In the present study, we demonstrated that administration with trilobatin alleviated obesity-induced insulin resistance by decreasing the levels of fasting blood glucose and insulin, improving glucose tolerance, and these beneficial effects were associated with trilobatin ameliorating the defects of IRS1 and AKT phosphorylation, recovering the translocation of GLUT4 in ob/ob mice. The gene discussed is SLC2A4; the disease is obesity due to melanocortin 4 receptor deficiency.