Augmenting Skeletal Muscle Estrogen Does not Prevent or Rescue Obesity-linked Metabolic Impairments in Female Mice

Abstract Aims We developed a novel mouse model with increased skeletal muscle estrogen content via inducible, skeletal-muscle–specific aromatase overexpression (SkM-Arom↑). We proposed to examine the effect that increased skeletal muscle estrogen both in gonadally intact and ovariectomized (OVX) female mice has on preventing or rescuing high-fat diet (HFD)-induced obesity. Methods In the prevention experiment, gonadally intact and OVX SkM-Arom↑ mice and littermate controls were fed a low-fat diet (LFD) or HFD for 13 weeks. SkM-Arom↑ was induced at the initiation of dietary treatment. In the intervention experiment, gonadally intact and OVX SkM-Arom↑ mice and littermate controls were fed an HFD for 14 weeks before induction of SkM-Arom↑ for 6 weeks. Glucose tolerance, insulin action, adipose tissue inflammation, and body composition were assessed. Liquid chromatography–mass spectrometry was used to determine circulating and skeletal muscle steroid content. Results SkM-Arom↑ significantly increased skeletal muscle 17β-estradiol (E2) and estrone (E1) in both experiments. Interestingly, this resulted in leakage of estrogens into circulation, producing a physiologically relevant E2 concentration. Consequently, bone mineral density (BMD) was enhanced and adipose tissue inflammation was reduced in the prevention experiment only. However, no benefits were seen with respect to changes in adiposity or metabolic outcomes. Conclusion We show that increasing skeletal muscle estrogen content does not provide a metabolic benefit in gonadally intact and OVX female mice in the setting of obesity. However, a chronic physiological concentration of circulating E2 can improve BMD and reduce adipose tissue inflammation independently of a metabolic benefit or changes in adiposity.