FNDC4 and FNDC5 Attenuate SARS-CoV-2 S1-Induced Inflammatory Responses in Human Adipose Tissue

Adipose tissue is recognised as a SARS-CoV-2 reservoir and potential infection site. We herein characterised SARS-CoV-2 entry points in visceral (VAT) and subcutaneous (SAT) adipose tissue from people with obesity and determined whether the adipo-myokines FNDC4 and FNDC5 modulate SARS-CoV-2 spike glycoprotein subunit 1 (S1)-induced inflammation in adipocytes and macrophages.

Plasma concentrations of FNDC4, FNDC5 and angiotensin-converting enzyme 2 (ACE2) were measured in 183 participants with obesity and normal weight. Expression of SARS-CoV-2 host cell entry receptors was analysed in paired VAT and SAT biopsies (n = 121). The effects of FNDC4 and FNDC5 on S1-induced inflammatory responses were evaluated in vitro using human visceral adipocytes and THP-1-derived macrophages.

Obesity was associated with higher circulating ACE2 and increased expression of SARS-CoV-2 entry receptors (ACE2, CD147, DPP4 and neuropilin-1) in VAT, whereas plasma FNDC4 and FNDC5 levels were reduced. FNDC4, FNDC5 and ACE2 co-localised with macrophage populations in VAT, and FNDC4 and FNDC5 transcripts positively correlated with genes involved in viral entry and priming. Both adipo-myokines attenuated S1-induced M1 macrophage polarisation and HMGB1 secretion and reduced HMGB1 expression in adipocytes.

Reduced FNDC4 and FNDC5 levels in obesity may amplify SARS-CoV-2 S1-induced inflammatory responses in VAT macrophages and adipocytes.