EXERCISE AND COVID: IRISIN MAY BE AN IMMUNITY ACTIVATOR.

The hormone irisin, released by muscles during physical activity, may have a therapeutic effect in cases of COVID-19. By analyzing gene expression data from adipose cells, researchers observed that the substance has a modulating effect on genes associated with increased replication of the novel coronavirus (SARS-CoV-2) within human cells.

The finding was based on transcriptome data (the set of RNA molecules expressed in a tissue) from SARS-CoV-2 uninfected adipose cells that received doses of irisin. "We confronted information about important genes in COVID-19 with our transcriptome data to draw correlations. The result represents a positive signal for the search for new treatments in this emergency moment with the pandemic. It is important to emphasize that these are preliminary data, a suggestion of the therapeutic potential of irisin for cases of COVID-19. We are indicating a research path to prove or disprove the beneficial effect of the hormone in infected patients," says Miriane de Oliveira, a researcher at the Faculty of Medicine at Unesp, in Botucatu (SP).

The article, published in the journal Molecular and Cellular Endocrinology, describes data generated in Oliveira's postdoctoral study, which analyzed the action of irisin and thyroid hormones in adipocytes. The study was supported by FAPESP.

Using sequencing techniques, researchers identified 14,857 genes expressed in a subcutaneous adipocyte lineage. When treating the cells with irisin, they observed that the expression of several genes was altered.

Due to the pandemic, researchers decided to investigate possible effects of irisin on genes related to SARS-CoV-2 replication. Treatment with irisin in adipose cells decreased the expression of TLR3, HAT1, HDAC2, KDM5B, SIRT1, RAB1A, FURIN, and ADAM10 genes, regulators of the ACE2 gene – fundamental for the virus's replication in human cells. ACE2 encodes the protein that the virus needs to bind to in order to invade human cells.

Another positive aspect found in the study was that irisin tripled the transcription levels of the TRIB3 gene. Previous study demonstrated the importance of maintaining TRIB3 expression. In elderly individuals, a decrease in the expression of this gene is common, which may be related to increased SARS-CoV-2 replication and the increased risk of this population to COVID-19.

"A third important aspect lies in the finding by other research groups that adipose tissue apparently serves as a reservoir for the virus. This helps to understand why obese individuals have a higher risk of developing severe COVID-19. Furthermore, obese individuals tend to have lower levels of irisin, as well as larger amounts of the virus receptor molecule [ACE2], when compared to non-obese individuals," he states (read more at: agencia.fapesp.br/33612/).

Irisin, normally produced endogenously during continuous physical exercise, is known for its function of metabolic modification of white adipose tissue – which stores triglycerides, lipids, accumulates fat, and can become inflamed – having a function similar to brown adipose tissue. This process favors energy expenditure, which makes irisin an endogenous therapeutic agent for metabolic diseases, such as obesity. The hormone's modulating capacity in the activity of macrophages (immune system defense cells) is also known, which confers potential anti-inflammatory properties.

Oliveira's study is an example of how managing data obtained from basic research can seed other discoveries and research lines.

"We initially performed a comparative analysis between the action of irisin and thyroid hormones in reducing lipid accumulation and modulating genes in adipose cells. The study generated a large volume of data, and as the pandemic came and other research groups discovered the genes associated with SARS-CoV-2 replication, we decided to investigate in our database how irisin [and thyroid hormones] could influence the disease," he reports to Agência FAPESP.

The original investigation by the research group sought to discover how these hormones play a thermogenic role in reducing adipose tissue and generating energy in adipocytes. "For this, we performed the transcriptome and identified which genes would be affected in the presence of these hormones. Data that served as the basis for the study on COVID-19," he says.

With the study, Oliveira identified that irisin not only decreases lipid accumulation but also increases the expression of uncoupling protein 1 (UCP1), associated with greater caloric expenditure. The increase in the expression of this protein is compatible with the reduction of DNA damage and oxidative stress.

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