Loss of Estrogen Receptor alpha Signaling Leads to Insulin Resistance and Obesity in Young and Adult Female Mice

Background/Aims: There are important sex-related differences in the prevalence of obesity, type 2 diabetes mellitus and cardiovascular disease. Indeed, premenopausal women have a lower prevalence of these conditions relative to age-matched men. Estrogen participates in the modulation of insulin sensitivity, energy balance, and body composition. In this paper, we investigated the impact of estrogen signaling through estrogen receptor alpha (ER alpha) on systemic insulin sensitivity and insulin signaling in skeletal muscle. Methods: In 14- and 30-week-old female ER alpha knockout (ER alpha KO) mice and age-matched controls, we assessed insulin sensitivity by a euglycemic-hyperinsulinemic clamp and intraperitoneal glucose tolerance testing. Blood pressure was evaluated by tail cuff and telemetry. We studied ex vivo insulin-stimulated glucose uptake in skeletal muscle tissue, as well as insulin metabolic signaling molecule phosphorylation by immunoblotting and oxidative stress by immunostaining for 3-nitrotyrosine. Results: Body weight was higher in ER alpha KO mice at 14 and 30 weeks of age. At 30 weeks, intraperitoneal glucose tolerance testing and clamp results demonstrated impaired systemic insulin sensitivity in ER alpha KO mice. Insulin-stimulated glucose uptake in soleus was lower in ER alpha KO mice at both ages. The insulin receptor substrate 1/phosphatidylinositol 3-kinase association and the activation of protein kinase B were decreased in ER alpha KO mice, whereas immunostaining for 3-nitrotyrosine was increased. Conclusions: Our data demonstrate a critical age-dependent role for estrogen signaling through ER alpha on whole-body insulin sensitivity and insulin metabolic signaling in skeletal muscle tissue. These findings have potential translational implications for the prevention and management of type 2 diabetes mellitus and cardiovascular disease in women, who are at increased risk for these conditions. Copyright (C) 2012 S. Karger AG, Basel