Activation of estrogen receptor is crucial for resveratrol-stimulating muscular glucose uptake via both insulin-dependent and -independent pathways.
OBJECTIVE
Estradiol (E(2)) is known to modulate insulin sensitivity and, consequently, glucose homeostasis. Resveratrol (RSV), an agonist of estrogen receptor (ER), has exerted antihyperglycemic effects in streptozotocin-induced type 1 diabetic rats in our previous study and was 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.


METHODS
Male Sprague-Dawley rats were given a high cholesterol-fructose (HCF) diet for 15 weeks and were treated with RSV for either 15 days or 15 weeks.


RESULTS
Here, we show that RSV shifts the metabolic characteristics of rats on an HCF diet toward those of rats on a 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 GLUT4 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 an 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 dependent on extracellular signal-related kinase/p38 (early phase, 1 h) and p38/phosphoinositide 3-kinase (late phase, 14 h) activation. 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.
Deng
Jen-Ying
JY
Department of Life Science and Center for Healthy and Aging Research, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Hsieh
Po-Shiuan
PS
Huang
Jiung-Pang
JP
Lu
Long-Sheng
LS
Hung
Li-Man
LM
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D003847:Deoxyglucose / Q000378:metabolism; D004040:Dietary Carbohydrates / Q000494:pharmacology; D005632:Fructose / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
D000975:Antioxidants; D002791:Cholesterol, Dietary; D004040:Dietary Carbohydrates; D007328:Insulin; D011960:Receptors, Estrogen; D013267:Stilbenes; D005632:Fructose; D003847:Deoxyglucose; D005947:Glucose; D000077185:Resveratrol