Interferon-gamma (IFN) is the hallmark cytokine of Th1 cells and plays a major role in immuno-mediated inflammation in type 1 diabetes. However, the role of IFN in initiating adipose inflammation and subsequent vascular dysfunction in type 2 diabetes remains to be determined. Accordingly, we hypothesized that IFN induces inflammatory cell infiltration and chemoattractant gene expression in mesenteric adipose tissue (MAT) and impairs vascular function of small mesenteric arteries (MA) of type 2 diabetic mice. To test this, we studied MAT inflammation, and vascular function of MA in control mice (m Lepr db ), diabetic mice (Lepr db ), m Lepr db treated with IFN, Lepr db treated with anti-IFN or anti-monocyte chemoattractant protein (MCP)-1. Acetylcholine (ACh)-induced vasodilation was impaired in Lepr db vs. m Lepr db , but sodium nitroprusside (SNP)-induced vasodilation was comparable. Both anti-IFN and anti-MCP-1 improved endothelial function in Lepr db , while IFN induced impaired vascular function in m Lepr db . Mesenteric bed weight and MAT adipocyte size were greatly elevated (P<0.05) in Lepr db vs. m Lepr db . Immunohistochemical staining results revealed that CD3-positve T-lymphocytes, F4/80 and Mac-3 positive macrophage infiltration into MAT was markedly increased in Lepr db and IFN-treated m Lepr db . It showed reduced MAT macrophages infiltration in Lepr db treated with anti-IFN vs. Lepr db . Interestingly, Mac-3 positive macrophage infiltration into the adventitia of small mesenteric arteries was significantly increased in Lepr db and IFN-treated m Lepr db , suggesting the possible crosstalk between adipose inflammation and vascular dysfunction. Western blotting results showed that anti-IFN decreased MAT IFN and MCP-1 protein expression in Lepr db , while IFN and MCP-1 expression was elevated in IFN-treated m Lepr db . Anti-MCP-1 treatment only decreased MCP-1 expression in Lepr db without affecting IFN levels, indicating that IFN may act as an initiator of MAT inflammation and chemoattractant gene expression. These results suggest a role for IFN in the regulation of visceral adipose inflammatory response and vascular dysfunction in type 2 diabetes. This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).