Xanthene derivatives increase glucose utilization through activation of LKB1-dependent AMP-activated protein kinase

• Published in: PloS one 2014-09, Vol.9 (9), p.e108771-e108771
• Main Authors: Kwon, Yonghoon, Song, Parkyong, Yoon, Jong Hyuk, Ghim, Jaewang, Kim, Dayea, Kang, Byungjun, Lee, Taehoon G, Kim, Jin-Ah, Choi, Joong-Kwon, Youn, In Kwon, Lee, Hyeon-Kyu, Ryu, Sung Ho
• Format: Article
• Language: English
• Subjects: Activation; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; Animals; Carboxylic acids; Cell Line; Derivatives; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - enzymology; Diabetes Mellitus, Experimental - metabolism; Diet, High-Fat; Drug development; Drugs; Energy conservation; Energy expenditure; Enzyme Activation; Fatty acids; Glucose; Glucose - metabolism; Glucose tolerance; Glucose transporter; Glucose Transporter Type 4 - metabolism; High fat diet; Homeostasis; Intravenous administration; Kinases; Life sciences; LKB1 protein; Male; Medical treatment; Medicine and Health Sciences; Metabolic disorders; Metabolism; Mice; Mice, Inbred C57BL; Muscles; Musculoskeletal system; Myotubes; Oxidative stress; Phosphorylation; Protein Transport; Protein-Serine-Threonine Kinases - metabolism; Protein-serine/threonine kinase; Proteins; Rats; Rodents; Skeletal muscle; Threonine; Translocation; Viruses; Xanthene; Xanthenes - pharmacology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0108771

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.