(A) Fasting glucose (mean ± SEM, two-way repeated measures ANOVA), (B) Fasting insulin (mean ± SEM, two-way repeated measures ANOVA with Holm-Sidak post-hoc; *p<0.05, **p<0.005), and (C) glycosylated hemoglobin (HbA1c) at baseline (week 0; solid) and week 14 (striped) in WT and ERα KO mice provided 45% HFD (TestDiet 58V8)±17α-E2 (14.4 ppm) (mean ± SEM, two-way repeated measures ANOVA with Holm-Sidak post-hoc; **p<0.005). (D) Glucose tolerance testing (GTT; 1 mg/kg) (mean ± SEM, two-way repeated measures ANOVA with Holm-Sidak post-hoc; *p<0.05 between WT HFD and WT HFD+17α), and (E) GTT AUC during week 10 of the study (mean ± SEM, two-way ANOVA with Holm-Sidak post-hoc; *p<0.05). Age-matched, male WT, chow-fed (TestDiet 58YP) mice were also evaluated as a normal-weight reference group and the corresponding means are depicted as dashed gray lines. n = 9–10 (WT HFD), 8–10 (WT HFD+17α), 9–10 (KO HFD), 8–10 (KO HFD+17α), 12–15 (WT Chow).