Role of costimulation in obesity-induced adipose inflammation and insulin resistance: pro- or anti-inflammatory? (P3105)

Abstract

Abstract Activation of T cells is thought to play an increasingly important role in the pathogenesis of inflammation and insulin resistance in obesity and Type 2 diabetes. Costimulation is essential for amplification of the T cell response, with the co-stimulatory molecules CD80 and CD86 playing an important role in the pathogenesis of a variety of inflammatory diseases. In this study, we used CD80/CD86 double knockout (B7 KO) mice to investigate the involvement of these key molecules in diet-induced obesity (DIO) and insulin resistance. Wild-type (WT) and B7 KO mice were fed either high fat diet (HFD) or normal chow. After 12 weeks of HFD feeding, WT and B7 KO mice had similar weight gain. B7 KO mice had less epidydymal fat (1.31±0.04 g vs. 0.92±0.06 g for WT vs. B7 KO) which was confirmed by MRI measures. Despite less systemic T cell activation, insulin resistance was significantly worse in the B7 KO mice. B7 KO mice had decreased Treg content which was a result of both impaired development and proliferation. A defect in Treg cells conferred enhanced classical activation of macrophages in the adipose tissue. Adoptive transfer of Treg into B7 KO mice restored insulin sensitivity in B7 KO mice on HFD. Taken together, lack of B7-mediated costimulation results in impaired development and proliferation of Treg and enhanced adipose inflammation and insulin resistance. Our results suggest an essential role for B7 in maintaining Treg numbers in experimental DIO.