Furthermore, preclinical and clinical findings indicate that MetS and obesity promote the polarization of macrophages from a reparative anti-inflammatory M2 phenotype to a pro-inflammatory M1 phenotype, leading to the secretion of substantial quantities of cytokines and mediators, including TNF-ɑ, IL-6, interleukin-2, and interleukin-1, which exacerbate synovitis and cartilage degradation54–56. Here, TNF is linked to obesity due to melanocortin 4 receptor deficiency.