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RSV-stimulating ER activation and glucose uptake OBJECTIVE Estradiol (E2) is known to modulate insulin sensitivity and consequently, glucose homeostasis. Resveratrol (RSV), an agonist of estrogen receptor (ER), has exerted antihyperglycemic effect in streptozotocin-induced type 1 diabetic rats in our previous study and also shown to improve insulin resistance in other reports. However, it remains unknown whether activation of ER is involved in the metabolic effects of RSV via insulin-dependent and independent mechanisms. RESEARCH DESIGN/METHODS AND RESULTS Here we show that RSV shifts the metabolic characteristics of rats on high cholesterol-fructose (HCF) diet towards those of rats on standard diet. RSV treatment increased insulin-stimulated whole body glucose uptake and steady-state glucose uptake of soleus muscle and liver in HCF-fed rats as well as enhanced membrane trafficking activity of glucose transporter 4 (GLUT 4) and increased phosphorylation of insulin receptor in insulin resistant soleus muscles. Interestingly, th