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Activation of Estrogen Receptor is Crucial for Resveratrol-stimulating Muscular Glucose Uptake via Both Insulin-dependent and Independent Pathways

¹Department of Life Science and Center for Healthy and Aging Research, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
²Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan
³Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan

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, the phosphorylated ER level in insulin-resistant soleus muscle was significantly elevated in rats with RSV treatment in both basal and euglycemic hyperinsulinemic conditions. RSV exerted insulin-like stimulatory effect on isolated soleus muscle, epididymal fat and hepatic tissue and C2C12 myotubes. The RSV-stimulated glucose uptake in C2C12 myotubes was depended on Erk/p38 (early phase, 1 hr) and p38/PI3k (late phase, 14 hrs) activation respectively. Inhibition of ER abrogated RSV-induced glucose uptake in both early and late phases.

CONCLUSIONS: Collectively, these results indicate that ER is a key regulator in RSV-stimulating insulin-dependent and independent glucose uptake which might account for the protective effects of RSV on diet-induced insulin resistance syndrome.

Key Words: estrogen receptor • high cholesterol-fructose diet • insulin resistance • glucose transporter • resveratrol

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