Preventive effect of oleate on palmitate-induced insulin resistance in skeletal muscle and its mechanism of action

Insulin resistance in skeletal muscle is a feature associated with exposure to an excess of saturated fatty acids such as palmitate. Oleic acid has been shown to blunt palmitate-induced insulin resistance in muscle cells. However, there is no literature available regarding the effect of oleic acid on palmitate-induced insulin resistance in intact muscle. Therefore, this study investigated the effect of oleic acid on palmitate-induced insulin resistance in rat soleus muscle and its underlying mechanisms. For these purposes, oleic acid (1 mM) was administered for 12 h in the absence or presence of palmitate (2 mM). At the end of the experiment, plasmalemmal GLUT4, the phosphorylation of AS160 and Akt-2, and the total expression of these signaling proteins were examined. We found that treatment with palmitate for 12 h reduced insulin-stimulated GLUT4 translocation and the phosphorylation of AS160 and Akt-2. However, the administration of oleic acid fully restored insulin-stimulated GLUT4 translocation (P < 0.05), as well as AS160 and Akt-2 phosphorylation (P < 0.05) despite the continuous presence of palmitate. Wortmannin, an inhibitor of PI3-K, only slightly prevented the oleic acid-induced improvements in insulin-stimulated GLUT4 translocation, and AS160 phosphorylation. However, this treatment completely inhibited the oleic acid-induced improvement in insulin-stimulated Akt-2 phosphorylation. In contrast, the oleic acid-induced improvement in insulin signaling was not affected by compound C, an AMPK specific inhibitor. In conclusion, the results clearly indicate that oleic acid administration alleviates palmitate-induced insulin resistance by promoting GLUT4 translocation in muscle, at least in part, by activating the PI3K pathway.