title: Inhibition of acetyl-CoA carboxylase 2 enhances skeletal muscle fatty acid oxidation and improves whole-body glucose homeostasis in db/db mice.
abstract: OBJECTIVE
  Excessive ectopic lipid deposition contributes to impaired insulin action in peripheral tissues and is considered an important link between obesity and type 2 diabetes mellitus. Acetyl-CoA carboxylase 2 (ACC2) is a key regulatory enzyme controlling skeletal muscle mitochondrial fatty acid oxidation; inhibition of ACC2 results in enhanced oxidation of lipids. Several mouse models lacking functional ACC2 have been reported in the literature. However, the phenotypes of the different models are inconclusive with respect to glucose homeostasis and protection from diet-induced obesity.
  
  
  METHODS
  Here, we studied the effects of pharmacological inhibition of ACC2 using as a selective inhibitor the S enantiomer of compound 9c ([S]-9c). Selectivity was confirmed in biochemical assays using purified human ACC1 and ACC2.
  
  
  RESULTS
  (S)-9c significantly increased fatty acid oxidation in isolated extensor digitorum longus muscle from different mouse models (EC(50) 226 nmol/l). Accordingly, short-term treatment of mice with (S)-9c decreased malonyl-CoA levels in skeletal muscle and concomitantly reduced intramyocellular lipid levels. Treatment of db/db mice for 70 days with (S)-9c (10 and 30 mg/kg, by oral gavage) resulted in improved oral glucose tolerance (AUC -36%, p < 0.05), enhanced skeletal muscle 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) uptake, as well as lowered prandial glucose (-31%, p < 0.01) and HbA(1c) (-0.7%, p < 0.05). Body weight, liver triacylglycerol, plasma insulin and pancreatic insulin content were unaffected by the treatment.
  
  
  CONCLUSIONS
  In conclusion, the ACC2-selective inhibitor (S)-9c revealed glucose-lowering effects in a mouse model of diabetes mellitus.
authors.affiliation: CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH& Co. KG, 88397, Biberach an der Riss, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Glund
authors.forename: C
authors.initials: C
authors.lastname: Schoelch
authors.forename: L
authors.initials: L
authors.lastname: Thomas
authors.forename: H G
authors.initials: HG
authors.lastname: Niessen
authors.forename: D
authors.initials: D
authors.lastname: Stiller
authors.forename: G J
authors.initials: GJ
authors.lastname: Roth
authors.forename: H
authors.initials: H
authors.lastname: Neubauer
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006706:Homeostasis; D007333:Insulin Resistance; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000103:Acetyl-CoA Carboxylase; D005227:Fatty Acids; D005947:Glucose; D006442:Glycated Hemoglobin; D008316:Malonyl Coenzyme A; D014280:Triglycerides; C498191:Acacb protein, mouse