Insulin resistance in macrophages results in a distinct metabolic profile promoting an M2-like phenotype affecting both acute and chronic innate immune responses (INM1P.430)

Abstract

Abstract Obesity and insulin resistance affects innate immune responses. In this study, we evaluated the role of insulin resistance on macrophage activation and metabolism and how these changes may affect acute inflammatory responses and sustained responses such as those regulating the gut microbiome. Herein we demonstrate that primary macrophages from mice exposed to high insulin concentration, either in vitro or in vivo in the model of High Fat Diet as well as macrophages from Akt2-/- mice or from mice lacking IGF1R from macrophages, develop insulin resistance as determined by defective glucose uptake in response to insulin. These macrophages obtained M2-like phenotype and acquired a distinct metabolic profile characterized by decreased glycolytic and increased oxidation capacity. Mice bearing insulin resistant macrophages exhibited reduced acute lung injury in response to polymicrobial sepsis, as evaluated using the Cecal Ligation and Puncture model. The intestinal microbiome was similar in Akt2-/-, LysMCre+/IGF1Rfl/fl and HFD-induced obese mice and differed from this of WT mice, suggesting that insulin resistant macrophages impact microbial flora composition. These data suggest that insulin resistance in macrophages promotes an M2-like phenotype and a distinct metabolic program affecting acute inflammatory responses and shaping the gut microbiome irrespective of the diet.