ACE2 expression in adipose tissue is associated with COVID-19 cardio-metabolic risk factors and cell type composition

Abstract

COVID-19 severity has varied widely, with demographic and cardio-metabolic factors increasing risk of severe reactions to SARS-CoV-2 infection, but the underlying mechanisms for this remain uncertain. We investigated phenotypic and genetic factors associated with subcutaneous adipose tissue expression of Angiotensin I Converting Enzyme 2 (ACE2), which has been shown to act as a receptor for SARS-CoV-2 cellular entry. In a meta-analysis of three independent studies including up to 1,471 participants, lower adipose tissue ACE2 expression was associated with adverse cardio-metabolic health indices including type 2 diabetes (T2D) and obesity status, higher serum fasting insulin and BMI, and lower serum HDL levels (P<5.32x10-4). ACE2 expression levels were also associated with estimated proportions of cell types in adipose tissue; lower ACE2 expression was associated with a lower proportion of microvascular endothelial cells (P=4.25x10-4) and higher macrophage proportion (P=2.74x10-5), suggesting a link to inflammation. Despite an estimated heritability of 32%, we did not identify any proximal or distal genetic variants (eQTLs) associated with adipose tissue ACE2 expression. Our results demonstrate that at-risk individuals have lower background ACE2 levels in this highly relevant tissue. Further studies will be required to establish how this may contribute to increased COVID-19 severity.

Diabetes, obesity, metabolism, and SARS-CoV-2 infection: the end of the beginning

“…Despite the contention that ACE2 expression may be upregulated in white adipose tissue (WAT), enabling WAT to serve as a functional reservoir for SARS-CoV-2 in obese individuals ( Ledford, 2020 ), data supporting this hypothesis are limited ( Figure 4 ). Gene expression profiles from 1,471 male and female individuals (ages 35–85) across three human datasets demonstrated lower ACE2 expression in subcutaneous WAT from individuals with obesity or T2D relative to control subjects ( El-Sayed Moustafa et al., 2020 ). Notably, expression of ACE2 and TMPRSS2 was relatively low in subcutaneous WAT and ACE2 expression was higher with increasing age.…”

Pathways to Severe COVID‐19 for People with Obesity

“…ACE2 expression is high in adipose relative to other tissues (60) and adipocyte expression of ACE2 is upregulated in obesity and DM. Increased expression of ACE2 in adipose tissue has been linked to worse clinical outcomes of COVID‐19 (61,62). In summary, these observations suggest a potential mechanism for SARS‐CoV‐2 viral adipotropy.…”

The Impact of Angiotensin-Converting Enzyme 2 (ACE2) Expression on the Incidence and Severity of COVID-19 Infection

“…This could be explained by an imbalance in the RAAS system secondary to obesity [ 59 ], and possibly linked to robust systemic response secondary to SARS-CoV-2 infection. Recent meta-analysis showed that individuals with lower level of ACE2 expression in adipose tissue are more likely to be associated with type 2 diabetes mellitus, cardiovascular comorbidities, metabolic syndrome, and a higher body mass index, which are all risk factors of severe COVID-19 [ 60 ].…”