Abdominal obesity triggers cytokine storm

Recent research published in journals PNAS reported that abdominal obesity is associated with an exaggerated inflammatory response and an increased risk of death in coronavirus disease 2019 (COVID-19) patients.

study: Apple-shaped obesity: Dangerous soil for exacerbation of cytokine acceleration in COVID-19. Image credit: fongbeerredhot / Shutterstock.com

Background

Novel coronavirus disease (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is a multifactorial disease. Excessive cytokine production and hyperinflammation are considered key features of severe novel coronavirus disease (COVID-19).

Increasing age, along with a range of comorbidities such as hypertension, diabetes, chronic kidney disease, and obesity, increases the risk of severe COVID-19 illness, hospitalization, and death. In Japan, the presence of abdominal obesity, defined as visceral adipose tissue-predominant obesity, is associated with poor prognosis in patients with COVID-19.

About research

In the current study, scientists are comparing COVID-19 outcomes in Japanese patients with and without abdominal obesity. To this end, we used abdominal computed tomography (CT) imaging to quantify adipose areas in the abdomen and subcutaneous tissue and correlated these values ​​with COVID-19 severity and outcome.

The researchers also investigated the characteristics of COVID-19 in two obese mouse models. These models included ob/ob mice with a genetic defect in the leptin ligand, whereas db/db mice had a genetic dysfunction of the leptin receptor. Compared to db/db mice, ob/ob mice exhibit higher liver and perirenal adipose tissue weights, indicating that this model can be used to mimic visceral adipose tissue (VAT)-predominant obesity. It has been.

key findings

Increased VAT accumulation was found to be an independent risk factor for COVID-19 mortality, even in the presence of other factors such as older age, history of infarction, and chronic kidney disease (CKD). Patients with VAT-driven obesity, also known as abdominal obesity, are more likely to suffer from severe COVID-19 and have a higher mortality rate than those with higher BMI or subcutaneous adipose tissue (SAT)-driven obesity. significantly higher. .

Increased adipose tissue was also weakly associated with C-related protein (CRP). D-dimer, ferritin levels at both early and peak stages of disease. High concentrations of macrophages and adipocytes in the VAT also caused an exaggerated inflammatory response, resulting in worse clinical outcomes, especially in younger patients.

of live Experiments revealed that exposure to SARS-CoV-2 increased the risk of mortality in ob/ob mice, whereas db/db and control mice all survived. Of note, ob/ob mice also displayed relatively higher numbers of SARS-CoV-2-positive cells within their alveoli compared to db/db and control mice. However, SARS-CoV-2-positive cells in the bronchi were comparable between each group.

We also observed a higher susceptibility to SARS-CoV-2-associated mortality in mice fed a high-fat diet (HFD) compared with mice fed a normal-fat diet (NFD). HFD-fed mice also exhibited immunopathological findings similar to those observed in obese ob/ob mice.

High levels of inflammation and acute lung injury were observed in HFD-fed and ob/ob mice. In contrast, obese mice with a predominance of SAT showed reduced local inflammation and lung injury upon SARS-CoV-2 exposure, thereby demonstrating a favorable COVID-19 outcome.

Increased rate of SARS-CoV-2 antigen-positive pulmonary macrophages were observed in mice with abdominal obesity. Electron microscopy analysis identified disrupted virus particles within these macrophages. Further analysis revealed upregulated type I/II interferon responses and interleukin-6 (IL-6) levels in the lungs of abdominally obese mice.

Ribonucleic acid (RNA) sequence analysis identified an enrichment of inflammation-related pathways in the lungs of abdominally obese mice. These include cytokine-cytokine receptor interactions, tumor necrosis factor (TNF) signaling, chemokine signaling, nucleotide binding, and oligomerization domain (NOD)-like receptor pathways.

These observations collectively indicate that pulmonary macrophages carrying viral antigens circulate systemically and induce an inflammatory response in abdominally obese mice.increased inflammation cytokine storm It may be responsible for increased mortality in SARS-CoV-2 infected mice with abdominal obesity.

Treatment of these mice with IL-6 receptor-targeted antibodies was found to significantly reduce mortality, further supporting the association between increased cytokine production and increased risk of death.

Modification of adipose tissue

The current study investigated the extent to which obesity affects the outcome of COVID-19 in mice given leptin prior to virus exposure. To this end, leptin-mediated weight loss improved survival after infection in abdominally obese mice.

In these mice, prophylactic leptin administration also decreased inflammatory lung macrophages, viral RNA levels, IL-6 production, interferon response, and adipose tissue weight. We observed attenuation of inflammation-related pathways and improved lysosomal function in alveolar macrophages in mice prophylactically given leptin.

Thus, excessive accumulation of adipose tissue in the abdomen is associated with delayed viral clearance, activation of inflammatory macrophages and cytokine production, and increased mortality in SARS-CoV-2-infected mice.

Significance of research

Study results indicate that abdominal obesity is a major risk factor for COVID-19, as it can significantly increase cytokine storm and mortality in SARS-CoV-2-infected patients . Based on these findings, COVID-19 patients with abdominal obesity may benefit from cytokine suppression therapy during the course of their disease.