When looking at the research on obesity, one thing becomes clear: it is complicated!
For years we have been told to eat less and exercise more.
While that is healthy-sounding advice, it doesn’t seem to be curing the obesity epidemic. According to the World Health Organization, obesity has doubled since 1980. Worldwide in 2014, 1.9 billion adults were overweight.[ref]
About 70% of people in the US are now classified as overweight or obese. This article digs into one cause of obesity – a virus.
Can obesity be triggered by a virus?
It seems odd to think about infectious diseases causing obesity. But an abundance of evidence shows that, for some people, this is likely a cause. Specific adenovirus strains have links to increased fat mass and obesity in humans and other animals.
You may be thinking like I was — “Really? A virus causing obesity? Sounds implausible!”
Let’s dig into the science on this…
Background on adenoviruses:
Adenovirus is a family of viruses with many different species causing a variety of symptoms in humans as well as other animal illnesses.
Human adenoviruses are non-enveloped, double-stranded DNA viruses. There are more than 50 distinct adenovirus types causing human infections, and most spread by direct contact.
Examples of illnesses caused by adenoviruses include respiratory illnesses (common cold symptoms) in humans and kennel cough in dogs (Canine adenovirus 2).
In humans, different types of adenoviruses can also cause gastroenteritis, croup, bronchitis, pneumonia, and more.[ref] Thus, adenoviruses are both varied and very common.
Adenoviruses can be modified and used to deliver specific sections of DNA. For example, the Johnson & Johnson COVID-19 vaccine is using adenovirus to deliver the DNA of the SARS-CoV-2 spike protein. The specific virus used in the Johnson vaccine is adenovirus 26, which doesn’t cause illness in people. The AstraZeneca vaccine also uses an adenovirus (chimpanzee virus) to deliver part of the SARS-CoV-2 spike protein.
Adenoviruses that trigger fat accumulation:
Certain species of the adenovirus (Ad-5 and Ad-36) now have links to adipogenesis, or the creation of fat cells, in humans and animals. This causes weight gain in people and is linked to an increased risk of obesity.[ref] (NOTE – I want to be perfectly clear that this is not the same strain of adenoviruses used in Covid vaccines.)
While it seems counterintuitive that a virus can cause obesity, let me explain a few of the hundreds of studies showing not only a link but also causation of increased fat accumulation due to adenovirus-36 (Ad-36):
- The first animal studies on adenovirus and obesity were done in the 90s. The avian adenovirus was determined to be causative for fat mass gain in chickens, while at the same time decreasing cholesterol and triglyceride levels.[ref]
- Interestingly, animal studies show that the gain in fat mass is not due to eating more or moving less…
- Studies on rats show that human adenovirus 36 (Ad-36) increases fat tissue significantly.[ref]
- Another study revealed that “Ad36, a human adenovirus, increases TNFα and MCP1 mRNA in adipose tissue, yet improves glycemic control in mice.”[ref] TNFα and MCP1 are inflammatory markers.
- Giving the human adenovirus 36 to monkeys causes a >3-fold body weight gain.[ref]
- From a series of animal studies, researchers have discovered that Ad-36 upregulates the expression of several genes, including C/EBPα and PPARγ, which leads to an increase in adipogenesis, resulting in more fat cells.[ref]
Human studies on adenoviruses and obesity:
- A twin study showed that the Ad-36 antibody-positive twin was “significantly heavier and fatter as compared with their antibody-negative counterparts”. This was a groundbreaking study indicating that the Ad-36 virus was likely causing obesity.[ref]
- Researchers found that children with obesity were 4-times more likely to have adenovirus-5 antibodies. The results of the study showed that 28% of obese children carried the Ad-5 antibodies vs. 6% of non-obese children. The same study also found a significant link between Ad-36 antibodies in obese children (27%) vs non-obese children (10%).[ref]
- A Turkish study replicates those results for adenovirus-36, with 27% of obese children carrying antibodies and 6% of non-obese children. In adults, the researcher found 18% of obese adults had Ad-36 antibodies, compared with 4% of non-obese adults. This is a 4-fold increase in obesity for the Ad-36 group.[ref]
- When combining the data from 24 different studies on adenovirus 36 and obesity in populations around the world, the results show a very strong association between viral infection and obesity. Overall, Ad-36 increases the risk of obesity by 77% in adults and 126% in children.[ref] More recent studies add to this data.[ref][ref][ref]
- A study in Sweden replicated the previous result (~2 fold increase in Ad-36 in obese vs lean). This study, though, also looked back at historical adenovirus data. The presence of Ad-36 positivity doubled from the mid-90s to the mid-2000s, which parallels the increase in obesity during that time period.[ref]
- While almost all studies show a positive link between Ad-36 and obesity, there are exceptions. A recent study in a Chinese Han population group did not find that Ad-36 was associated with obesity. This study claims to be the first on adenoviruses and obesity in the Chinese population, so it may be that other inherited factors play a role here.[ref] Additionally, vitamin D levels seem to play a role in the relationship between Ad-36 and weight gain.[ref] It may be that population groups with higher vitamin D status don’t show a correlation between Ad-36 and obesity. For example, a recent study in Mexican children found no link between Ad-36 and obesity.[ref]
Why do certain adenoviruses cause obesity?
Viruses enter certain types of cells in a host via a receptor, and then the virus hijacks the cell’s own cellular functions to replicate. Different viruses use different receptors to enter a cell. For example, the SARS-CoV2 virus uses the ACE2 receptor that is prevalent in lung cells and intestinal cells, while HIV hijacks the immune cells via the CCR5 receptor.[ref]
Adenovirus 36 infects adipose tissue and alters metabolism there. It upregulates the production of new fat cells.
The research studies on the fat gain from adenoviruses show that infection by the virus increases cellular glucose uptake. Specifically, the adenovirus infection causes increased adipocytes (fat cells) and also increases GLUT4, a glucose receptor.[ref]
Both animal and human studies show that this has both benefits and drawbacks.
On the plus side, Ad-36 infection may improve glycemic control which decreases the risk of diabetes. The virus upregulates the PI3K and GLUT4 pathways causing pre-adipocytes to take up more glucose. This increases fat mass while simultaneously decreasing blood glucose levels. Not all is good, though, in regards to the effects of Ad-36. In addition to promoting fat accumulation, it also increases a couple of inflammatory markers including TNF-alpha and MCP-1.[ref]
Interesting side note: I mentioned above that obesity has doubled since 1980 — and that adenovirus seropositivity had also doubled (Swedish study). One piece of the puzzle as to why this could be happening is the increase in kids in daycare, which has been rising since the 80s. A study looking at overweight kids (9-12) found that Ad-36 increased the risk of obesity by 3-fold and that kids who were in daycare before age 24 months were also at an almost 3-fold risk of obesity.[ref]
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While your genes play a significant role in which viruses are likely to infect you, there isn’t a lot of direct research on adenoviruses, obesity, and genetics.
Variants involved in adenovirus 36 susceptibility:
PCSK1 gene: encodes proprotein convertase 1
Check your genetic data for rs6232 (23andMe v4, v5; AncestryDNA):
- C/C: increased risk of infection by Ad-36[ref]
- C/C: increased risk of infection by Ad-36
- T/T: typical
Members: Your genotype for rs6232 is —.
BDNF gene: codes for brain-derived neurotrophic factor
Check your genetic data for rs4923461 (23andMe v4, v5; AncestryDNA):
- G/G: slightly increased risk of infection by Ad-36[ref]
- A/G: slightly increased risk of infection by Ad-36
- A/A: typical risk
Members: Your genotype for rs4923461 is —.
Tentative Connections: Below are several genes involved in both adenovirus infection and obesity — but keep in mind that there isn’t research yet to directly connect the variants to an increased risk of obesity from the adenoviruses.
IL-10 gene: encodes interleukin-10, a part of the innate immune system that modulates the inflammatory system and keeps inflammation under control.
Researchers investigated the connection between IL-10, adenovirus titers, and obesity. The results showed that obese people with high adenovirus titers had a large increase in IL-10. The study also found that people with different IL-10 genetic variants had significant changes in lipid levels and BMI. It concludes: “According to present findings, obesity is linked to increased IL‐10 production that is the result of, or lead to, an altered response to pathogens and ensuing chronic low‐grade inflammation, perhaps in the context of partial T‐cell inactivation.”[ref]
Check your genetic data for rs1800871 -819T>C (23andMe v4, v5; AncestryDNA):
- G/G: increase inflammation[ref], higher BMI, and increased waist circumference[ref]
- A/G: slightly increased inflammation
- A/A: typical
Members: Your genotype for rs1800871 is —.
PPAR-gamma: A 2011 study looked at the impact of the adenovirus-36 infection on PPARγ. Results showed that Ad36 up-regulates PPARγ, which is important in regulating fatty acid storage, as well as improving glycemic control.[ref]
PPARG gene polymorphisms have also been studied in reference to high-fat diets and, separately, cardiovascular disease. A meta-analysis investigating 60 studies of the rs1801282 variant found that people with the G allele had a reduced risk of Type 2 diabetes.[ref]
Check your genetic data for rs1801282 (23andMe v4, v5; AncestryDNA):
- C/C: typical
- C/G: increased risk of metabolic syndrome and insulin resistance (healthy adults); decreased risk of diabetes in some populations (depending on diet, exercise)
- G/G: increased risk of metabolic syndrome and insulin resistance (healthy adults)[ref]; decreased risk of diabetes in some populations (depending on diet, exercise)[ref]
Members: Your genotype for rs1801282 is —.
Adenovirus Receptor Variant CXADR: Coxsackie and adenovirus receptor (CAR) is encoded by the CXADR gene. This receptor is a receptor for the Coxsackie B virus and adenovirus 2 and 5.[ref] CARs have been studied in conjunction with their involvement in virus-mediated myocarditis and, more recently, as a risk factor in ventricular fibrillation.[ref] A polymorphism near the CXADR gene, rs2824292, has been found to be associated with levels of expression of CXADR. “Individuals carrying one or two copies of the risk allele (A/G or G/G genotype) displayed significantly lower (0.6 fold) CXADR mRNA expression compared to individuals with the non-risk (A/A) genotype.”[ref] That study did not look at an association with the adenovirus infection in reference to the polymorphism.
Check your genetic variants for rs2824292 (23andMe v4, v5; AncestryDNA):
- G/G: reduced adenovirus 5 receptors (CXADR)[ref]
- A/G: reduced adenovirus 5 receptors (CXADR)
- A/A: typical
Members: Your genotype for rs2824292 is —.
You may be wondering why you don’t hear a lot about a viral cause of obesity. It’s a fair question, and after looking at the researcher I’m wondering why no one seems to be looking for a cure that works for this specific cause of obesity.
One doctor theorizes that: “The government and insurance companies do not want to admit that obesity is a disease because then they would have to cover treatment as they do for other diseases.”[ref]
Mulberry extract reduces Adenovirus 36 replication in mice. Supplementation with mulberry extract brought about a reduction in weight and in pro-inflammatory cytokines.[ref] It would be great to see a study that looked at mulberry extract in humans in regards to Ad-36.
Vitamin D – In a study on children with obesity and Ad-36, the results showed that increasing vitamin D levels modified the effect of the adenovirus on adiposity.[ref] More recent studies have also shown the same results — Ad-36 doesn’t seem to cause obesity (in children) with higher vitamin D levels. In fact, one study found the weight difference for the lowest vitamin D to be 8-fold higher with Ad-36 antibodies.[ref]
Mediterranean diet and exercise: A study in patients with Ad36 positivity compared to those without found that they had a greater response to nutritional interventions. In this case, the researchers had overweight study participants follow a lower calorie Mediterranean diet, increase physical activity, and have lifestyle counseling. Interestingly, liver health improved even without much weight loss for people on the healthier diet and also Ad-36 positive.[ref]
More exercise? It may not be as easy to lose weight via exercise with an adenovirus 36 infection. Increasing exercise improved blood glucose, insulin, and cholesterol, but in children with obesity and Ad-36, exercise wasn’t very effective for weight loss.
In mice, an experimental adenovirus 36 vaccine prevented fat gain when given before Ad-36 exposure.[ref]
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