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 1

Systemic administration of Scd1 ASO downregulates liver Scd1 expression and activity in OF rats.

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Systemic administration of Scd1 ASO downregulates liver Scd1 expression ...
(A) Schematic of Scd1 role in lipid synthesis. CE, cholesteryl esters; PL, phospholipids; WE, wax esters. (B) Protocol for Scd1 ASO delivery (top panel). Rats received an i.p. injection of either a control ASO (SCR ASO) or Scd1 ASO (100 mg/kg of body weight) on day 0; on day 3, the animals were switched to a lard-enriched diet (HF) and received a second injection of ASOs; lastly, on day 5, an insulin clamp procedure was performed. The livers of OF animals treated with Scd1 ASO (black bars) displayed an 80% decrease in Scd1 mRNA and a 50% decrease in both Scd1 activity and C18 desaturation index. OF (gray bars) did not modify any of these parameters when compared with SC rats (white bars). (C) OF caused a decrease in hepatic LCFA CoA levels, which were restored to SC levels by Scd1 ASO treatment (top left panel). Liver Scd1 deficiency in OF animals (black bars) resulted in a 3.5-fold increase in liver TG (top right panel) when compared with SCR ASO OF animals (gray bars). JNK phosphorylation and activity were markedly increased in OF Scd1-deficient animals as compared with OF control animals, while OF (gray bars) did not have any effect when compared with SC animals (white bars). Wet wt, wet weight. *P < 0.05 versus SCR ASO OF.