The main findings of our study are that: (i) obesity and T2D increase gene expression levels of PIEZO1 in VAT being associated with SWELL1 and key markers of inflammation, (ii) a static compression of VAT explants promotes an upregulation of PIEZO1 together with a robust inflammatory response, and (iii) the secretome of adipocytes from patients with obesity upregulates PIEZO1 levels in THP-1-derived macrophages. Here, PIEZO1 is linked to obesity due to melanocortin 4 receptor deficiency.