Visfatin, a novel adipokine, stimulates glucose uptake through the Ca2+-dependent AMPK-p38 MAPK pathway in C2C12 skeletal muscle cells

Abstract

Visfatin is a novel adipocytokine produced by visceral fat. In the present study, visfatin increased AMP-activated protein kinase (AMPK) phosphorylation in mouse C2C12 skeletal muscle cells. It also increased phosphorylation of the insulin receptor, whose knockdown blocked visfatin-induced AMPK phosphorylation and glucose uptake. Visfatin stimulated glucose uptake in differentiated skeletal muscle cells. However, inhibition of AMPK alpha 2 with an inhibitor or with knockdown of AMPK alpha 2 using siRNA blocked visfatin-induced glucose uptake, which indicates that visfatin stimulates glucose uptake through the AMPK alpha 2 pathway. Visfatin increased the intracellular Ca2+ concentration. STO-609, a calmodulin-dependent protein kinase kinase inhibitor, blocked visfatin-induced AMPK phosphorylation and glucose uptake. Visfatin-mediated activation of p38 MAPK was AMPK alpha 2-dependent. Furthermore, both inhibition and knockdown of p38 MAPK blocked visfatin-induced glucose uptake. Visfatin increased glucose transporter type 4 (GLUT4) mRNA and protein levels. In addition, visfatin stimulated the translocation of GLUT4 to the plasma membrane, and this effect was suppressed by AMPK alpha 2 inhibition. The present results indicate that visfatin plays an important role in glucose metabolism via the Ca2+-mediated AMPK-p38 MAPK pathway.