title: Arctigenin, a natural compound, activates AMP-activated protein kinase via inhibition of mitochondria complex I and ameliorates metabolic disorders in ob/ob mice.
abstract: OBJECTIVE
  Arctigenin is a natural compound that had never been previously demonstrated to have a glucose-lowering effect. Here it was found to activate AMP-activated protein kinase (AMPK), and the mechanism by which this occurred, as well as the effects on glucose and lipid metabolism were investigated.
  
  
  METHODS
  2-Deoxyglucose uptake and AMPK phosphorylation were examined in L6 myotubes and isolated skeletal muscle. Gluconeogenesis and lipid synthesis were evaluated in rat primary hepatocytes. The acute and chronic effects of arctigenin on metabolic abnormalities were observed in C57BL/6J and ob/ob mice. Changes in mitochondrial membrane potential were measured using the J-aggregate-forming dye, JC-1. Analysis of respiration of L6 myotubes or isolated mitochondria was conducted in a channel oxygen system.
  
  
  RESULTS
  Arctigenin increased AMPK phosphorylation and stimulated glucose uptake in L6 myotubes and isolated skeletal muscles. In primary hepatocytes, it decreased gluconeogenesis and lipid synthesis. The enhancement of glucose uptake and suppression of hepatic gluconeogenesis and lipid synthesis by arctigenin were prevented by blockade of AMPK activation. The respiration of L6 myotubes or isolated mitochondria was inhibited by arctigenin with a specific effect on respiratory complex I. A single oral dose of arctigenin reduced gluconeogenesis in C57BL/6J mice. Chronic oral administration of arctigenin lowered blood glucose and improved lipid metabolism in ob/ob mice.
  
  
  CONCLUSIONS
  This study demonstrates a new role for arctigenin as a potent indirect activator of AMPK via inhibition of respiratory complex I, with beneficial effects on metabolic disorders in ob/ob mice. This highlights the potential value of arctigenin as a possible treatment of type 2 diabetes.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zu Chong Zhi Road 555, Shanghai 201203, People's Republic of China.
authors.forename: S-L
authors.initials: SL
authors.lastname: Huang
authors.forename: R-T
authors.initials: RT
authors.lastname: Yu
authors.forename: J
authors.initials: J
authors.lastname: Gong
authors.forename: Y
authors.initials: Y
authors.lastname: Feng
authors.forename: Y-L
authors.initials: YL
authors.lastname: Dai
authors.forename: F
authors.initials: F
authors.lastname: Hu
authors.forename: Y-H
authors.initials: YH
authors.lastname: Hu
authors.forename: Y-D
authors.initials: YD
authors.lastname: Tao
authors.forename: Y
authors.initials: Y
authors.lastname: Leng
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D005663:Furans / Q000494:pharmacology*; D044882:Glucose Metabolism Disorders / Q000188:drug therapy*; D017705:Lignans / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D005663:Furans; D017705:Lignans; D055372:AMP-Activated Protein Kinases; D042967:Electron Transport Complex I; C071942:arctigenin
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