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 7

Scd1 deficiency enhances hepatic insulin signaling in OF rats.

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Scd1 deficiency enhances hepatic insulin signaling in OF rats. (A) To in...
(A) To investigate the effect of Scd1 deficiency on early insulin signaling, we injected fasted rats with an i.p. bolus of insulin and sampled the livers 5 minutes later. The acute administration of insulin failed to stimulate the phosphorylation of Irs1 (B and D) and its association with PI3K (B and E). However, treatment of OF rats with Scd1 ASO partly restored insulin responses (B, D, and E). (B) Western blot analysis of immunoprecipitated tyrosine-phosphorylated IRβ and Irs1, Irs1-associated p85α subunit of PI3K, and PTP1B in livers from control (SCR ASO) or Scd1 ASO–treated OF rats in the basal (–Ins) or insulin-stimulated state (+Ins). Densitometric analysis revealed a 35% decrease in PTP1B protein in Scd1 ASO– compared with SCR ASO–treated livers (data not shown). (C) Densitometric analysis showed that insulin-stimulated tyrosine phosphorylation of IRβ was modestly increased by Scd1 deficiency. (D) Densitometric analysis showed that insulin-stimulated tyrosine phosphorylation of Irs1 was markedly enhanced by Scd1 deficiency. (E) The recruitment of p85α PI3K to Irs1 was also enhanced in livers from Scd1-deficient (black bars) when compared with SCR ASO (white bars) OF rats. In C and D, left panels show basal and insulin-stimulated values while right panels show percentage increase from basal values. *P < 0.05 versus SCR ASO OF; n = 3–6 (average ± SEM). pY, phosphotyrosine.