Inhibition of acetyl-CoA carboxylase 2 enhances skeletal muscle fatty acid oxidation and improves whole-body glucose homeostasis in db/db mice

• Published in: Diabetologia Vol. 55; no. 7; pp. 2044 - 2053
• Main Authors: Glund, S., Schoelch, C., Thomas, L., Niessen, H. G., Stiller, D., Roth, G. J., Neubauer, H.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-07-2012; Springer; Springer Nature B.V
• Subjects: Acetyl-CoA Carboxylase - genetics; Acetyl-CoA Carboxylase - metabolism; Animals; Biological and medical sciences; Body Weight; Diabetes; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Fatty Acids - metabolism; Fundamental and applied biological sciences. Psychology; Glucose; Glucose - metabolism; Glycated Hemoglobin A - metabolism; Homeostasis; Human Physiology; Insulin Resistance; Internal Medicine; Kinases; Laboratory animals; Lipids; Male; Malonyl Coenzyme A - metabolism; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Mice, Inbred NOD; Muscle, Skeletal - metabolism; Musculoskeletal system; Obesity; Obesity - metabolism; Oxidation; Striated muscle. Tendons; Triglycerides - metabolism; Vertebrates: osteoarticular system, musculoskeletal system; Weight control; Germany; Diabetes; Intramyocellular lipid; Muscle lipid; Metabolic flexibility; IMCL; Pharmacological inhibitor; Carbon-carbon ligases; Endocrinopathy; Enzyme; Diabetes mellitus; Rodentia; Homeostasis; Lipids; Glucose; Striated muscle; Fatty acids; Vertebrata; Mammalia; Acetyl-CoA carboxylase; Mouse; Ligases; Animal; Oxidation; Inhibition
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-012-2554-9

Aims/hypothesis
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/interpretation
In conclusion, the ACC2-selective inhibitor (
S
)-9c revealed glucose-lowering effects in a mouse model of diabetes mellitus.