Virus-induced Obesity Research Articles

Obesity induced by Borna disease virus in rats: key roles of hypothalamic fast-acting neurotransmitters and inflammatory infiltrates.

Human obesity epidemic is increasing worldwide with major adverse consequences on health. Among other possible causes, the hypothesis of an infectious contribution is worth it to be considered. Here, we report on an animal model of virus-induced obesity which might help to better understand underlying processes in human obesity. Eighty Wistar rats, between 30 and 60days of age, were intracerebrally inoculated with Borna disease virus (BDV-1), a neurotropic negative-strand RNA virus infecting an unusually broad host spectrum including humans. Half of the rats developed fatal encephalitis, while the other half, after 3-4months, continuously gained weight. At tripled weights, rats were sacrificed by trans-cardial fixative perfusion. Neuropathology revealed prevailing inflammatory infiltrates in the median eminence (ME), progressive degeneration of neurons of the paraventricular nucleus, the entorhinal cortex and the amygdala, and a strikingly high-grade involution of the hippocampus with hydrocephalus. Immune histology revealed that major BDV-1 antigens were preferentially present at glutamatergic receptor sites, while GABAergic areas remained free from BDV-1. Virus-induced suppression of the glutamatergic system caused GABAergic predominance. In the hypothalamus, this shifted the energy balance to the anabolic appetite-stimulating side governed by GABA, allowing for excessive fat accumulation in obese rats. Furthermore, inflammatory infiltrates in the ME and ventro-medial arcuate nucleus hindered free access of appetite-suppressing hormones leptin and insulin. The hormone transport system in hypothalamic areas outside the ME became blocked by excessively produced leptin, leading to leptin resistance. The resulting hyperleptinemic milieu combined with suppressed glutamatergic mechanisms was a characteristic feature of the found metabolic pathology. In conclusion, the study provided clear evidence that BDV-1 induced obesity in the rat model is the result of interdependent structural and functional metabolic changes. They can be explained by an immunologically induced hypothalamic microcirculation-defect, combined with a disturbance of neurotransmitter regulatory systems. The proposed mechanism may also have implications for human health. BDV-1 infection has been frequently found in depressive patients. Independently, comorbidity between depression and obesity has been reported, either. Future studies should address the exciting question of whether BDV-1 infection could be a link, whatsoever, between these two conditions.

Characteristics of adipose tissue macrophages and macrophage-derived insulin-like growth factor-1 in virus-induced obesity.

Various pathogens are implicated in the induction of obesity. Previous studies have confirmed that human adenovirus 36 (Ad36) is associated with increased adiposity, improved glycemic control and induction of inflammation. The Ad36-induced inflammation is reflected in the infiltration of macrophages into adipose tissue. However, the characteristics and role of adipose tissue macrophages (ATMs) and macrophage-secreted factors in virus-induced obesity (VIO) are unclear. Although insulin-like growth factor-1 (IGF-1) is involved in obesity metabolism, the contribution of IGF secreted by macrophages in VIO has not been studied. Four-week-old male mice were studied 1 week and 12 weeks after Ad36 infection for determining the characteristics of ATMs in VIO and diet-induced obesity (DIO). In addition, macrophage-specific IGF-1-deficient (MIKO) mice were used to study the involvement of IGF-1 in VIO. In the early stage of VIO (1 week after Ad36 infection), the M1 ATM sub-population increased, which increased the M1/M2 ratio, whereas DIO did not cause this change. In the late stage of VIO (12 weeks after Ad36 infection), the M1/M2 ratio did not change because the M1 and M2 ATM sub-populations increased to a similar extent, despite an increase in adiposity. By contrast, DIO increased the M1/M2 ratio. In addition, VIO in wild-type mice upregulated angiogenesis in adipose tissue and improved glycemic control. However, MIKO mice showed no increase in adiposity, angiogenesis, infiltration of macrophages into adipose tissue, or improvement in glycemic control after Ad36 infection. These data suggest that IGF-1 secreted by macrophages may contribute to hyperplasia and hypertrophy in adipose tissue by increasing angiogenesis, which helps to maintain the 'adipose tissue robustness'.

Vaccination protects against virus-induced obesity

Vaccination protects against virus-induced obesity

Reduction of adenovirus 36‐induced obesity and inflammation by mulberry extract

Adenovirus 36 (Ad36) is known to be associated with human obesity and to trigger inflammation in murine models. However, to date no clinical drugs for treating virus-induced obesity have been developed. Therefore, in this study, the anti-obesity and anti-inflammation effects of mulberry extract on Ad36 were evaluated in mice. The mulberry extract-fed group showed a reduction in total body weight and in epidermal fat pads. A combination of various mulberry components (1-deoxynojirimycin, kuromanin chloride and resveratrol) and a mulberry extract prevented viral replication by 50% and 70%, respectively, compared with an untreated Ad36-infected group. Moreover, the extract decreased both concentrations of proinflammatory cytokines, such as MCP-1 and TNF-α, and the numbers of infiltrating immune cells and macrophages in epidermal fat pads. In conclusion, dietary mulberry extract might offer an avenue for the development of therapeutic approaches for treating or preventing virus-induced obesity and inflammation-related metabolic diseases.

Proof-of-concept for a virus-induced obesity vaccine; vaccination against the obesity agent adenovirus 36

Human adenovirus 36 (Ad36) is positively associated with obesity in humans and animals. Ad36 infection is characterized by increased adiposity and inflammation. To investigate the possibility that a prophylactic vaccine candidate might protect against Ad36-induced obesity and inflammation, we purified Ad36 and ultraviolet-irradiated virus to obtain a vaccine candidate. After immunizing the mice with the vaccine candidate (vaccinated group), live Ad36 was injected into mice as a challenge test. Unvaccinated mice (control group) were immunized with phosphate-buffered saline and then challenged with live Ad36. Fourteen weeks after challenge, we compared adiposity and inflammation in vaccinated and control mice. The control group showed 17% greater body weight and 20% more epididymal fats compared with the vaccinated group. In addition, the vaccinated group had decreased serum levels of pro-inflammatory cytokines, and infiltrated immune cells, especially M1 macrophages, in fat tissue. Therefore, the vaccine candidate for Ad36 was able to protect against Ad36-increased body weight and fat as well as inflammatory states after challenge. These results provide proof-of-concept for prophylactic vaccination against virus-induced adiposity.

Adenovirus 36 as an Obesity Agent Maintains the Obesity State by Increasing MCP-1 and Inducing Inflammation

Although it is well known that adenovirus 36 (Ad36) is associated with obesity in humans as well as in animals, the detailed cellular mechanism is unclear. Wild-type (WT) mice and monocyte chemoattractant protein-1 knockout (MCP-1(-/-)) mice were infected with Ad36, and their weights and inflammatory status were measured. Macrophage infiltration was examined in their reproductive fat pads and in a coculture system. The correlation between Ad36 antibody presence and MCP-1 levels was tested in human samples. We have shown that Ad36 infection stimulated an inflammatory state by increasing the level of MCP-1 through the activation of nuclear factor κB, which in turn induced the infiltration of macrophages into adipocytes. This induced inflammation resulted in viral obesity, which caused chronic inflammation and affected lipid metabolism. In contrast to WT mice, MCP-1(-/-) mice were protected from Ad36-induced inflammation and obesity. The MCP-1 levels in Ad36-antibody-positive human group were higher than those in the antibody-negative group. These findings support the proposition that virus-induced inflammation is the cellular mechanism underlying Ad36-induced obesity. These results also suggest that MCP-1 plays a critical role in Ad36-induced obesity and that MCP-1 may be a therapeutic target in preventing virus-induced obesity.

Virus-Induced Obesity in Humans

In 1998, officials 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, defined 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.

Could viruses contribute to the worldwide epidemic of obesity?

The prevalence of obesity in children increased rapidly starting about 1980 in both developed and developing countries. Studies of changes in diet and physical activity, television watching, and food advertisements on television suggest that these are not sufficient to explain the epidemic. The pattern of rapid spread is suggestive of an infectious origin. The concept of virus-induced obesity is not new. Eight viruses have been shown to cause obesity in animals and there is evidence for virus-induced obesity in humans. Recent evidence on animal and human adenoviruses suggests that these adenoviruses may infect adipocytes to alter enzymes and transcription factors resulting in accumulation of triglycerides and differentiation of preadipocytes into mature adipocytes. The E4orf1 gene of Ad-36 has been shown to be responsible for the adipogenic effect. It appears that a portion of the worldwide epidemic of obesity since 1980 could be due to infections with human adenoviruses.

Identification of Urop11, a novel leptin-modulated gene that is upregulated in the hypothalamus of mice with virus-induced obesity

Obesity results from disturbances of tightly regulated interactions between the nervous, endocrine, and metabolic systems that can be caused by external factors, such as viral infections. A mouse model of obesity induced by brain infection with a morbillivirus, canine distemper virus, allowed us to identify obesity-related genes. Using a subtractive library for the hypothalamus, the main brain structure regulating energy homeostasis, we identified a new gene on mouse chromosome 19 which we named upregulated obese product (Urop) 11 and, which has no homology with any known mRNA. A step-by-step molecular approach allowed us to isolate the full-length mRNA, predict the protein sequence, and identify consensus sites. Urop11 was mainly detected in the hypothalamus and adipocytes, and was dramatically upregulated in these central and peripheral structures in obese mice. Urop11 was also expressed in human neural and lymphoid samples and its expression seemed to be regulated by the state of lymphocyte activation. Interestingly, Urop11 expression was strongly upregulated both in vivo in mouse hypothalamus and in vitro in mouse neural cell lines, after leptin treatment. Taken together, our data show that Urop11 is a target of leptin, the satiety factor produced by adipocytes, in physiological and pathological conditions, including obesity. This new gene can be considered a key molecule in the hypothalamic integration pathway and demonstrates the importance of Urop11 as a target of leptin action.

Virus-induced obesity

the human adenovirus-36 (Ad-36) was first described in 1980, about the time that the prevalence of obesity began to increase ([15][1]). Prevalence of obesity increased by 30% between 1980 and 1990 and by 61% between 1990 and 2000 with no indication that this increase is lessening ([12][2]). The

Increased adiposity in animals due to a human virus

Four animal models of virus-induced obesity including adiposity induced by an avian adenovirus have been described previously. This is the first report of adiposity induced in animals by a human virus. We investigated the adiposity promoting effect of a human adenovirus (Ad-36) in two different animal models. Due to the novel nature of the findings we replicated the experiments using a chicken model three times and a mammal model once. In four separate experiments, chickens and mice were inoculated with human adenovirus Ad-36. Weight matched groups inoculated with tissue culture media were used as non-infected controls in each experiment. Ad-36 inoculated and uninfected control groups were housed in separate rooms under biosafety level 2 or better containment. The first experiment included an additional weight matched group of chickens that was inoculated with CELO (chick embryo lethal orphan virus), an avian adenovirus. Food intakes and body weights were measured weekly. At the time of sacrifice blood was drawn and visceral fat was carefully separated and weighed. Total body fat was determined by chemical extraction of carcass fat. 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 CELO virus. Sections of the brain and hypothalamus of Ad-36 inoculated animals did not show any overt histopathological changes. Ad-36 DNA could be detected in adipose tissue, but not skeletal muscles of randomly selected animals for as long as 16 weeks after Ad-36 inoculation. Data from these animal models suggest that the role of viral disease in the etiology of human obesity must be considered.

Virus-Induced Obesity in Mice: Association with a Hypothalamic Lesion

In an earlier study we found that a substantial percentage of mice surviving infection with canine distemper virus (CDV) slowly developed a morbid obesity syndrome. In the present study we wished to explore the role of the virus in the development of this syndrome. The distribution of viral antigen(s) in brains of pre-obese animals shortly after intracerebral infection was mapped using immunocytochemical procedures. A distinctive pattern of cell labeling was found, extending from the anterior periventricular hypothalamus ventrally and caudally toward the posterior hypothalamus. The heaviest concentration of labeled cells was found in the arcuate-ventromedial area. Viral antigen-containing cells were not found in obese brain specimens. However, the latter revealed, by glial fibrillary acidic protein immunostaining, a gliotic lesion of the hypothalamus that approximated topographically the pattern of virus tropism. Examination of the arcuate area revealed a significant reduction in tyrosine hydroxylase immunoreactive and pro-opiomelanocortin mRNA positive perikarya. We suggest that the loss of critical populations of hypothalamic neurons as a result of an antecedent viral infection led ultimately to the development of morbid obesity.

Hyperinsulinemia induced by canine distemper virus infection of mice and its correlation with the appearance of obesity

1. 1. Weanling Swiss mice surviving an acute infection with canine distemper virus were persistently infected. Among these mice, up to 30% had hyperinsulinemia and this was followed by an obesity syndrome. 2. 2. Analysis of the lipid composition of various organs revealed that compared to control animals, the obese had an accumulation of triglycerides in both liver and adipose tissue. 3. 3. Studies on the lipid metabolism using a number of radioactive lipid precursors showed a specific accumulation of the triglycerides of the obese animals. 4. 4. A decrease of lipogenesis was observed in white adipose tissue of obese mice. Glycogenesis and serum glucose levels were unaffected during obesity. 5. 5. The model of canine distemper virus-induced obesity is compared with other experimental models.