Our study provides evidence that sitagliptin can effectively ameliorate the progression of obesity-induced insulin resistance and hepatic steatosis by suppressing inflammation, via regulating macrophage M1/M2 polarization and NF-κB and JNK/AP1 pathway, enhancing autophagy through the AMPK/mTOR signaling pathway in the liver. The gene discussed is NFKB1; the disease is obesity due to melanocortin 4 receptor deficiency.