Inflammatory factors that aggravate COVID-19 can come from adipose tissue

Reviewed by Emily Henderson, B.Sc.November 20, 2020

There is growing evidence that adipose tissue plays a key role in the aggravation of COVID-19. One of the theories under investigation is that fat cells (adipocytes) act as reservoirs for SARS-CoV-2 and increase viral load in obese or overweight individuals. Scientists also suspect that during infection, fat cells release substances into the bloodstream that enhance the inflammatory reaction triggered by the virus in the body.

These hypotheses are being studied by researchers at the Faculty of Medicine of the University of Sao Paulo (FM-USP) in Brazil under the coordination of Marilia Cerqueira Leite Seelaender, professor at the Department of Clinical Surgery. Peter Ratcliffe, a professor at Oxford University in the UK and one of the winners of the 2019 Nobel Prize in Medicine, is collaborating.

A cytokine storm resulting in systemic inflammation similar to sepsis occurs in some severe patients with COVID-19. We believe these inflammatory factors come from adipose tissue. It has been shown that when adipocytes expand too much, they can cause inflammation throughout the body, including in the brain. “

Marilia Cerqueira Leite Seelaender, Professor in the Department of Clinical Surgery

The FM-USP group analyzed adipose tissue samples obtained from autopsies of people who died of COVID-19, and also from patients infected with SARS-CoV-2 who needed to undergo emergency surgery at the university hospital for appendicitis or other reasons not related to viral infection. Preliminary results confirmed that the virus can be found in fat cells, whose membranes are rich in ACE-2, the main receptor used by the virus to invade human cells. Researchers have yet to confirm that once it invades adipocytes, it can stay there long enough to replicate within them.

“It is worth noting that visceral adipocytes [located deep in the abdomen and around internal organs] they have a lot more ACE2 than subcutaneous fatty tissue, “Seelaender said.” Furthermore, they are much more inflammatory. As a result, visceral obesity tends to be even more damaging with regards to COVID-19. “

Preliminary results also revealed a change in the exosome secretion pattern in adipose tissue of infected people. Exosomes are extracellular vesicles, comparable to tiny bubbles, released from cells into the bloodstream with proteins and other types of signaling molecules. This is one of the mechanisms by which information is exchanged between different tissues as the body adapts to changes in its environment.

The objectives of the research conducted by the FM-USP group include investigating whether SARS-CoV-2 infection causes adipocytes to release multiple exosomes containing inflammatory factors. So far it has been shown that the number of vesicles released into the bloodstream actually increases. The researchers will now analyze the contents of these circulating vesicles, as well as those that remain inside the cells. They also plan to study the inflammatory pathways allegedly activated by these molecules.

“We first hypothesized that when a person gets fat, their fatty tissue becomes hypoxic, which means the person has less oxygen available. Hypoxia itself is a cause of inflammation, so one of the things we want to investigate is whether COVID-19 causes adipocyte hypoxia, “Seelaender said.

Research on how human cells adapt to hypoxia won Ratcliffe the Nobel Prize with William G. Kaelin (Harvard University) and Gregg Semenza (Johns Hopkins School of Medicine). Currently, his work focuses on analyzing autopsy samples to find out how SARS-CoV-2 affects the carotid body, a cluster of chemoreceptors and supporting cells in the carotid artery that function as an oxygen sensor. When it detects that the oxygen levels in the blood are too low, the carotid body activates responses that increase heart rate and breathing.

Ratcliffe believes the virus infects the carotid body and impairs its functioning, which explains why many COVID-19 patients are slow to recognize that they are hypoxic, not least because they don’t feel short of breath (“silent hypoxia”).

The FM-USP group, meanwhile, is focusing on an effort to understand the effect of the infection on adipose tissue. “We are analyzing everything that is secreted by fat cells: proteins, saturated fatty acids, prostaglandins [lipids with diverse hormone-like effects], microRNA [small non-coding RNA molecules that regulate gene expression] and exosomes, ”Seelaender said.

Inflammatory factors released from adipose tissue in COVID-19 patients may be the cause of the damage to the heart, lungs and nervous system described in such patients, he added. “Our hypothesis is that obese COVID-19 patients undergo a similar process to that observed in the adipose tissue of patients with cachexia. [significant rapid weight loss and muscle wasting associated with AIDS, heart failure and cancer, among other diseases]”he said.” Adipocytes in cachexic individuals release multiple exosomes and their content is altered to have a pro-inflammatory profile. We know there is inflammation in both cachexia and obesity. The difference lies in the type of inflammatory mediator released and the signaling pathways activated. “

Seelaender and her group have been studying the links between cachexia and inflammation since 2013 with support from FAPESP.

Opposite but similar

In an article published in the magazine Advances in Nutrition, Seelaender and her group discuss how nutritional status can affect a patient’s response to COVID-19. According to the authors, both obesity and malnutrition – including cachexia and sarcopenia (loss of skeletal muscle mass associated with aging) – can impair the immune response and prevent the body from fighting viral infection.

“Immune cells require more energy during an infectious process, especially if the body takes a long time to get through it. Their metabolism must change so that they can multiply quickly, but in an undernourished organism this is not possible. of T lymphocytes in a malnourished individual is much smaller than in a eutrophic one [well-nourished] individual, ”Seelaender said.

In addition, he continued, undernourished organisms suffer from atrophy of the lymphoid organs (especially bone marrow, thymus and lymph nodes), in which lymphocytes are produced and reach maturity. As a result, the number of circulating defense cells decreases. Animal experiments have also shown that an organism suffering from malnutrition takes longer to eliminate viruses.

“Fat can be a problem when it is too much or too little. As paradoxical as it may seem, both extremes are dangerous,” he explained. “Adipose tissue secretes leptin, a hormone that regulates the metabolism of T lymphocytes. Leptin signaling falls in a body with very low fat. Excessively high fat makes cells less sensitive to leptin, hence the amount of leptin released. significantly increases “.

Aging affects many of the factors Seelaender mentioned. The immune system becomes less reactive. Skeletal muscle mass decreases, visceral fat increases, and the ratio of lean to fat worsens.

“Loss of lean mass can worsen the outcome of chronic and acute diseases in older people. Muscle is a reservoir of energy substrate [amino acids] which can be mobilized in times of need, such as during an infection, “he said.” This is why it is important to point out that not only adiposity, but also the ratio of lean mass to fat mass is a problem in COVID-19 patients. If a person has a lot of fat and little muscle, that’s worse than if they have a lot of fat but good muscle condition. “