) causes adiposity in animals.11
Adenoviruses are naked DNA viruses with icosahedral symmetry and a diameter of
65-80 nm. In humans, adenoviruses are frequently associated with acute upper
respiratory tract infections, and may also cause enteritis and conjunctivitis.
Adenoviral infections are transmitted via respiratory, fomite, droplet,
venereal, and fecal-oral routes; these are easily isolated from nasal swabs or
from feces. There are more than 50 types of human adenoviruses listed with the
American Type Culture Collection. Ad-36 cross-reacts minimally, or not at all,
with other human adenoviruses13,14 and apparently is antigenically
unique. Ad-36 was first isolated in 1978 in Germany in the feces of a
6-year-old girl suffering from diabetes mellitus and enteritis.14
In 4 separate
experiments, chickens and mice were inoculated with human adenovirus Ad-36.11
These animals developed a syndrome of increased adipose tissue and paradoxically
low levels of serum cholesterol and triglycerides. This syndrome was not
present in chickens inoculated with avian adenovirus chick embryo lethal orphan
virus (CELO).11 Sections of the brain and hypothalamus of Ad-36
inoculated animals did not show any overt histopathological changes. Ad-36 DNA
was detected in the adipose tissue, but not in skeletal muscles for as long as
16 weeks after Ad-36 inoculation. Subsequently, to ascertain if blood
transfusion from Ad-36 infected chickens could produce adiposity in uninfected
animals, 4 age- and weight-matched groups of chickens were used: infected
donors and recipients (I-D, I-R) and control donors and recipients (C-D, C-R).15
Blood was taken from the I-D and C-D groups and injected into the recipient
groups. The I-D and the I-R groups developed 2.5 and 1.8 times more visceral
fat as compared with the C-D group. Ad-36 DNA was detected in the adipose
tissues of I-D and I-R groups, but not in the controls. The 2 infected groups
showed significantly decreased serum cholesterol levels and the I-D group had a
significant reduction in serum triglycerides. These data confirmed that Ad-36
produces adiposity and paradoxical reductions in serum lipids. In addition, the
study fulfilled a Koch’s postulate, namely that adiposity was transmitted from
infected animals (I-D group) to a new set of animals (I-R group).
studies were conducted in nonhuman primates to investigate the
adiposity—promoting potential of Ad-36.16 In the first study,
spontaneously occurring Ad-36 antibodies were detected in stored serum samples
from adult male rhesus monkeys that were collected over a 7-year period at the Regional Primate Research Center located at the University of Wisconsin, Madison, WI. The monkeys gained approximately 0.1 kg of body weight during the year preceding
seroconversion, and gained 1.8 kg of weight during the following year. Serum
cholesterol fell about 35 mg/dL after the appearance of Ad-36 antibodies. In
the second experiment, male marmosets inoculated with Ad-36 had a 4-fold weight
gain, with a 60% increase in body fat, and a 34mg/dL reduction in serum
cholesterol levels as compared with controls over a 6-month period. These data
demonstrate that Ad-36 is capable of increasing body fat in non-human primates.
Mechanism of Action
The exact mechanism of action on adipocytes by Ad-36 is
incompletely understood (Figure 1). Ad-36 was recently reported to up-regulate
preadipocyte differentiation in-vitro.17,18 Inoculation of 3T3-L1
preadipocytes with Ad-36, but not Ad-2, a non-adipogenic human adenovirus,
resulted in increased adipocyte number, cellular lipid accumulation and
glycerol 3-phosphate dehydrogenase levels (an adipocyte differentiation
specific enzyme marker).17,18 On the other hand, expression and
secretion of leptin (an adipocytokine involved in body weight regulation) by
Ad-36 inoculated fat cells was reduced compared to uninfected controls.19
The phenomenon of increased lipid accumulation and decreased leptin secretion
was observed in 3T3-L1 preadipocytes inoculated with Ad-36 or Ad-37, but not in
Ad-2 inoculated cells.20 Extrapolation of these findings to an in-vivo
situation would suggest increased adipogenesis due to a relative absence of
leptin. Thus, the mechanism may involve up-regulation of fat cell
differentiation due to a local, direct effect of the virus, as well as a
systemic effect of leptin.21 The interaction of the viral and the
cellular genes involved has not yet been elucidated.
Adipose Tissue-Immune System Interaction
In light of well documented interactions of adipose
tissue involvement with modulators and mediators of immune response, an
adipogenic effect of certain pathogens should not be surprising. Cousin et al22
reported that preadipocytes function like macrophages and possess phagocytic
and microbicidal activity. Adipocytes too, participate in the immune response.
Leptin, an adipocytokine, enhances proliferation and activation of human
circulating T lymphocytes and stimulates cytokine production.23 In
addition to leptin-induced modulation of cytokine release, adipocytes
themselves secrete various cytokines 24,25 and, in turn,
preadipocytes and adipocytes are subject to cytokine directed modulations.26,27
Certain cytokines, such as tumor necrosis factor alpha (TNF-a), down-regulate preadipocyte
differentiation 27,28 and increase leptin secretion by adipocytes30
and adenoviral proteins sensitize cells to TNF a.31
Although Ad-36 reduces leptin expression and secretion from fat cells,19
its effect on TNF a is unknown. It is
hypothesized, but not tested that Ad-36 proteins decrease both TNF a levels and leptin, thereby contributing to
up-regulation of preadipocyte differentiation by their relative absence.
Considering the extensive interaction between the immune
system and the adipose tissue, expansion of the latter in response to certain
infections is conceivable. For instance, Macrophage colony-stimulating factor,
which promotes the production of macrophages, is also secreted by adipocytes
and, when overexpressed in vivo, induces significant adipose tissue
hyperplasia.32 It is unknown if any of the obesity promoting
pathogens stimulates macrophage colony-stimulating factor production leading to
the growth of adipose tissue.
Human Adenovirus Type-37
There are other adenoviruses with adipogenic potential
properties. In preliminary studies it was demonstrated that Ad-37 increased
adiposity in chickens, but that Ad-2 and Ad-31 did not.33 Currently,
minimal additional information is available on Ad-37, but the adipogenic mechanism
of this virus may be similar to Ad-36 (Figure 1). However, these results
demonstrate that more than one human adenovirus is capable of producing obesity
in an animal model, but the adipogenic property is not necessarily shared by
all human adenoviruses.
Adenovirus and Human Obesity
studies, human serum samples were obtained from over 500 obese (BMI ≥ 30 kg/M2) and non-obese volunteers
from 3 different sites (Wisconsin, Florida, and New York). The sera were
screened for the presence of Ad-36 antibodies using serum neutralization
assays. A positive antibody status is suggestive of previous exposure of the
individual to the virus. The prevalence of Ad-36 antibodies pooled across the 3
experimental sites was 11% for the non-obese and 30% for the obese subjects.34,35
Antibody-positive subjects had a significantly higher BMI than
antibody-negative individuals. Also, antibody-positive obese subjects had
significantly lower serum cholesterol levels compared with the
antibody-negative individuals.34,35 Serum triglyceride measurements
were only available at the Wisconsin site, the levels were significantly lower
in the antibody-positive subjects versus the antibody-negative counterparts.
These data demonstrated that antibody-positive humans were heavier and had
lower serum cholesterol and triglycerides levels; these findings were similar
to the data of experimentally infected animals with Ad-36. However, extensive
research will be needed to establish the contribution of Ad-36 to the etiology
of human obesity.
Adenoviral Infections and Weight Gain in Children:
It is well known that
respiratory viral infections including adenoviral infections are very common
among children.36,37 Additionally, a very high prevalence of
adenovirus is reported in lymphoid tissue obtained by tonsillectomy.38
Although adipogenic properties of all adenoviruses have not been examined, it
is interesting to note that excess weight gain occurs with or without gain in
height in children undergoing tonsillectomy.39-41 It is not known if
tonsillectomy provides the impetus for latent adenoviruses to promote the
weight gain. In addition, obese and overweight children have higher levels of
markers of inflammation.42 It is now believed that excess body
weight is associated with a state of chronic low-grade inflammation in children
as measured by higher levels of C-reactive protein.43 It is unknown
if the inflammatory process is due to infections, or whether it is a causative
factor for weight gain in children. Duncan and colleagues44 showed
that fibrinogen and other putative markers of inflammation can predict weight
gain in middle-aged adults, which suggests a possible contribution of
inflammation to weight gain and/or to co-morbidities associated with obesity.
Longitudinal studies that track weight changes in children with and without
adenovirus infections are needed to address these issues.
SMAM-1 Avian Adenovirus
SMAM-1, an avian adenovirus identified in the early 1980s
during a poultry epidemic,45 was found to produce adiposity in
chickens.8,9 We inoculated 3-week-old chickens with SMAM-1 and noted
development of excessive visceral fat and paradoxically lower levels of serum
lipids compared to the uninfected controls.8,9 Uninoculated chickens
sharing the same room with inoculated chickens (in-contact group) developed the
obesity syndrome, presumably due to infection with virus particles carried in
the air.8,9 There was no difference in food intake among the
controls, inoculated, and the in-contact group. Visceral fat was greater by 53%
and 33% in the inoculated and in-contact groups, respectively.
SMAM-1 was reported to
be associated with human obesity. Antibodies to SMAM-1 were found in 11 of 52
subjects.46 Antibody-positive subjects were heavier (95.1 + 2.1 kg
vs 80.1 + 0.6 kg, p < 0.02) and had a higher BMI (35.3 + 1.5 kg/ m2,
vs 30.7 + 0.6 kg/m2, p< 0.001) vs the antibody-negative group.
Serum cholesterol was 15% lower and triglycerides were 60% lower in SMAM-1
antibody-positive subjects. Since the prevailing thought was that avian
adenoviruses do not infect humans and that human adenoviruses do not
cross-react with avian adenoviruses,47 the findings were surprising.
It is possible that a human adenovirus antigenically similar to SMAM-1 produced
antibodies that cross-reacted with SMAM-1. Further research is necessary to
determine if SMAM-1 is capable of producing obesity and changes in serum lipids
in humans. The potential mechanisms whereby infections with this virus lead to
obesity remain to be proven (Figure 1).
Borna Disease Virus
Borna disease virus
(BDV) has also been implicated in obesity. This virus was first described in
the early 1800s.48 BDV, has been recently characterized as an
enveloped, nonsegmented, negative-stranded RNA virus with a genomic size of approximately
9 kb and nuclear site for replication and transcription.49-51 The
genomic organization is similar to that of members of the Mononegavirales
order; therefore, BDV is the prototype of the new family Bornaviridae within
this order. BDV infects a broad range of warm-blooded animals from birds to
primates. It replicates at lower levels than most known viruses,52,53
is not lytic, and persists in the nervous system despite a vigorous immune
response. Infected animals exhibit movement and behavior disorders.54,55
BDV-specific antibodies were detected in asymptomatic horses in several
countries.56-60 suggesting that natural infections in animals remain
subclinical in most cases.
Gosztonyi and Ludwig10
reported that BDV infection produces a syndrome of obesity in rats,
characterized by lympho-monocytic inflammation of the hypothalamus, hyperplasia
of pancreatic islets, and elevated serum glucose and triglyceride levels. The
expression of BDV-induced obesity syndrome varies with the age of the animals
at the time of inoculation, the genetic background of the host and the viral
strain used.10 Rats infected as newborns with BDV show progressive
neurological disease. On the other hand, weanling or adult rats similarly
inoculated with BDV develop acute encephalitis and die within 1 to 4 months.
Some of these rats survive the infection and develop marked obesity.61
The obese phenotype has a characteristic distribution of inflammatory lesions
and BDV-antigen in the rat brain. Infiltration with mononuclear immune cells
and viral antigen expression are restricted to the septum, hippocampus,
amygdala and ventromedian tuberal hypothalamus. Therefore, infection with
obesity-inducing BDV most likely results in neuroendocrine dysregulations
leading to development of obesity.62 This might be due to the
restriction of viral antigen expression and inflammatory lesions to brain areas
that are involved in the regulation of body weight and food intake (Figure 1).62
BDV may also be a human pathogen.48
BDV-specific antigen and BDV-RNA were detected in 4 autopsied human brains with
hippocampal sclerosis and astrocytosis. BDV-seropositive neurologic patients
have been observed to become ill with lymphocytic meningoencephalitis.63
In humans BDV is also associated with schizophrenia and mental depression64,65
that are responsive to treatment by amantadine, an antiviral agent.66,67
However, the contribution of BVD infections and the relationship to obesity in
humans is unknown. Although it would be interesting to know if those with such infections
gain more weight; such a relationship has not been reported.
The relationship between Chlamydia (C) pneumoniae infection
and coronary heart disease (CHD) is of interest. There are studies that showed
that C. pneumoniae was related to the development of CHD.68
While others have found negative results,72-74 in Australia newly
identified cases of CHD compared with matched controls were tested for the
presence of serum IgG and IgM against C. pneumonia, C. trachomatis
and C. Psittaci. None of the subjects had IgM against chlamydia and only
few were positive for C. trachomatis and/or C. psittaci.73
The prevalence of seropositivity for C. pneumoniae was not significantly
different for subjects with or without CHD. Similarly, a number of known CHD
risk factors such as hypertension, serum lipids, and glucose levels lacked a
significant difference between the antibody-positive and antibody-negative
groups. However the antibody-positive group had significantly greater BMI and
smaller LDL particle size. Antibody prevalence was significantly greater for
subjects with insulin levels above the median and for those with LDL particle
size below the median. However, after multivariate analysis, only BMI continued
to be associated with seropositivity.
Although the association of C. pneumoniae
antibodies with CHD may be questioned, the increased BMI with seropositivity to
this infection is very intriguing. Approximately 10% of the subjects were
obese. The greater prevalence of antibodies in patients in the highest
BMI quartile as well as the relationship of BMI with the presence of positive C.
pneumoniae antibodies may be the result of impaired immunity. Unlike C.
pneumoniae, antibodies to C. trachomatis and C. psittaci did
not show such a selective or high prevalence among those with higher BMI. A
possible explanation offered by Dart et al,68 which has neither been
proved nor disproved, is that C. pneumoniae infection may be causally
related to increased BMI, though the mechanism involved in this process is not
Scrapie is a
neurodegenerative disease of prion proteins, with a long incubation period,
known to occur in sheep and goats. Scrapie affects the brain and is
transmissible from animal to animal. The key features of such infections
include abnormal behavior and deficits in motor function. Certain scrapie
strains induce obesity in experimental animals.70,71 The
obesity-promoting characteristic is a function of the scrapie strain, but not
the mouse type. Regardless of the mouse strain tested, scrapie strain ME7
induced obesity. The effect was not observed with scrapie strains 139A or 22L
in mice.78 Vacuolation in the forebrain of the mouse was caused by
ME7, whereas 22L and 139A caused vacuolation in the cerebellum and white
matter, respectively.77 The difference in the obesity-promoting
potential of the agents may be linked to the differences in the brain lesions.
Kim et al79 demonstrated that ME7-induced weight gain in mice was
associated with increased adrenal gland weight and adrenalectomy prevented
ME7-induced obesity. Based on these findings, they suggested that
scrapie-induced obesity depends on an effect of scrapie on the
hypothalamic–pituitary–adrenal axis (Figure 1). Recently, Vorbrodt et al80
demonstrated differences in the distribution of glucose transporter (GLUT-1) in
the microvascular endothelium of scrapie-infected SJL/L hyperglycemic mice.
These animals showed clinical signs of scrapie, obesity, and reduced glucose
tolerance. GLUT-1 receptor density was significantly lower in microvasculature
supplying the thalamus, cerebellum and, to a lesser degree, the hippocampus,
but was unaffected in microvessels supplying the cerebral cortex and olfactory
bulb.80 Glucose, the major energy source for the brain, is passed
across the blood–brain barrier by facilitative diffusion catalyzed by GLUT-1.
Reduced GLUT-1 density in the scrapie-infected mice impairs transvascular
glucose transport in the above-mentioned brain regions and presumably disturbs
their function, which may lead to obesity.79
Canine Distemper Virus
Canine distemper virus
(CDV) was reported to cause obesity in mice in 1982.5 CDV is a
member of the genus Morbillivirus of the family Paramyxoviridae that causes
severe health problems including respiratory, gastrointestinal, and central
nervous system disease in dogs and other wild mammals.81 CDV-induced
encephalomyelitis in dogs is the most common cause of death.82 CDV
invades the nervous system and replicates in neurons and glial cells of the
white matter during a period of severe viral-induced immunosuppression.83 An
increase in body weight and fat cell size and number was reported in Swiss
albino mice experimentally infected with canine distemper virus.5
Six to 20 weeks after CDV infection obesity was observed in approximately 26%
of the mice with intracereberal infection compared to 16% of mice with
intraperitoneal infection. Catecholamine levels were reduced significantly in
the infected obese mice. The phenomenon of CDV-induced obesity in mice is believed
to be due to virus-induced hypothalamic damage.84-86 Bernard et al87
reported down-regulation of expression of the leptin receptor in the
hypothalamus of CDV infected obese mice, and suggested this as the cause of the
weight gain. Recently Verlaeten et al88 demonstrated that
melanin-concentrating hormone precursor mRNA, an anorexigenic neuromodulator
was down-regulated in the late stage of acute phase of CDV infection in mice.
Bernard et al87 speculated that the data demonstrated a “hit and
run” type of relationship between CDV and the expression of obesity, ie, the
initial viral impact in the hypothalamus may initiate changes that would
continue to promote obesity in animals even after the acute infection subsided.
CDV is not considered a human pathogen, and its contribution to human obesity
is unknown. However, measles virus is a human virus closely related to the CDV,
and both belong to the paramyxovirus family, though its relationship to human
obesity is not known. Animal experiments showing the effect of measles virus on
adiposity are also unavailable.
Rous Associated Virus 7
Carter et al6
reported that Rous-associated virus 7 (RAV-7) induced obesity in chicken
characterized by stunting, hyperlipidemia, and hypercholesterolemia.
Inoculation of 10-day-old chick embryos with RAV-7 produced fat deposition
around crop and abdominal fat pads in the adult birds.6 Intravenous
inoculation of 1-day-old chickens with RAV-7 did not produce stunting and
Chicken embryos infected with RAV-7 developed fatty,
yellow colored livers, hepatomegaly, anemia, and immune suppression.6
Livers of infected animals constituted 6.2% of the body weight vs 2.4% of the
body weight in the uninfected controls. These signs and symptoms manifested
within 3 to 4 weeks after hatching. Obesity, stunting of growth and
hyperlipidemia were the most striking features observed in the RAV-7 infected
chickens. The mean body weight of the 50-day-old RAV-7 infected chickens was
515 g compared to 194 g of the same age controls. Both the RAV-7 infected and
control groups were offered the same amount of food. Although the usual
triglycerides levels for chickens are around 100 mg/dL, chickens from the RAV-7
group had serum triglycerides levels over 2000 mg /dL. The authors suggested that
the reduced thyroid hormone level in the RAV-7 infected chickens was the cause
of the observed obesity and hyperlipidemia.6 Although lymphoblastoid
infiltration of the thyroid gland was noted in the RAV-7 infected chickens,
antibodies to thyroglobulin indicative of autoimmune thyroiditis, were absent.
Administration of exogenous thyroxine prevented the syndrome.
CONCLUSIONS AND SPECULATION
Although obesity has multiple causes, an overlooked
possibility is that in some instances obesity could be due to an infection.
Seven viral pathogens are reported to cause obesity in animals. Of which, at
least 4 are human pathogens and are associated with human obesity. In addition Chlamydia
pneumoniae has also been associated to human obesity; however more research
is needed to further define the mechanisms and the role of these pathogens in
its etiology and/or co-morbidities.
It is possible that
viral infections exacerbate and facilitate the development of obesity, or its
complications, by working in conjunction with other adipogenic factors. For
example obese children have been shown to have a cluster of conditions that put
them at a high risk for developing diabetes and heart disease.89
Over one-third of obese children studied presented with dysmetabolic syndrome, defined
as hypertension, low HDL cholesterol, high insulin levels, elevated blood
glucose and triglyceride levels. In addition, they presented elevated levels of
C-reactive protein (CRP); which reflect an inflammatory reaction associated
with an increased risk of heart disease. Furthermore, there were decreased
levels of adiponectine with increased adiposity. Adiponectine is an
anti-inflammatory hormone produced in fat cells that helps regulate glucose and
cholesterol metabolism and may help protect blood vessels.
The insidious onset of
human obesity makes it is difficult to retrospectively link obesity or any of
its co-morbidities to a particular episode of infection. Thus, a causative role
for infectious pathogens in human obesity is difficult to establish. Due to
ethical considerations, humans cannot be experimentally infected with these
pathogens; linking the infection to long term weight gain is often impossible.
In order to determine the role for viral pathogens in human obesity it is
necessary to collect overwhelming indirect evidence in the area, and that
remains to be done.
Elucidating the role
of obesity of infectious origin could have two goals, prevention and treatment.
The prevention of obesity of infectious origin could be achieved by vaccination
against individual adipogenic pathogens; whereas the treatment may be more
difficult and will depend on the adipogenic mechanism of individual pathogens.
Antiviral agents may be of help only if the body continues to harbor the
pathogen. Antivirals may be useless if the virus operates in a “hit and run”
fashion. In such cases, the offending pathogen will have been cleared from the
body long before its resulting impact on weight gain is noticed. Such cases
will have to be treated by responding to the metabolic consequences of the
infection in a genetically susceptible individual.
causes and the mechanisms of obesity of infectious origin will be of immense
help in individualizing the management of obesity by permitting cause-specific
treatments. Recognizing the role of the above-stated pathogens and identifying
more such candidates contributing to human obesity is the first step.
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