Myricetin Ameliorates Defective Post-Receptor Insulin Signaling viaβ-Endorphin Signaling in the Skeletal Muscles of Fructose-Fed Rats

摘要

β-Endorphin plays a major role in the amelioration of insulin resistance. The present study documents that myricetin (3,5,7,3′,4′,5′-hexahydroxyflavone) ameliorates insulin resistance by enhancingβ-endorphin production in insulin-resistant rats. The rats were induced for insulin resistance by feeding them a diet containing 60% fructose for 6 weeks. The degree of insulin resistance was measured by the homeostasis model assessment of basal insulin resistance (HOMA-IR). The plasma levels of insulin andβ-endorphin were measured by an enzyme-linked immunosorbent assay. The insulin receptor-related signaling mediators in the soleus muscles of rats were evaluated by immunoprecipitation or immunoblotting. Myricetin was injected daily (1 mg kg−1per injection, thrice daily) for 14 days. Consequently, the high-glucose plasma levels in fructose-fed rats decreased significantly concomitant with an increase in plasmaβ-endorphin. The reduction of the elevated HOMA-IR index following treatment with myricetin was subsequently inhibited by the administration ofβ-funaltrexamine hydrochloride (β-FNA) at doses sufficient to blockμ-opioid receptors (MOR). The myricetin treatment was also observed to affect the phosphorylation of the insulin receptor, insulin receptor substrate-1, Akt and Akt substrate of 160 kDa, with subsequent effects on glucose-transporter subtype 4 translocation, all of which were blocked byβ-FNA pretreatment. These results indicated that enhancement ofβ-endorphin secretion, which in turn leads to peripheral MOR activation, is involved in the action of myricetin on the amelioration of impaired signaling intermediates downstream of insulin receptors.