title: Xanthene derivatives increase glucose utilization through activation of LKB1-dependent AMP-activated protein kinase.
abstract: 5' AMP-activated protein kinase (AMPK) is a highly conserved serine-threonine kinase that regulates energy expenditure by activating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. Therefore AMPK activators are considered to be drug targets for treatment of metabolic diseases such as diabetes mellitus. To identify novel AMPK activators, we screened xanthene derivatives. We determined that the AMPK activators 9H-xanthene-9-carboxylic acid {2,2,2-trichloro-1-[3-(3-nitro-phenyl)-thioureido]-ethyl}-amide (Xn) and 9H-xanthene-9-carboxylic acid {2,2,2-trichloro-1-[3-(3-cyano-phenyl)-thioureido]-ethyl}-amide (Xc) elevated glucose uptake in L6 myotubes by stimulating translocation of glucose transporter type 4 (GLUT4). Treatment with the chemical AMPK inhibitor compound C and infection with dominant-negative AMPKa2-virus inhibited AMPK phosphorylation and glucose uptake in myotubes induced by either Xn or Xc. Of the two major upstream kinases of AMPK, we found that Xn and Xc showed LKB1 dependency by knockdown of STK11, an ortholog of human LKB1. Single intravenous administration of Xn and Xc to high-fat diet-induced diabetic mice stimulated AMPK phosphorylation of skeletal muscle and improved glucose tolerance. Taken together, these results suggest that Xn and Xc regulate glucose homeostasis through LKB1-dependent AMPK activation and that the compounds are potential candidate drugs for the treatment of type 2 diabetes mellitus.
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk, Republic of Korea.
authors.forename: Yonghoon
authors.initials: Y
authors.lastname: Kwon
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk, Republic of Korea.
authors.forename: Parkyong
authors.initials: P
authors.lastname: Song
authors.affiliation: NovaCell Technology Inc., Pohang, Kyungbuk, Republic of Korea.
authors.forename: Jong Hyuk
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk, Republic of Korea.
authors.forename: Jaewang
authors.initials: J
authors.lastname: Ghim
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk, Republic of Korea.
authors.forename: Dayea
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk, Republic of Korea.
authors.forename: Byungjun
authors.initials: B
authors.lastname: Kang
authors.affiliation: NovaCell Technology Inc., Pohang, Kyungbuk, Republic of Korea.
authors.forename: Taehoon G
authors.initials: TG
authors.lastname: Lee
authors.affiliation: Korea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
authors.forename: Jin-Ah
authors.initials: JA
authors.lastname: Kim
authors.affiliation: Korea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
authors.forename: Joong-Kwon
authors.initials: JK
authors.lastname: Choi
authors.affiliation: Department of Pharmaceutical Engineering, Pai Chai University, Daejeon, Republic of Korea.
authors.forename: In Kwon
authors.initials: IK
authors.lastname: Youn
authors.affiliation: Korea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
authors.forename: Hyeon-Kyu
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk, Republic of Korea.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Ryu
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism; D059305:Diet, High-Fat; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D014966:Xanthenes / Q000494:pharmacology*
chemical_list: D051275:Glucose Transporter Type 4; D014966:Xanthenes; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; C488755:Stk11 protein, rat; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose