AMP-Activated Protein Kinase의 근육 세포 내 활성 조절 기작 및 기능에 관한 연구

Abstract

AMP-activated protein kinase (AMPK) is an energy sensing enzyme that plays an important role in the regulation of glucose and lipid metabolism and thus has been of great interest as a therapeutic target for the treatment of metabolic disorders. Many natural compounds have been shown to exhibit distinct biological functions despite the fact that their mechanisms of action are not well known. Recently, a number of bio-active natural compounds, which have been studied as potential drug target in health and disease, have been found to have beneficial effects on metabolic function through the actions of AMPK First, I report that honokiol exerts its metabolic effect on insulin signaling through the activation of AMPK in skeletal muscle cells. Previously, honokiol, an active component purified from the magnolia plant, was known to have potent anti-inflammatory, anti-oxidant, anti-angiogenic and anti-tumor properties. In this study, I found that honokiol increased AMPK phosphorylation in a LKB-dependent manner. Honokiol also increased p38 MAPK activity. Pharmacological inhibition of either AMPK or p38 MAPK significantly blocked honokiol-mediated glucose uptake, suggesting the involvement of AMPK and p38 MAPK in honokiol-mediated signaling. In particular, insulin-mediated Akt phosphorylation and Glut4 translocation were further increased in the presence of honokiol. In addition, honokiol decreased high glucose-induced O-GlcNAc modification of insulin-mediated IRS-1 and Akt. In contrast, insulin-stimulated phosphorylation of IRS-1 and Akt was increased. Furthermore, honokiol inhibits glutamine:fructose-6-phosphate amidotransferase (GFAT) enzyme activity through AMPK-mediated direct phosphorylation. Taken together, these findings suggest that honokiol has a beneficial metabolic effect on insulin signaling and glucose uptake in skeletal muscles through AMPK activation.Next, I report that curcumin activates AMPK in rat L6 myotubes and also increases glucose uptake in rat L6 myotubes. The hypoglycemic function of curcumin has also been well established. However, the biological functions of curcumin, as well as the molecular mechanisms exploited within the skeletal muscles, remains largely unclear. In this study, I found that curcumin activates mitogen-activated protein kinase kinase (MEK)3/6-p38 mitogen-activated protein kinase (MAPK) signaling pathways in the downstream of the AMPK cascade. Moreover, the inhibition of either AMPK or p38 MAPK resulted in the blockage of curcumin-induced glucose uptake. Furthermore, the administration of curcumin to mice increased AMPK phosphorylation in the skeletal muscles. Taken together, these results indicate that the hypoglycemic effect of curcumin can be explained by its ability to activate AMPK-p38 MAPK pathways in the skeletal muscles.In conclusion, these results may provide important clues for better understanding of the metabolic function of these natural compounds in muscle cells.