Soraphen, an inhibitor of the acetyl-CoA carboxylase system, improves peripheral insulin sensitivity in mice fed a high-fat diet.
OBJECTIVE
Inhibition of the acetyl-CoA carboxylase (ACC) system, consisting of the isozymes ACC1 and ACC2, may be beneficial for treatment of insulin resistance and/or obesity by interfering with de novo lipogenesis and beta-oxidation. We have evaluated effects of pharmacological inhibition of ACC by soraphen (SP) on high fat (HF) diet-induced insulin resistance in mice.


METHODS
Male C57Bl6/J mice were fed control chow, a HF diet or a HF diet supplemented with SP (50 or 100 mg/kg/day).


RESULTS
Body weight gain and total body fat content of SP-treated animals were significantly reduced compared with HF-fed mice. Fractional synthesis of palmitate was significantly reduced in mice treated with SP, indicative for ACC1 inhibition. Plasma beta-hydroxybutyrate levels were significantly elevated by SP, reflecting simultaneous inhibition of ACC2 activity. Mice treated with SP showed improved peripheral insulin sensitivity, as assessed by hyperinsulinaemic euglycaemic clamps.


CONCLUSIONS
Pharmacological inhibition of the ACC system is of potential use for treatment of key components of the metabolic syndrome.
Schreurs
M
M
Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, PO Box 30.001, Groningen 9700 RB, The Netherlands. m.schreurs@med.umcg.nl
van Dijk
T H
TH
Gerding
A
A
Havinga
R
R
Reijngoud
D-J
DJ
Kuipers
F
F
D020155:3-Hydroxybutyric Acid / Q000097:blood; D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage*; D015309:Glucose Clamp Technique; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D019308:Palmitic Acid / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D012313:RNA / Q000378:metabolism; D000077278:RNA, Mitochondrial; D015430:Weight Gain / Q000187:drug effects
D004041:Dietary Fats; D007328:Insulin; D018942:Macrolides; D000077278:RNA, Mitochondrial; C086151:soraphen A; D019308:Palmitic Acid; D012313:RNA; D002784:Cholesterol; D000103:Acetyl-CoA Carboxylase; D020155:3-Hydroxybutyric Acid