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 4

Selective attenuation of liver Scd1 expression normalizes hepatic insulin action in OF rats.

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Selective attenuation of liver Scd1 expression normalizes hepatic insuli...
(A) Protocol for the intraportal Scd1 ASO treatment (top panel). An indwelling catheter was placed into the portal vein, and 2 days later (day 0), the animals received a first intraportal injection of either SCR ASO or Scd1 ASO (25 mg/kg of body weight). On day 3, the rats 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 (See Figure 2A). (B) Intraportal Scd1 ASO (black bar) decreased liver Scd1 mRNA when compared with SCR ASO (white bar; left panel). Selective attenuation of liver Scd1 (black bar) in OF rats improved hepatic insulin action when compared with SCR ASO (white bar) as shown by a significant decrease in glucose production (GP) (center panel) and a significant increase in insulin’s ability to inhibit GP (right panel). (C–F) To examine whether the decreased expression of SCD1 in adipose tissue is required for the effects of Scd1 ASO on GP, we compared subgroups of OF rats displaying similar decreases in liver SCD1 induced by either i.p. (C and D) or intraportal (E and F) ASO. (C) i.p. Scd1 ASO markedly suppressed Scd1 expression in liver and white fat. (E) Intraportal Scd1 ASO markedly decreased Scd1 expression in the liver but not in adipose tissue. (D and F) The 2 treatment regimens led to similar improvements in hepatic insulin action. *P < 0.05 versus SCR ASO OF; n = 5–6.