There is increasing evidence that adipose tissue plays a key role in the worsening of Covid-19, points out an article by Karina Toledo, from Fapesp agency. One of the theories under investigation is that adipocytes serve as a reservoir for SARS-CoV-2, contributing to increase the viral load of obese or overweight individuals. In addition, scientists suspect that during infection, fat cells release substances into the bloodstream that amplify the inflammatory reaction triggered by the virus in the body.
These hypotheses are being investigated by researchers from the Faculty of Medicine of the University of São Paulo (FM-USP), under the coordination of the professor at the Department of Surgery Marilia Cerqueira Leite Seelaender. The project has the collaboration of Peter Ratcliffe, professor at the University of Oxford in the United Kingdom, and one of the winners of the Nobel Prize in Medicine in 2019.
“It has been shown that in the body of patients with COVID-19, a cytokine storm occurs that results in systemic inflammation similar to sepsis. We believe that these inflammatory factors are coming from adipose tissue. It has already been shown that adipocytes when they expand too much become capable of promoting inflammation throughout the body, even in the brain ”, says Seelaender to Agência FAPESP.
The FM-USP group has been analyzing fat tissue samples from people who died of COVID-19, obtained during autopsy, and also from patients infected with SARS-CoV-2 who needed to undergo emergency surgery (unrelated to the infection, for example, cases of appendicitis) at the University Hospital of USP.
Preliminary results confirm that the new coronavirus can be found inside the fat cell, whose outer membrane is rich in ACE2 (angiotensin-converting enzyme 2). This protein is the main “door” used by SARS-CoV-2 to invade human cells. What remains to be confirmed is whether, in addition to entering the adipocyte, the new coronavirus can remain and replicate within the cell.
“An interesting thing to note is that the visceral adipocyte [que compõe a gordura que se acumula entre os órgãos] it has much more ACE2 than that of subcutaneous adipose tissue. In addition, it is much more inflammatory. Therefore, visceral obesity tends to be even more harmful with regard to COVID-19 ”, explains the researcher.
The first findings of the study also reveal that in the adipose tissue of infected people there is a change in the pattern of exosome secretion – small vesicles that the cell releases into the circulation and that may contain signaling molecules of different types. This is one of the mechanisms that allow the exchange of information between different tissues, aiming to adapt the body to eventual changes in the environment.
One of the objectives of the research conducted at FM-USP is to confirm whether infection by SARS-CoV-2 causes adipocytes to release more exosomes containing inflammatory factors. Analyzes already revealed that there is an increase in the number of vesicles released into the circulation. Now, the researchers intend to characterize the contents of these vesicles – both circulating and those found inside the cells. In addition, they intend to investigate the inflammation pathways supposedly activated by these molecules.
“We start from the assumption that, as the person gets fat, the adipose tissue becomes hypoxic, in other words, it has less oxygen available. Hypoxia itself is a cause of inflammation. Therefore, one of the things we intend to investigate is whether COVID-19 causes hypoxia in adipocytes ”, says Seelaender.
The strategies for adapting human cells to situations of hypoxia were the subject of the research that won the Nobel prize for Ratcliffe and also for William G. Kaelin (Harvard University) and Gregg Semenza (Johns Hopkins School of Medicine).
Currently, the British researcher has been concentrating on studying, with samples obtained by autopsy, the effect of SARS-CoV-2 on the carotid body – a set of cells existing inside the carotid and that functions as an oxygen sensor. Upon perceiving a drop in blood oxygenation, the carotid body activates responses to increase heart and respiratory rate.
Ratcliffe believes that the virus infects the carotid body and disrupts its functioning, which would explain why many patients with COVID-19 are slow to realize that they have respiratory failure – a process that became known as silent hypoxia.
The FM-USP group has focused on understanding the effect of infection on adipose tissue. “We are analyzing everything that is being secreted by the fat cells: proteins, saturated fatty acids, prostaglandins [um tipo de lipídeo com ação similar à de hormônios], microRNAs [pequenas moléculas que não codificam proteínas mas têm ação reguladora sobre a expressão de genes] and exosomes ”, says the researcher.
In Seelaender’s evaluation, it is possible that the inflammatory factors released by the adipose tissue of patients with COVID-19 are the cause of the damage already described in the heart, lung and nervous system of patients.
“We postulate that a process similar to the one observed in the fat tissue of patients with cachexia occurs in the obese with COVID-19 [perda severa e rápida de peso e de massa muscular associada a doenças como Aids, insuficiência cardíaca e câncer]. The cachectic individual’s adipocytes release more exosomes and the contents of these vesicles are altered, with a pro-inflammatory profile. We know that there is inflammation in both cachexia and obesity. What changes is the type of inflammatory mediator released and the signaling pathways activated ”, he explains.
Research on the relationship between cachexia and inflammation has been conducted since 2013, with support from FAPESP (read more at: agencia.fapesp.br/31630).
Opposites, but similar
In an article published in the magazine Advances in Nutrition, Seelaender’s group discusses how the patient’s nutritional status can influence the response to COVID-19. According to the authors, both obesity and malnutrition – and in this last condition are inserted cachexia and sarcopenia (loss of lean mass associated with the aging process) – can compromise the immune response and make it difficult to fight viral infections.
“Immune cells have an increased demand for energy during infectious processes, especially those that take time to be eliminated. There is a change in the metabolism of these cells so that they can multiply quickly, but in the malnourished organism this is not possible. During an infection, the number of T lymphocytes in a malnourished individual is much less than that of an eutrophic person [bem nutrida]”, account.
Also according to Seelaender, in the malnourished organism there is atrophy of Organs lymphoid organs, responsible for the production and maturation of the lymphocytes. Consequently, there is a decrease in the number of circulating defense cells. Animal experiments have also shown that the malnourished organism takes longer to eliminate the virus – whatever it may be.
“The rate of fat can be a problem when it is excessive or insufficient. Although it seems paradoxical, the two extremes are harmful. That’s because the adipose tissue secretes a hormone called leptin, which regulates the metabolism of T lymphocytes. When you have less fat, there is low leptin signaling. When you have too much fat, the cells become less sensitive to leptin, which starts to be released in large quantities ”, says the researcher.
Aging, in turn, affects several of the factors mentioned by Seelaender. The immune system becomes less responsive. There is a decrease in lean mass, an increase in visceral adiposity and a worsening in the ratio between lean and fat mass.
“The loss of lean mass can worsen the outcome of chronic and acute diseases in the elderly. Muscle is a reservoir of energetic substrate [aminoácidos] that can be mobilized in times of need, such as during an infection ”, he says. “That is why it is important to note that, at COVID-19, not only is adiposity a problematic factor, but also the relationship between lean and fat mass. If the individual has a lot of fat and little muscle it is worse than if he has a lot of fat, but a good muscle condition. ”
Coronavirus Disease 2019 (COVID-19) and Nutritional Status: The Missing Link? can be read at https://academic.oup.com/advances/advance-article/doi/10.1093/advances/nmaa125/5911598?rss=1.
This text was originally published by Agência FAPESP under the Creative Commons CC-BY-NC-ND license. Read the original here.