ABSTRACT Background 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. Methods 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. Results 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. Conclusion Reduced FNDC4 and FNDC5 levels in obesity may amplify SARS‐CoV‐2 S1‐induced inflammatory responses in VAT macrophages and adipocytes.
Neira et al. (2026) studied this question.