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 5

Scd1 deficiency normalizes hepatic insulin action in HF-fed mice.

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Scd1 deficiency normalizes hepatic insulin action in HF-fed mice. (A) Pr...
(A) Protocol for Scd1 ASO treatment in mice. Male C57BL/6J mice were allocated to a HF diet for 3 weeks. Five days before the completion of the protocol (day 0), the mice received an i.p. injection of either a SCR ASO or Scd1 ASO (100 mg/kg of body weight); on day 3, the animals received a second ASO injection, and vascular catheters were implanted; finally, on day 5, the mice were subjected to an insulin clamp procedure. (B) Scd1 ASO (black bars) markedly decreased the hepatic levels of Scd1 mRNA and protein compared with SCR ASO (grey bars) in HF diet–fed mice. (C) Protocol for the insulin clamp procedure in mice. (D) The enzymatic (desaturase) activity of Scd1 was markedly increased by HF feeding in mice (gray versus white bars) and dramatically lowered by treatment with Scd1 ASO (black bars). The rapid attenuation of liver Scd1 expression and activity prevented the development of hepatic insulin resistance induced by HF feeding in mice but did not modify insulin action on glucose uptake. *P < 0.05 versus SCR ASO; n = 6–10.