A new study by researchers from University of Campinas-Brazil (UNICAMP) and Ribeirão Preto Medical School, University of São Paulo-Brazil (USP) has found that the SARS-CoV-2 virus has a greater affinity for visceral adipocytes compared to subcutaneous adipocytes, replicating faster and causing higher viral loads which in turn increases the various inflammatory triggers leading to increased disease severity and increased risk of mortality.
The study also found that visceral fat can also be viral reservoirs of the novel coronavirus.
The study findings were published in the peer reviewed journal: Nature Communications.
https://www.nature.com/articles/s41467-022-33218-8
Our results provide a mechanistic framework to help explain the exacerbated metabolic and inflammatory symptoms manifested by COVID-19 patients (Fig. 6). Early reports characterized hyperglycemia and poorly controlled blood glucose levels as risk factors of severe illness by COVID-19 4,9,33,34.
Confirming a possible role for adiponectin in COVID-19-related metabolic dysfunction, we observed a trend toward downregulation of adiponectin protein levels in subcutaneous adipose tissue cells infected with CoV-2(B) (q value = 0.06; Supplementary Data 1).
We also saw upregulation of genes encoding proinflammatory cytokines in visceral adipose tissue cells infected by SARS-CoV-2 [mainly the CoV-2(B) lineage], unveiling yet another potential underlying contributor to metabolic dysfunction in COVID-19 patients.
Indeed, visceral adipose tissue inflammation is one of the main determinants of type 2 diabetes in individuals with obesity 38,39. This is partly because the liver is in direct contact with visceral fat through the portal vein, which causes proinflammatory cytokines produced in the visceral adipose tissue to reach the liver at high levels and induce hepatic insulin resistance.
The systemic impact of such inhibition remains to be determined, considering that reports are conflicting regarding the levels of free fatty acids in COVID-19 patients41,42,43.
Although our in vitro model does not allow for a certain distinction of the cell types serving as the primary sites for SARS-CoV-2 infection and replication in adipose tissue, we speculate that adipocytes are likely a major site. We conclude that based on several reasons.
Firstly, we found adipocytes infected by SARS-CoV-2 in the adipose tissue of COVID-19 patients. Moreover, whereas there are considerable amounts of undifferentiated preadipocytes in our cell cultures, the culture is enriched with differentiated adipocytes and, as demonstrated by ref. 10 and ref. 8, undifferentiated preadipocytes are not infected by SARS-CoV-2.
These results are consistent with recent studies demonstrating that SARS-CoV-2 replication is favored in lipid-laden cells 5,10, further indicating that adipocytes are propitious sites for SARS-CoV-2 infection and propagation.
Macrophages are yet another potential site for SARS-CoV-2 replication in adipose tissue, although our in vitro model did not include these cells in relevant abundance. In a recent report, adipose tissue macrophages have also been found to bear SARS-CoV-2 and, along with infected adipocytes, promote adipose tissue inflammation and contribute to tissue dysfunction 8.
In addition to confirming the potential of SARS-CoV-2 to infect adipose tissue cells, here we demonstrate that visceral fat, which is more abundant in the population at greater risk for the severe illness from COVID-19 15,16,17,18, has cells that are more prone to SARS-CoV-2 infection and respond differently to the virus when compared to its subcutaneous counterpart.
We also show that, although significant cell death is observed in cells from both depots in response to SARS-CoV-2 infection, which could further exacerbate tissue dysfunction and inflammation and induce adipose tissue remodeling 11, visceral fat cells are intrinsically more susceptible to the viral infection, potentially serving as a more critical virus reservoir in COVID-19 patients.
Finally, we demonstrate that visceral adipose tissue cell infection by the ancient SARS-CoV-2 lineage leads to the downregulation of proteins involved in the interferon signaling pathway despite a pronounced induction of proinflammatory markers.
This is in sharp contrast with the response of visceral fat cells to the infection with the gamma variant, which leads to the upregulation of proteins involved in the interferon signaling pathway and results in a much milder induction of proinflammatory markers.
This finding corroborates the relevance of visceral adipose tissue infection in COVID-19 pathophysiology, considering that attenuation of viral pathogenicity is a common phenomenon in light of evolution 44.
In future studies, it would be interesting to compare the behavior of adipose tissue SARS-CoV-2 infection to other viruses that have been shown to infect fat cells (e.g., influenza A virus, human immunodeficiency virus, adenovirus) 45,46,47, as well as to investigate whether the way obesity influences the pathogenesis of infectious diseases other than COVID-19 (e.g., influenza)48,49 is also linked to the abundance of visceral vs. subcutaneous fat or the differential susceptibility to infection these fat depots may exhibit.
In summary, based on the data presented hitherto, we conclude that adipose tissue infection represents a relevant feature of COVID-19 and should be considered in all its complexity when evaluating the impact of different VOCs on disease pathogenesis and symptomatology.
