In summary, our findings reveal that GC-inducible KLF9 in macrophages inhibits the expression of Il6, Ptgs2, Il10, Arg1, and Chil3, thereby inhibiting p65 and STAT3 binding to the promoter regions and expression of these target genes, subsequently leading to macrophage deactivation, increased lipogenesis, and reduced thermogenesis in adipocytes, ultimately leading to obesity. This evidence concerns the gene PTGS2 and obesity due to melanocortin 4 receptor deficiency.