Visceral fat cell infection may contribute to worsening Covid-19, study suggests

Experiments carried out at Unicamp (State University of Campinas) and at USP (University of São Paulo) indicate that visceral fat —that which surrounds vital organs and is considered a risk factor for cardiovascular diseases, diabetes and hypertension— contributes more to the aggravation of Covid-19 than the fat existing under the skin, which forms the infamous “love handles”.

To arrive at this conclusion, Marcelo Mori, a professor at Unicamp’s Institute of Biology, one of the research leaders, infected two types of adipocytes in the laboratory: one obtained from human stem cells isolated from subcutaneous adipose tissue and another differentiated from of stem cells from 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 of the ACE-2 protein [à qual o vírus se conecta para invadir a célula] on the cellular surface”, Mori tells Agência Fapesp.

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 the journal Nature Communications, had the participation of several research groups from Unicamp, as well as collaborators from USP, LNBio-CNPEM (National Biosciences Laboratory), Inca (National Cancer Institute) and Idor ( D’Or Institute for Research and Teaching).

Among the coordinators are professors Luiz O. Leiria (USP), Mariana Osako (USP) and Daniel Martins de Souza (Unicamp). The investigation received funding from FAPESP through 20 projects.

viral reservoir

Mori’s team at Unicamp was the first in the world to show —in July 2020— that SARS-CoV-2 was capable of infecting human fat cells and to suggest that adipose tissue would serve as a reservoir for the virus (read more here).

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

“Our hypothesis is 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, besides, it demands 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 (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 capacity 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. That is, 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 perhaps these individuals are being more careful because they know they belong to a risk group”, he 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 if the infection changes the risk of the individual developing diabetes or cardiovascular diseases, for example. morphological and functional characteristics in the visceral adipose tissue”, he says.

The article SARS-CoV-2 infects adipose tissue in a fat depot- and viral lineage-dependent manner can be read here.