Genistein Enhances GLUT4 Expression and Translocation in the Gastrocnemius Muscle and Improves Systemic Glucose Metabolism in Ovariectomized Mice

<b>Background</b>: Premenopausal women typically exhibit superior glucose metabolism compared to males, but this metabolic advantage is lost after menopause. The primary cause is the sharp decline in estrogen levels post-menopause. Genistein, a natural compound predominantly derived from leguminous plants, possesses structural similarity to estrogen. This enables specific binding to estrogen receptors, allowing genistein to exert estrogen-mimicking effects under conditions of estrogen deficiency. The aim of this study was to investigate the effects and potential mechanisms of genistein on glucose metabolism in the liver and skeletal muscle of ovariectomized (OVX) mice fed a high-fat diet (HFD). <b>Methods</b>: Animal experiments were performed using 8-week-old mice that were OVX to construct a model of estrogen deficiency and impaired their glucose metabolism by a continuous HFD. Genistein was administered by gavage (50 mg/kg-day) for 10 weeks and 17β-estradiol was administered subcutaneously (50 μg/kg) every 4 days for 10 weeks as a positive control. <b>Results</b>: Genistein significantly improved glucose metabolism (including fasting glucose, postprandial glucose, serum glucose levels, and HOMA-IR index) but did not affect serum estrogen levels and uterine weights in OVX mice. Genistein promoted increased expression and translocation of glucose transporter 4 (GLUT4) in the gastrocnemius muscle, enhanced phosphorylation of the PI3K/AKT pathway, and upregulated expression of the G protein-coupled estrogen receptor (GPER). Concurrently, it stimulates hepatic glycogen accumulation and upregulates GLUT2 expression in the liver. <b>Conclusions</b>: GEN improves glucose metabolism in ovariectomized mice, and this improvement is primarily attributed to increased expression and membrane translocation of GLUT4 in the gastrocnemius muscle mediated by the GPER-PI3K/AKT pathway.