Objective To study the regulatory role of macrophage MED1 in the development of insulin resistance. Methods Eight-week-old and specific-pathogen-free male macrophage-specific MED1 knockout(MED1^ΔMac)and wild-type (MED1^{fl/ fl}) mice were used in this animal model study. Mice were fed a high-fat diet (HFD) for 0, 4, 8, 12, 16, 20 weeks to induce obesity and insulin resistance. Body weight, total triglyceride, total cholesterol and blood glucose were dynamically monitored every 4 weeks. Hematoxylin-eosin ( HE ) staining was used to observe liver and adipose histopathology after an HFD for 20 weeks. Results After an HFD regime, the body weight increase of MED1^ΔMac mice tended to be greater than that of the MED1^{fl/ fl} control group. The blood glucose of MED1^ΔMac mice increased significantly (P< 0. 01) compared with that of MED1^{fl/ fl} mice after an HFD for 20 weeks. Compared with the MED1^{fl/ fl} mice, the liver weight, subcutaneous fat weight and visceral fat weight of MED1^ΔMac mice also showed a tendency to increase. In addition, the hepatic steatosis was more severe in MED1^ΔMac mice than in MED1^{fl/ fl} mice. Furthermore, a glucose tolerance test (GTT) and insulin tolerance test (ITT) showed no significant difference in glucose tolerance or insulin sensitivity between the two groups. Conclusions Deficiency of macrophage MED1 promoted an increase in blood glucose levels but had no obvious effect on insulin resistance, suggesting macrophage MED1 has a key regulatory role in glucose metabolism.