Critical role of stearoyl-CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance

Stearoyl-CoA desaturase-1 (SCD1) catalyzes the synthesis of monounsaturated fatty acids from saturated fatty acids. Mice with a targeted disruption of Scd1 gene locus are lean and display increased insulin sensitivity. To examine whether Scd1 activity is required for the development of diet-induced...

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Bibliographic Details
Published in:The Journal of clinical investigation 2006-06, Vol.116 (6), p.1686-1695
Main Authors: Gutiérrez-Juárez, Roger, Pocai, Alessandro, Mulas, Claudia, Ono, Hiraku, Bhanot, Sanjay, Monia, Brett P, Rossetti, Luciano
Format: Article
Language:English
Subjects:
Animals
Biomedical research
Diet
Dietary Fats
Drug therapy
Glucose - metabolism
Glucose-6-Phosphatase - metabolism
Humans
Insulin - metabolism
Insulin Resistance
Isoenzymes - genetics
Isoenzymes - metabolism
Lipid Metabolism
Liver - enzymology
Liver - physiology
Male
Medical research
Medicine, Experimental
Mice
Mice, Inbred C57BL
Oligonucleotides, Antisense - administration & dosage
Oligonucleotides, Antisense - genetics
Oligonucleotides, Antisense - metabolism
Phosphoenolpyruvate Carboxykinase (GTP) - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Random Allocation
Rats
Rats, Sprague-Dawley
Signal Transduction - physiology
Stearoyl-CoA Desaturase - genetics
Stearoyl-CoA Desaturase - metabolism
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Summary:Stearoyl-CoA desaturase-1 (SCD1) catalyzes the synthesis of monounsaturated fatty acids from saturated fatty acids. Mice with a targeted disruption of Scd1 gene locus are lean and display increased insulin sensitivity. To examine whether Scd1 activity is required for the development of diet-induced hepatic insulin resistance, we used a sequence-specific antisense oligodeoxynucleotide (ASO) to lower hepatic Scd1 expression in rats and mice with diet-induced insulin resistance. Treatment of rats with Scd1 ASO markedly decreased liver Scd1 expression (approximately 80%) and total Scd activity (approximately 50%) compared with that in rats treated with scrambled ASO (control). Insulin clamp studies revealed severe hepatic insulin resistance in high-fat-fed rats and mice that was completely reversed by 5 days of treatment with Scd1 ASO. The latter treatment decreased glucose production (by approximately 75%), gluconeogenesis, and glycogenolysis. Downregulation of Scd1 also led to increased Akt phosphorylation and marked decreases in the expression of glucose-6-phosphatase (Glc-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Thus, Scd1 is required for the onset of diet-induced hepatic insulin resistance.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI26991