期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 116, 期 6, 页码 1686-1695出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI26991
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资金
- NIA NIH HHS [AG 21654, P01 AG021654] Funding Source: Medline
- NIDDK NIH HHS [P60 DK020541, P30 DK020541, R01 DK048321, DK 45024, DK 48321, R01 DK045024, DK 20541, R37 DK048321] Funding Source: Medline
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 (similar to 80%) and total Scd activity (similar to 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 similar to 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.
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