Male Mice Lacking Estrogen Receptor Beta Develop Obesity but Are Protected from Diet-Induced Insulin Resistance in Skeletal Muscle

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)