P283 SORTILIN DEFICIENCY IMPROVES HEPATIC AND ADIPOSE TISSUE INSULIN RESISTANCE AND INFLAMMATION IN DIET-INDUCED OBESITY

Abstract

Background and Aims: Sortilin is a trafficking molecule directing newly synthesized molecules from the trans-Golgi network to secretory pathways, endosomes, lysosomes or cell surface. Several of the molecules trafficked by sortilin, such as acidic sphingomyelinase (ASM) and sphingolipid activating proteins (SAPs), regulate the synthesis of ceramide, a major modulator of insulin signaling. We hypothesized that in sortilin mice, reduced hepatic ASM may improve insulin sensitivity and reduce steatosis in a diet-induced obesity (DIO) model. Methods: DIO and insulin resistance were induced by feeding high fat diet for 10 weeks to WT and sortilin mice. Results: Sortilin mice had significantly reduced body weight and visceral fat, despite similar food intake. Sortilin mice had better insulin tolerance test and displayed increased insulin signaling in both liver and adipose tissue as demonstrated by increased Akt phosphorylation. In accordance with the proposed role of sortilin in ASM trafficking, ASM activity in both liver and adipose tissue of sortilin mice was significantly reduced. Sortilin mice had almost no steatosis and a three-fold reduction in total hepatic triglyceride levels compared to WT mice. In addition, expression of proinflammatory cytokines was reduce in both livers and adipose tissue of sortilin. Looking at ceramide synthesis enzymes, we observed a significant reduction in ceramide synthase 6, which synthesizes long chain ceramides, in both liver and adipose tissue of sortilin. Conclusions: Sortilin deficiency induces a beneficial metabolic phenotype in DIO, with respect to both liver and adipose tissue, which may be mediated in part by reduced ASM activity and reduced ceramide levels.