Vitamin D3 has been found to produce therapeutic effects on obesity-associated insulin resistance and dyslipidemia through its potent anti-inflammatory activity,but the precise immunomodulatory mechanism remains poorly understood.In the present study we found that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3],the biologically active form of vitamin D3,significantly attenuated monosodium glutamate (MSG)-induced obesity and insulin resistance as indicated by body weight reduction,oral glucose tolerance improvement,and a glucose infusion rate increase as detected with hyperinsulinemiceuglycemic clamp.Moreover,1,25(OH)2D3 not only restored pancreatic islet functions but also improved lipid metabolism in insulin-targeted tissues.The protective effects of 1,25(OH)2D3 on glycolipid metabolism were attributed to its ability to inhibit an obesity-activated inflammatory response in insulin secretory and targeted tissues,as indicated by reduced infiltration of macrophages in pancreas islets and adipose tissue while enhancing the expression of Tgf-β1 in liver tissue,which was accompanied by increased infiltration of Treg cells in immune organs such as spleen and lymph node as well as in insulintargeted tissues such as liver,adipose,and muscle.Together,our findings suggest that 1,25(OH)2D3 serves as a beneficial immunomodulator for the prevention and treatment of obesity or metabolic syndrome through its anti-inflammatory effects.