title: [6]-Gingerol Affects Glucose Metabolism by Dual Regulation via the AMPKα2-Mediated AS160-Rab5 Pathway and AMPK-Mediated Insulin Sensitizing Effects.
abstract: [6]-Gingerol has been used to control diabetes and dyslipidemia; however, its metabolic role is poorly understood. In this study, [6]-gingerol increased adenosine monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation in mouse skeletal muscle C2C12 cells. Stimulation of glucose uptake by [6]-gingerol was dependent on AMPKα2. Moreover, both Inhibition and knockdown of AMPKα2 blocked [6]-gingerol-induced glucose uptake. [6]-Gingerol significantly decreased the activity of protein phosphatase 2A (PP2A). Inhibition of PP2A activity with okadaic acid enhanced the phosphorylation of AMPKα2. Moreover, the interaction between AMPKα2 and PP2A was increased by [6]-gingerol, suggesting that PP2A mediates the effect of [6]-gingerol on AMPK phosphorylation. In addition, [6]-gingerol increased the phosphorylation of Akt-substrate 160 (AS160), which is a Rab GTPase-activating protein. Inhibition of AMPKα2 blocked [6]-gingerol-induced AS160 phosphorylation. [6]-gingerol increased the Rab5, and AMPKα2 knockdown blocked [6]-gingerol-induced expression of Rab5, indicating AMPK play as an upstream of Rab5. It also increased glucose transporter 4 (GLUT4) mRNA and protein expression and stimulated GLUT4 translocation. Furthermore, insulin-mediated glucose uptake and Akt phosphorylation were further potentiated by [6]-gingerol treatment. This potentiation was not observed in the presence of AMPK inhibitor compound C. In summary, our results suggest that [6]-gingerol plays an important role in glucose metabolism via the AMPKα2-mediated AS160-Rab5 pathway and through potentiation of insulin-mediated glucose regulation.
authors.affiliation: Department of Anatomy, Korea University College of Medicine, Seoul, Korea.
authors.forename: Jung Ok
authors.initials: JO
authors.lastname: Lee
authors.affiliation: Department of Anatomy, Korea University College of Medicine, Seoul, Korea.
authors.forename: Nami
authors.initials: N
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Korea University College of Medicine, Seoul, Korea.
authors.forename: Hye Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Anatomy, Korea University College of Medicine, Seoul, Korea.
authors.forename: Ji Wook
authors.initials: JW
authors.lastname: Moon
authors.affiliation: Department of Anatomy, Korea University College of Medicine, Seoul, Korea.
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Department of Anatomy, Korea University College of Medicine, Seoul, Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Korea University College of Medicine, Seoul, Korea.
authors.forename: Joong Kwan
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Korea University College of Medicine, Seoul, Korea.
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Anatomy, Korea University College of Medicine, Seoul, Korea.
authors.forename: Hyeon Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002396:Catechols / Q000494:pharmacology*; D002460:Cell Line; D004357:Drug Synergism; D005233:Fatty Alcohols / Q000494:pharmacology*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D002396:Catechols; D005233:Fatty Alcohols; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; C007845:gingerol; D055372:AMP-Activated Protein Kinases; D054648:Protein Phosphatase 2; D020696:rab5 GTP-Binding Proteins; D005947:Glucose
keywords: AMPK; DIABETES; INSULIN SENSITIZING; SIGNAL TRANSDUCTION; [6]-GINGEROL