Interferon-gamma induced adipose tissue inflammation is linked to endothelial dysfunction in type 2 diabetic mice

Interferon-gamma (IFN gamma) has previously been associated with immuno-mediated inflammation in diet-induced obesity and type 1 diabetes. This study sought to define the role of IFN gamma-induced adipose tissue inflammation in endothelial dysfunction in type 2 diabetes. We examined mesenteric adipose tissue (MAT) inflammation, and endothelial function of small mesenteric artery (SMA) in control mice (m Lepr(db)), diabetic mice (Lepr(db)), m Lepr(db) treated with IFN gamma, and Lepr(db) treated with anti-IFN gamma or anti-monocyte chemoattractant protein-1 (anti-MCP-1). mRNA and protein expression of IFN gamma and MCP-1 were increased in MAT of Lepr(db), accompanied by increased T-lymphocyte and macrophage infiltration. Anti-IFN gamma reduced MAT inflammatory cell infiltration and inflammatory cytokine expression in Lepr(db), while IFN gamma treatment showed the opposite effects in m Lepr(db). Acetylcholine (ACh)-induced vasorelaxation of SMA was impaired in Lepr(db) versus m Lepr(db), but sodium nitroprusside (SNP)-induced vasorelaxation was comparable. Both anti-IFN gamma and anti-MCP-1 improved endothelial function of Lepr(db), while IFN gamma treatment impaired endothelial function of m Lepr(db). Superoxide production was higher in both MAT and SMA of Lepr(db) mice, and anti-IFN gamma reduced MAT and SMA superoxide production. Macrophage accumulation in the adventitia of SMA, and mRNA expression of MCP-1 in SMA were increased in Lepr(db) and IFN gamma-treated m Lepr(db), but reduced in anti-IFN gamma treated Lepr(db). These findings suggest IFN gamma has a key role in the regulation of visceral adipose tissue inflammatory response and endothelial dysfunction in type 2 diabetes.