Viruses and obesity: a link between the outcome of viral infection or a cause of obesity?

In both the developed and non-developed world an increase in the number of obese children has been observed since the late 1970s/early 1980s. Since then, numerous studies contributed this increase to changes in diet, physical activity, television watching, computer games and food advertising to name a few. The very same studies however also indicated that these reasons alone can not explain the increase in childhood obesity fully and consequently the pattern of the rapid spread of obesity has been (partially) attributed to other reasons such as being the result of inflammation caused by bacterial or viral infections.
Research in animal models (chicken, mice, sheep, rats, goat, dogs and hamsters) indeed led to the identification of eight viruses to cause obesity in animals and research identified both human and animal Adenoviruses -specifically human Adenovirus 36 (Ad 36)- capable to infect adipocytes, resulting in the accumulation of triglycerides in adipocytes and changes in transcription factors involved in the differentiation of pre-adipocytes into (mature) adipocytes as well as in the modulation of the inflammatory response. Indeed, a higher percentage of obese (30%) than non-obese subjects (11%) tested seropositive for Adenovirus 36 antibodies.
Moreover, adenoviral induced obesity been implicated in increased risk of Influenza virus infection and morbidity during non-pandemic and pandemic Influenza seasons. 
So how might pathogens like Adenovirus induce obesity and how might this contribute to increase risk of morbidity following infection with Influenza virus.

                              Inflammation and obesity

An important role in the antiviral response is played by pattern-recognition response factors (PRR) such as Toll-like receptor 3 (TLR-3), Retinoic acid-inducible gene I (RIG-1) and Melanoma Differentation-Associated antigen-5 (MDA5), all of them which are expressed in pre-adipocytes and mature adipocytes alike upon induction by activated IFN regulatory factor 3 (IFN3) and up regulation of pro-inflammatory factors IL-6 and TNF-α by nuclear factor kappa B (NF-κB). 
Experimentally this system can be induced by transfecting Poly (I:C), leading to the expression of leptin, resistin and adiponectin in mature adipocytes as well as the differentiation of pre-adipocytes into (mature) adipocytes. Blocking this system by using inhibitors specifically targeting IRF3 (BX795) or NF-κB (BAY11-7082) or using cells deficient in TLR-3 (TLR-3 -/-) showed that in particular RIG-1 or MDA5 are responsible for the inflammatory response since both are inducing the expression of pro-inflammatory cytokines. Notably, transfected Poly (I:C) inhibits the differ-entiation of pre-adipocytes to adipocytes and might thus contribute to increased insulin resistance. In addition, blocking this system might also be effect the expression of Interferon stimulated genes.

Poly (I:C) is considered to be mimetic of (specifically viral) dsRNA and does not occur in nature and stimulates TLR-3 in a wide variety of immune cells including dendritic cells and B-Lymphocytes.

The attentive reader however might know that Adenoviruses are double stranded (ds) DNA viruses, i.e. that their genome is consists of dsDNA (other viruses have single stranded DNA or RNA as a genome for instance) and thus are known to activate a TLR mediated antiviral respon-se. Consequently it is conceivable that the infection of Pre-adipocytes with Adenovirus might prevent the differentiation of Pre-adipocytes into mature adipocytes and furthermore induce insulin resistance. Voila, case closed or quod erat demonstrandum as the mathematician would say. Except that both experimental and causative evidence is far from certain since the disease is after all multi-causative.


What about the increased mortality due to obesity in patients in-fected with Influenza viruses? As outlined above, the activation of PPRs in pre-adipocytes downregulates the immune response and increases the expression of inflammatory cytokines. Indeed it is has been speculated that one reason of the increased morbidity in patients infected with A/H1N1/1918 was a “cytokine storm”. If however this is the case in the obese patients infected with current Influenza virus is open to speculation. 

Last but no least, in the case of Ad36, the E4orf1 gene product has been implicated to be responsible for the adipogenic effect observed in obese patients. Currently, the experimental proof is still far from certain.

What about other viruses? TLR-3 recognizes dsRNA and is part of the antiviral response of RNA viruses such as Rhinovirus and other Picornaviruses. A study from 1981 linked encephalomyocarditis virus to the development of diabetes in mice but in humans a link has not been demonstrated and the pathogenetic analysis showed only a destruction of pancreatic cells in obese mice but not in lean littermates. The inflammation was accompanied by an infiltration of macrophages. Indeed the cytokines expressed as a result of Poly (I:C) transfection into pre-adipocytes and adipocytes might also recruit Macrophages and thus induce an inflammatory response. 

Finally, other pathogens might cause similar problems since the bacteria can induce an antibacterial response akin to the antiviral response. 

Further reading:

van Ginneken V, Sitnyakowsky L, & Jeffery JE. (2009) "Infectobesity: viral infections (especially with human adenovirus-36: Ad-36) may be a cause of obesity. Medical hypotheses, 72(4), 383-8. PMID: 19138827

van Ginneken V, Sitnyakowsky L, & Jeffery JE. (2009) "Infectobesity: viral infections (especially with human adenovirus-36: Ad-36) may be a cause of obesity. Medical hypotheses, 72(4), 383-8. PMID: 19138827

Atkinson, Richard L. (2008-01--1) Could viruses contribute to the worldwide epidemic of obesity?. , 3(s1), 37-43. DOI: 10.1080/17477160801896754

Hur, Sun Jin. (2019-10--1) Effect of adenovirus and influenza virus infection on obesity. , 93(16), 531-535. DOI: 10.1016/j.lfs.2019.08.016 

Cocoros, Noelle M. (2019-01--1) Obesity as a risk factor for severe influenza-like illness. , 8(1), 25-32. DOI: 10.1111/irv.12156 Yu, Lili. (2019-02--1) Pattern recognition receptor-initiated innate antiviral response in mouse adipose cells. , 92(2), 105-115. DOI: 10.1038/icb.2019.66 

Genoni, Giulia. (2019-01--1) Obesity and infection: two sides of one coin. , 173(1), 25-32. DOI: 10.1007/s00431-013-2178-1