Therefore, we aimed (i) to characterize the transcript levels of PIEZO1 in VAT in obesity and obesity-associated T2D together with its relationship with NLRP3, SWELL1 and caveolin 1 (CAV1), (ii) to explore the role of compression forces on the expression of PIEZO1 and key inflammation- and ECM-related factors, (iii) to analyze the impact of weight loss on the expression of Piezo1 in an animal model of diet-induced obesity (DIO) and (iv) to evaluate the effect of the adipocyte secretome from patients with obesity in the expression of PIEZO1 in THP-1-derived macrophages. This evidence concerns the gene LRRC8A and obesity due to melanocortin 4 receptor deficiency.