A recent study published within the journal PNAS reports that abdominal obesity is related to excessive inflammatory responses and an increased risk of mortality in coronavirus disease 2019 (COVID-19) patients.

Study: Apple-shaped obesity: A dangerous soil for cytokine-accelerated severity in COVID-19.​​​​​ Image Credit: fongbeerredhot / Shutterstock.com

Background

COVID-19, which is brought on by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a multifactorial disease. Excessive cytokine production and hyperinflammation are considered to be major hallmarks of severe COVID-19.

Along with increasing age, various comorbidities, including hypertension, diabetes, chronic kidney disease, and obesity, increase the danger of severe COVID-19, hospitalization, and mortality. In Japan, the presence of abdominal obesity, which is defined as visceral adipose tissue-dominated obesity, is related to poor prognosis in COVID-19 patients.

Concerning the study

In the present study, scientists compare COVID-19 outcomes between Japanese patients with and without abdominal obesity. To this end, abdominal computed tomography (CT) imaging was used to quantify fat areas within the abdomen and subcutaneous tissues and correlate these values to COVID-19 severity and outcomes.

The researchers also investigated the characteristic features of COVID-19 in two obese mouse models. These models included ob/ob mice, which have a genetic defect of their leptin ligand, whereas db/db mice have a genetic dysfunction of the leptin receptor. As in comparison with db/db mice, ob/ob mice exhibit higher liver and perirenal adipose tissue weights, thus indicating that this model might be used to resemble visceral adipose tissue (VAT)-dominant obesity.

Necessary observations

Increased VAT accumulation was found to be an independent risk factor for COVID-19 mortality, even when other aspects similar to old age, a history of infarction, and chronic kidney disease (CKD) were also present. Patients with VAT-dominated obesity, which might otherwise be described as abdominal obesity, were also significantly more prone to severe COVID-19 and mortality as in comparison with those with high body mass index (BMI) or subcutaneous adipose tissue (SAT)-dominated obesity.

Increased adipose tissue was also weakly related to C-related protein (CRP), D-dimer, and ferritin levels at each early and peak stages of the disease. The upper concentration of macrophages and adipocytes in VAT also led to a hyperinflammatory response and, in consequence, worse clinical outcomes, particularly amongst young patients.

The in vivo experiments revealed that exposure to SARS-CoV-2 increases the danger of mortality in ob/ob mice, whereas all db/db and control mice survived. Notably, ob/ob mice also exhibited relatively higher numbers of SARS-CoV-2-positive cells within the alveoli as in comparison with db/db and control mice; nonetheless, SARS-CoV-2-positive cells throughout the bronchi were comparable between each group.

The next susceptibility to SARS-CoV-2-related mortality was also observed in high-fat food regimen (HFD)-fed mice as in comparison with that in normal fat food regimen (NFD)-fed mice. HFD-fed mice also exhibited similar immunopathological findings as those observed in ob/ob mice with abdominal obesity.

A high level of inflammation and acute lung injury was observed in HFD-fed mice and ob/ob mice. In contrast, mice with SAT-dominated obesity exhibited localized inflammation and attenuated lung injury upon SARS-CoV-2 exposure, thereby indicating favorable COVID-19 outcomes.

An increased proportion of SARS-CoV-2 antigen-positive lung macrophages was observed in mice with abdominal obesity. Electron microscopic evaluation identified disrupted viral particles in these macrophages. Further evaluation revealed an upregulated type I/II interferon response and interleukin-6 (IL-6) level within the lungs of abdominal obesity mice.

Ribonucleic acid (RNA) sequencing evaluation identified an enrichment of inflammation-related pathways within the lungs of abdominal obesity mice. These included cytokine-cytokine receptor interaction, tumor necrosis factor (TNF) signaling, chemokine signaling, and nucleotide-binding, and oligomerization domain (NOD)-like receptor pathways.

These observations collectively indicate that viral antigen-carrying lung macrophages flow into systemically and induce inflammatory responses in mice with abdominal obesity. Increased inflammation characterised by a cytokine storm could be chargeable for higher mortality in SARS-CoV-2-infected mice with abdominal obesity.

Treatment of those mice with IL-6 receptor-targeting antibodies revealed a big reduction in mortality rates, which further confirms the association between increased cytokine production and better mortality risk. 

Adipose tissue modification

The present study explored the extent to which obesity influences COVID-19 outcomes in mice treated with leptin before viral exposure. To this end, leptin-mediated reduction in body weight led to improved survival rates after infection in mice with abdominal obesity.

Prophylactic leptin administration also led to a discount in inflammatory lung macrophages, viral RNA load, IL-6 production, interferon response, and adipose tissue weight in these mice. An attenuation in inflammation-related pathways and improvement in lysosomal function of alveolar macrophages were observed in mice that received preventive leptin.

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

Study significance

The study findings indicate that abdominal obesity is a serious risk factor for COVID-19, as it may possibly significantly increase the danger of cytokine storm and mortality in patients infected with SARS-CoV-2. Based on these findings, COVID-19 patients with abdominal obesity might profit from cytokine-suppressing therapies throughout the disease course.