Critical role of stearoyl-CoA desaturase–1 (SCD1) in the onset of diet-induced hepatic insulin resistance
Roger Gutiérrez-Juárez, … , Brett P. Monia, Luciano Rossetti
Roger Gutiérrez-Juárez, … , Brett P. Monia, Luciano Rossetti
Published June 1, 2006
Citation Information: J Clin Invest. 2006;116(6):1686-1695. https://doi.org/10.1172/JCI26991.
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Research Article Metabolism

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

Abstract

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 (~80%) and total Scd activity (~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 ~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.

Authors

Roger Gutiérrez-Juárez, Alessandro Pocai, Claudia Mulas, Hiraku Ono, Sanjay Bhanot, Brett P. Monia, Luciano Rossetti

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Figure 3

Scd1 deficiency negates the effects of OF on hepatic glucose fluxes.

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Scd1 deficiency negates the effects of OF on hepatic glucose fluxes. (A)...
(A) Protocol for the hyperinsulinemic-pancreatic clamp procedure. (B) Glucose infusion rate, glucose uptake, and inhibition of glucose production (expressed as percentage inhibition from basal) during the clamp period in SC (white bars), control OF (gray bars), and Scd1-deficient OF animals (black bars). (C) Schematic of the major pathways and enzymatic reactions contributing to glucose production in the liver. [14C]-PEP, 14C-phosphoenolpyruvate; 3H/14C-UDPG, 3H/14C-UDP glucose; GK, glucokinase. (D) Glucose production, Glc-6-Pase flux, and glucose cycling during the clamp period in control SC (white bars), control OF (gray bars), and liver Scd1–deficient OF animals (black bars). (E) Rate of hepatic gluconeogenesis and glycogenolysis in control SC (white bars), control OF (gray bars), and liver Scd1–deficient OF animals (black bars). *P < 0.05, versus SCR ASO OF; n = 5–6 per condition.