title: DMC (2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone) improves glucose tolerance as a potent AMPK activator.
abstract: OBJECTIVE
  We investigated the effect and regulatory mechanism of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) isolated from Cleistocalyx operculatus on metabolic parameters in myotubes, adipocytes and an obese mouse model.
  
  
  METHODS
  Myotubes and adipocytes were incubated with or without DMC. Glucose uptake, fatty acid oxidation, AMPK activation and adipocytes differentiation were investigated. To examine in vivo effect of DMC, 30mg/kg/day DMC was administered by oral gavage for 2weeks in high fat fed C57BL/6 male mice and intra-peritoneal glucose tolerance test was performed. In order to examine whether DMC directly activates AMPK, we performed cell free AMPK assay and surface plasmon resonance spectroscopy analysis.
  
  
  RESULTS
  DMC increases glucose uptake and fatty acid oxidation (FAO) in myotubes. Also, DMC inhibits adipocyte differentiation in 3T3-L1 cells. Interestingly, DMC stimulates phosphorylation of AMP-dependent protein kinase (AMPK) alpha subunit (T172) by directly binding to AMPK, which results in the activation of AMPK. Furthermore, DMC binds AMPK with a higher affinity than AMP. When AMPK was knocked down, the stimulatory effect of DMC on FAO and its inhibitory effect on adipogenesis were abolished. These results suggest that the effects of DMC were primarily mediated by AMPK activation. In addition, treating mice fed a high fat diet with DMC improved glucose tolerance and significantly increased FAO of the muscles.
  
  
  CONCLUSIONS
  DMC, as a novel AMPK activator, shows anti-diabetic effects in cell culture systems, such as myotubes and adipocytes, and in a diet-induced obese mouse model.
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Min
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Hyundong
authors.initials: H
authors.lastname: Song
authors.affiliation: Nanomol Inc. and Gil Hospital, Incheon 21565, Republic of Korea.
authors.forename: Cheol Soon
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Korea Bioactive Natural Material Bank, Research Institute of Pharmaceutical Sciences, Seoul National University College of Pharmacy, Seoul 08826, Republic of Korea.
authors.forename: Won Keun
authors.initials: WK
authors.lastname: Oh
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Chung
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. Electronic address: kspark@snu.ac.kr.
authors.forename: Kyong Soo
authors.initials: KS
authors.lastname: Park
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017667:Adipocytes / Q000187:drug effects; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D047188:Chalcones / Q000302:isolation & purification / Q000627:therapeutic use*; D020536:Enzyme Activators / Q000627:therapeutic use*; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000188:drug therapy*; D005951:Glucose Tolerance Test; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000187:drug effects; D009765:Obesity / Q000378:metabolism; D027842:Syzygium / Q000737:chemistry
chemical_list: C501649:2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone; D047188:Chalcones; D020536:Enzyme Activators; D005227:Fatty Acids; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: AMPK activator; Adipogenesis; DMC; Fatty acid oxidation; Obesity