Abstract 11414: Transplantation of Epididymal Adipose Tissue from Mice with Myeloid Deletion of RAGE Induces Insulin Resistance in Wild-Type Mice

Abstract

Introduction: Obesity is a major global health problem and often associated with insulin resistance (IR). Our previous work showed that global and adipose tissue specific Ager deletion provide protection from HFD induced weight gain and insulin resistance. We identified that myeloid-specific of Ager deletetion (MDR) further impairs insulin sensitivity in mice fed HFD without further increasing body weight vs. control animals. These effects of myeloid Ager deletion were reversed upon simultaneous deletion of adipocyte Ager in HFD feeding. In parallel, the expression of inflammatory genes was significantly higher in the epididymal adipose tissue (eWAT) of MDR vs. all other mice groups. We tested the hypothesis that eWAT-borne factors from mice bearing myeloid Ager deletion induce IR upon transplantation to wild-type mice fed low fat chow. Methods: We generated mice with myeloid-specific (MDR) LyzMCre(+/+).Ager flox/flox and adipocyte and myeloid-specific (Double Knockouts (KO)) AdipoQCre(-/+)LyzMCre(+/+).Ager flox/flox deletion of Ager and LysMCre mice (Cre control) were used as control. Mice were fed HFD (60% kcal/fat) for 3 months starting at age 6 weeks. Mice were assessed for body mass and glucose and insulin sensitivities. After 12 weeks of HFD feeding, eWAT from these HFD fed mice was transplanted into C57BL/6 (WT) mice. The transplanted recipient mice were maintained on a low fat diet and their body mass, blood glucose and insulin sensitivity were monitored. Results: 6 weeks after eWAT transplantation into WT mice, only the WT low fat diet-fed recipients of MDR eWAT displayed IR in comparison to recipients of Cre control or Double KO eWAT. Despite no difference in the body weight, native eWAT adipocyte size was significantly higher in the recipients of MDR eWAT vs. all other groups. Differences in F4/80-positive crown like structures were also observed in native recipient eWAT, which might underlie mechanisms of IR. Conclusion: Transplantation of eWAT from mice devoid of myeloid Ager and previously fed HFD confers IR to low fat diet WT mice. The molecular mechanisms mediating these effects are under investigation.