1727-P: Mice Deficient in Myeloid Cell-Derived Interleukin-1a Are Protected from Diet-Induced Obesity and Insulin Resistance

Interleukin (IL)-1α is a major mediator of inflammation, and functional polymorphism of IL-1α is associated with human obesity. We have recently generated mice with genetic ablation of IL-1α selectively in myeloid cells. On chow diet, Lyz-IL-1α KO mice showed normal metabolic phenotypes. In contrast, when male Lyz-IL-1α KO mice were fed a high-fat diet (HFD), whole body fat mass was markedly reduced in these mice (Figure 1; *P<0.05). Metabolic cage study found that this was mostly due to a 2-fold increase in physical activity in Lyz-IL-1α KO mice (Figure 2). Food intake and energy expenditure were not affected in these mice. We performed a hyperinsulinemic-euglycemic clamp to measure insulin sensitivity in awake mice (n=7). HFD-fed Lyz-IL-1α KO mice were more insulin sensitive than HFD-fed wild type (WT) mice with a 2-fold increase in glucose infusion rates (Figure 3). Whole body glucose turnover and glycolysis were significantly increased in HFD-fed Lyz-IL-1α KO mice (Figure 3). Basal hepatic glucose production (HGP) was not altered, but clamp HGP was reduced by 40% in Lyz-IL-1α KO mice. As a result, hepatic insulin action was markedly increased in HFD-fed Lyz-IL-1α KO mice (Figure 4).

In conclusion, these results indicate that Lyz-IL-1α KO mice are protected from diet-induced obesity and insulin resistance, and our findings identify IL-1α as a novel therapeutic target in obesity and type 2 diabetes.

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