Infection of fat cells may contribute to the worsening of Covid-19, says study

Experiments conducted at the State University of Campinas (Unicamp) and the University of São Paulo (USP) indicate that visceral fat – the fat that surrounds vital organs and is considered a risk factor for cardiovascular disease, diabetes and hypertension – contributes more to the worsening Covid-19 than the fat under the skin.

To arrive at this conclusion, professor at Unicamp’s Institute of Biology Marcelo Mori, one of the leaders of the research, infected two types of cells (adipocytes) in the laboratory: one obtained from human stem cells isolated from subcutaneous adipose tissue and the other differentiated from stem cells of visceral adipose tissue.

“It was possible to observe that visceral adipocytes are more susceptible to infection by SARS-CoV-2, as the viral load increases much more in this type of fat cell than in subcutaneous adipocytes. We believe that this is mainly due to the greater presence of the ACE-2 protein [à qual o vírus se conecta para invadir a célula] on the cell surface”, explains Mori.

In addition, the researchers noticed that, when infected, the visceral adipocyte produces a greater amount of pro-inflammatory cytokines – molecules that signal to the immune system the existence of a threat to be fought.

The research, published in Nature Communications magazine, had the participation of several research groups from Unicamp, in addition to collaborators from USP, the National Biosciences Laboratory (LNBio-CNPEM), the National Cancer Institute (Inca) and the Instituto D ‘Or Research and Teaching (Idor). Among the coordinators are professors Luiz O. Leiria (USP), Mariana Osako (USP) and Daniel Martins-de-Souza (Unicamp). The investigation received funding from the Research Support Foundation of the State of São Paulo (FAPESP) through 20 projects.

viral reservoir

Mori’s team at Unicamp was one of the first to reveal, in July 2020, that the coronavirus was capable of infecting human fat cells and to suggest that adipose tissue would serve as a reservoir for the virus.

“After that, other works confirmed that the adipocyte can indeed be infected. And, when analyzing samples from patients who died of Covid-19, we saw that the presence of the virus in adipose tissue is relatively frequent, around 50% of cases”, says the researcher.

The group then decided to investigate whether there was a difference in how visceral and subcutaneous fat cells responded to infection. With regard to metabolic diseases, evidence from the scientific literature shows that visceral fat is the main villain, while subcutaneous fat tends to be neutral or even beneficial.

“We wanted to assess whether there was a similar relationship in the context of Covid-19,” says Mori. “And in fact, our model suggests that the more abundant the visceral adipose tissue is in the individual with obesity, the more chances the virus has to replicate and this ends up amplifying the inflammatory process”.

In the subcutaneous adipocyte, on the other hand, the group observed that the infection leads to a decrease in lipolysis, as the process of breaking lipids into fatty acid molecules that can be used as a source of energy during physical activity or fasting periods is known. .

“We hypothesize that this represents an antiviral cellular response. There are studies showing that the inhibition of lipolysis decreases the replicative capacity of SARS-CoV-2, which can be explained by the fact that the virus needs lipids to produce its envelope and, in addition, requires energy from the cell to make copies of its genetic material”, explains Mori.

According to the researcher, therefore, the decrease in lipolysis in the subcutaneous adipose tissue can be something positive for us humans and bad news for the virus.

antagonistic responses

Visceral adipocytes were exposed to two different strains of SARS-CoV-2: the ancestral one, originating from Wuhan, China, and isolated from one of the first Brazilians diagnosed with Covid-19; and the gamma variant (P.1.), which emerged at the end of 2020 in Manaus. The difference in susceptibility with respect to subcutaneous adipocytes was seen only with the ancestral strain.

“We saw that the Manaus variant has a lower ability to infect visceral cells compared to the ancestral strain. And, through proteomics [análise do conjunto de proteínas produzidas pela célula]we observed that, while the Wuhan strain leads to a decrease in several proteins related to the interferon response in the cell [mecanismo do sistema imune para combater vírus], the gamma leads to an increase. In other words, with the Manaus strain, the adipocyte produces more proteins that promote an antiviral response,” says Mori.

According to the researcher, recent studies indicate that, with the new viral variants, there is a drop in severe cases of Covid-19 among people with obesity.

“But this phenomenon may be influenced by other factors, such as vaccination or previous infection. Or maybe these individuals are more careful because they know they belong to a risk group, ”she says.

In order to try to advance in the understanding of the subject, the group intends to carry out new experiments in cultures of adipocytes with the delta and omicron strains. Another future objective is to investigate possible metabolic impacts of SARS-CoV-2 infection in the medium and long term.

“We want to find out whether the infection changes the individual’s risk of developing diabetes or cardiovascular disease, for example. For this, one possibility is to study samples of patients who had Covid-19 and then underwent bariatric surgery and verify whether morphological and functional changes occur in the visceral adipose tissue with the infection”, he says.