Both adipo-myokines attenuated S1-induced M1 macrophage polarisation and HMGB1 secretion and reduced HMGB1 expression in adipocytes.<h4>Conclusion</h4>Reduced FNDC4 and FNDC5 levels in obesity may amplify SARS-CoV-2 S1-induced inflammatory responses in VAT macrophages and adipocytes. Here, FNDC5 is linked to obesity due to melanocortin 4 receptor deficiency.