Estrogen has an important role in regulating female metabolism. Whereas the role of estrogen receptor (ER) α on female reproductive system is well defined, the role of ERβ (encoded by Esr2) remains unclear. Here we examined the metabolic effects of high-fat diet (HFD) in male Esr2-/- mice on BALB/c background (n=8∼9). After 6 weeks of HFD, Esr2-/- mice became more obese than wild type (WT) mice (Figure 1; *P<0.05). Surprisingly, metabolic cage study showed significantly increased energy expenditure in Esr2-/- mice, likely resulting from skeletal muscle as lean mass tended to be higher in these mice (Figure 2). We performed a hyperinsulinemic-euglycemic clamp to measure insulin sensitivity in awake mice. Despite being more obese, HFD-fed Esr2-/- mice tended to show increased insulin sensitivity with 20% increases in whole body glucose turnover and glycolysis (Figure 3). This was mostly due to a significant increase (52%) in skeletal muscle glucose uptake in HFD-fed Esr2-/- mice (Figure 4). Interestingly, glucose uptake into brown fat tended to be reduced by 50% in HFD-fed Esr2-/- mice. In conclusion, these results indicate that deletion of Esr2 in male mice increases diet-induced obesity, but selectively prevents muscle insulin resistance. Our findings implicate a potential therapeutic role of estrogen signaling to treat insulin resistance. Disclosure R.H. Friedline: None. H. Noh: None. S. Suk: None. C. Goral: None. K.A. Dunphy: None. A.L. Roberts: None. D.A. Tran: None. L.A. Tauer: None. X. Hu: None. L.H. Kim: None. A.M. Kim: None. D. Jerry: None. J.K. Kim: None. Funding National Institutes of Health (5U2CDK093000)
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. Disclosure S. Suk: None. R.H. Friedline: None. H. Noh: None. X. Hu: None. D.A. Tran: None. L.A. Tauer: None. A.M. Kim: None. L.H. Kim: None. J.K. Kim: None. Funding National Institutes of Health (5U2CDK093000)
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