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

OBJECTIVE-High-fat diet (HFD)-induced adipose tissue inflammation 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-1RI(-/-)mice by glucose tolerance and insulin tolerance tests. Macrophage recruitment and cytokine signature of adipose tissue macrophages was evaluated. Insulin sensitivity and cytokine secretion from adipose explants was quantified. Cytokine secretion and adipocyte insulin sensitivity was measured in cocultures of WT or IL-1RI(-/-)macrophages with 3T3L1 adipocytes. Synergistic effects of IL-1 beta with tumor necrosis factor (TNF)-alpha on inflammation was monitored in WT and IL-1RI(-/-)bone-marrow macrophages and adipose explants. RESULTS-Lean and obese IL-1RI(-/-)animals exhibited enhanced glucose homeostasis by glucose tolerance test and insulin tolerance test. M1/M2 macrophage number in adipose tissue was comparable between genotypes; however, TNF-alpha. and IL-6 secretion was lower from adipose tissue macrophages. IL-1RI(-/-)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. Coculture of WT, but not EL-1RI(-/-)macrophages, with 3T3L1 adipocytes enhanced IL-6 and TNF-alpha secretion, reduced adiponectin secretion, and impaired adipocyte insulin sensitivity. TNF-alpha and 1L-1 beta 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 HE'D-induced IR coincident with reduced local adipose tissue inflammation, despite equivalent immune cell recruitment. Diabetes 60:16881698, 2011