The Role of Adipocytes and Adipocyte-Like Cells in the Severity of COVID-19 Infections

Abstract

Coronavirus disease-2019 (COVID-19), caused by the highly pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), demonstrates high morbidity and mortality caused by development of a severe acute respiratory syndrome connected with extensive pulmonary fibrosis. In this Perspective, we argue that adipocytes and adipocyte-like cells, such as pulmonary lipofibroblasts, may play an important role in the pathogenic response to SARS-CoV-2. Expression of angiotensin-converting enzyme 2 (the functional receptor for SARS-CoV) is upregulated in adipocytes of patients with obesity and diabetes, which turns adipose tissue into a potential target and viral reservoir. This may explain why obesity and diabetes are potential comorbidities for COVID-19 infections. Similar to the recently established adipocyte-myofibroblast transition, pulmonary lipofibroblasts located in the alveolar interstitium and closely related to classical adipocytes demonstrate the ability to transdifferentiate into myofibroblasts that play an integral part of pulmonary fibrosis. This may significantly increase the severity of the local response to SARS-CoV-2 in the lung. To reduce the severity and mortality associated with COVID-19, we propose to probe for the clinical response to thiazolidinediones, peroxisome proliferator activated receptor γ agonists that are well-known antidiabetic drugs. Thiazolidinediones are able to stabilize lipofibroblasts in their "inactive" state, preventing the transition to myofibroblasts and thereby reducing the development of pulmonary fibrosis and stimulating its resolution.

Figure 1

Top: Increased expression of ACE2 (the SARS‐CoV‐2 receptor) on obese and diabetic adipose tissue. This dysfunctional adipose tissue also displays increased fibrosis, at least in part because of a adipocyte‐myofibroblast transition. PPARγ agonists (thiazolidinediones [TZDs]) along with adiponectin (a TZD target as well) are potently antifibrotic and restore functional adipose tissue. Bottom: Lipofibroblasts are the local adipocyte equivalent in the lung and also display the ability to dedifferentiate into myofibroblasts that contribute in an integral way to pulmonary fibrosis. Similar to adipose tissue, TZDs have the potential to act on the myofibroblasts and partially convert them back to lipofibroblasts. In that role, TZDs and adiponectin act as antifibrotic agents as well and have the potential to restore a higher degree of functionality in lung tissue. [Color figure can be viewed at wileyonlinelibrary.com]