Lack of Interleukin-1 Receptor I (IL-1RI) Protects Mice From High-Fat Diet–Induced Adipose Tissue Inflammation Coincident With Improved

OBJECTIVE—High-fat diet (HFD)-induced adipose tissue in-flammation is a critical feature of diet-induced insulin resistance (IR); however, the contribution of interleukin-1 receptor I (IL-1RI)-mediated signals to this phenotype has not been defined. We hypothesized that lack of IL-1RI may ameliorate HFD-induced IR by attenuating adipose tissue inflammation. RESEARCH DESIGN AND METHODS—Glucose homeostasis was monitored in chow- and HFD-fed wild-type (WT) and IL-1RI2/2 mice by glucose tolerance and insulin tolerance tests. Macrophage recruitment and cytokine signature of adipose tissue macrophages was evaluated. Insulin sensitivity and cytokine se-cretion from adipose explants was quantified. Cytokine secretion and adipocyte insulin sensitivity was measured in cocultures of WT or IL-1RI2/2 macrophages with 3T3L1 adipocytes. Synergistic effects of IL-1b with tumor necrosis factor (TNF)-a on inflamma-tion was monitored in WT and IL-1RI2/2 bone-marrow macro-phages and adipose explants. RESULTS—Lean and obese IL-1RI2/2 animals exhibited en-hanced glucose homeostasis by glucose tolerance test and insulin tolerance test. M1/M2 macrophage number in adipose tissue was comparable between genotypes; however, TNF-a and IL-6 secre-tion was lower from IL-1RI2/2 adipose tissue macrophages. IL-1RI2/2 adipose exhibited enhanced insulin sensitivity, elevated pAKT, lower cytokine secretion, and attenuated induction of phosphorylated signal transducer and activator of transcription 3 and suppressor of cytokine signaling molecule 3 after HFD. Cocul-ture of WT, but not IL-1RI2/2macrophages, with 3T3L1 adipocytes enhanced IL-6 and TNF-a secretion, reduced adiponectin secre-tion, and impaired adipocyte insulin sensitivity. TNF-a and IL-1b potently synergized to enhance inflammation in WT macrophages and adipose, an effect lost in the absence of IL-1RI. CONCLUSIONS—Lack of IL-1RI protects against HFD-induced IR coincident with reduced local adipose tissue inflammation, despite equivalent immune cell recruitment. Diabetes 60:1688