Furthermore, studies in rodents have further confirmed the link between IL-1Ra and insulin resistance. In a short five day study, administration of IL-1Ra led to a decrease in whole body insulin sensitivity in rats while whole body deletion of IL-1Ra significantly improved insulin sensitivity in mice. However, the IL-1Ra whole body KO mouse is particularly lean which raises the possibility that the complete absence of IL-1Ra from birth may cause growth or sickness issues. Taken together, these results provide a strong link between IL-1Ra and insulin action but to better define the role of IL-1Ra in vivo, in the present study we investigated the hypothesis that normalization of IL-1Ra would improve insulin sensitivity. To address this hypothesis we used antisense oligonucleotides to knock down both the secreted and intracellular forms of IL-1Ra in high fat diet -fed obese mice. Overall our studies show that reduction of IL-1Ra levels improves hepatic insulin sensitivity. Differences in body Atorvastatin Calcium weight and the degree of obesity strongly impact insulin action. An important finding was that in HFD-fed mice, IL-1Ra ASO treatment not only improved insulin action, but also reduced body weight by,10% after 6 weeks of treatment. Thus, it is possible that improvement in insulin sensitivity in IL1Ra ASO-treated mice was simply due to the lower body weight. To address this confounding variable we performed detailed measurements of whole-body and tissue specific insulin action using hyperinsulinemic-euglycemic clamps in body weight matched mice using the lighter control ASO treated mice and Aminoguanidine heavier IL-1Ra ASO treated mice in the cohort. Significantly, our results revealed that the improvements in whole-body insulin sensitivity were independent of changes in body weight. In addition, these improvements were due to significantly enhanced hepatic insulin sensitivity, with no improvements in muscle or adipose insulin sensitivity. Furthermore, inflammatory gene expression and triglyceride levels were also significantly and specifically reduced in the liver of IL-1Ra ASO treated mice compared with control treated HFD mice.