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 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.
Gutiérrez-Juárez
Roger
R
Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA.
Pocai
Alessandro
A
Mulas
Claudia
C
Ono
Hiraku
H
Bhanot
Sanjay
S
Monia
Brett P
BP
Rossetti
Luciano
L
D000818:Animals; D004032:Diet; D004041:Dietary Fats; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism*
D004041:Dietary Fats; D007328:Insulin; D007527:Isoenzymes; D016376:Oligonucleotides, Antisense; D013230:Stearoyl-CoA Desaturase; D051057:Proto-Oncogene Proteins c-akt; D005952:Glucose-6-Phosphatase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose