The estrogen receptor is required and sufficient to maintain physiological glucose uptake in the mouse heart

Rationale: Estrogens attenuate cardiac hypertrophy and increase cardiac contractility via their cognate receptors ER and ER. Since female sex hormones enhance global glucose utilization and because myocardial function and mass are tightly linked to cardiac glucose metabolism we tested the hypothesis that expression and activation of the estrogen receptor (ER) might be required and sufficient to maintain physiological cardiac glucose uptake in the murine heart. Methods and Results: Cardiac glucose uptake quantified in vivo by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was strongly impaired in ovarectomized compared to gonadal intact female C57BL/6JO mice. The selective ER agonist 16-LE2 and the non-selective ER and ER agonist 17-estradiol completely restored cardiac glucose uptake in ovarectomized mice. Cardiac FDG uptake was strongly decreased in female ER knockout mice (ERKO) compared to wild type littermates. Biochemical assays, affymetrix cDNA array analysis, western blotting and immuno-staining of cardiac glucose transporters revealed a positive correlation of ER dependent cardiac FDG uptake with preserved cardiac glucose transporter-1 expression and micro-vascular localization. Conclusions: Systemic activation of the ER estrogen receptor is sufficient and its expression is required to maintain physiological glucose uptake in the murine heart, which is likely to contribute to known cardio-protective estrogen effects.

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