title: Therapeutic potential of panduratin A, LKB1-dependent AMP-activated protein kinase stimulator, with activation of PPARα/δ for the treatment of obesity.
abstract: OBJECTIVE
  AMP-activated protein kinase (AMPK) activators have shown potential as therapeutic agents for metabolic disorders. This study was conducted to evaluate therapeutic potential of panduratin (PAN) A, a natural AMPK stimulator, with activation of PPARα/δ for the treatment of obesity.
  
  
  METHODS
  We used the novel AMPK activator PAN A, a natural compound isolated from Boesenbergia pandurata rhizomes, to investigate the regulation of LKB1-dependent AMPK-PPARα/δ signalling by western blot, reporter gene assay and small interfering RNA knockdown analysis. In addition, the antiobesity effects of PAN A were evaluated in C57BL/6J mice with high-fat diet (HFD)-induced obesity.
  
  
  RESULTS
  PAN A stimulated AMPK signalling, induced nuclear translocation of the AMPKα2 subunit and activated PPARα/δ; LKB1, a kinase that lies upstream of AMPK, mediated these effects. PAN A stimulated the direct binding of the AMPKα2 subunit to PPARα/δ, but PPARδ activation required direct interaction with PPARγ coactivator 1α (PGC-1α). Further, PAN A (50 mg/kg/day) reduced weight gain, fat mass, fatty liver and improved serum lipid profiles in obese mice. Additionally, PAN A reduced ectopic fat accumulation and increased the proportion of slow-twitch myofibres and mitochondria content in skeletal muscle, thereby increasing running endurance.
  
  
  CONCLUSIONS
  PAN A, an LKB1-dependent AMPK stimulator, activated PPARα/δ and attenuated HFD-induced obesity and dysregulation of lipid metabolism. Our findings suggest that PAN A is a potent AMPK activator and show a novel molecular mechanism for the treatment of metabolic disorders.
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seongsanno, Seodaemun-gu, Seoul, Korea.
authors.forename: D
authors.initials: D
authors.lastname: Kim
authors.forename: M-S
authors.initials: MS
authors.lastname: Lee
authors.forename: K
authors.initials: K
authors.lastname: Jo
authors.forename: K-E
authors.initials: KE
authors.lastname: Lee
authors.forename: J-K
authors.initials: JK
authors.lastname: Hwang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019440:Anti-Obesity Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D047188:Chalcones / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019440:Anti-Obesity Agents; D047188:Chalcones; D047493:PPAR alpha; C482884:panduratin A; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases