Here, we discovered a previously unrecognized role of adipocytes in the inflammatory activation of adipose-resident immune cells to promote obesity-associated chronic inflammation and metabolic disorders, which is mediated through β2 microglobulin (B2M)-dependent mechanisms involving major histocompatibility complex class I (MHC-I) antigen presentation and iron transport. This evidence concerns the gene HLA-G and obesity due to melanocortin 4 receptor deficiency.