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PMID: 16741579 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Critical role of stearoyl-CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance.

The Journal of clinical investigation ·Vol. 116 ·No. 6 ·2006-06-00 ·Pages 1686-95

Gutiérrez-Juárez R, Pocai A, Mulas C, Ono H, Bhanot S, Monia BP, Rossetti L

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 (approximately 80%) and total Scd activity (approximately 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 approximately 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.

MeSH Terms
Animals Diet Dietary Fats Glucose/metabolism Glucose-6-Phosphatase/metabolism Humans Insulin/metabolism Insulin Resistance Isoenzymes/genetics,metabolism Lipid Metabolism Liver/enzymology,physiology Male Mice Mice, Inbred C57BL Oligonucleotides, Antisense/administration & dosage,genetics,metabolism Phosphoenolpyruvate Carboxykinase (GTP)/metabolism Proto-Oncogene Proteins c-akt/metabolism Random Allocation Rats Rats, Sprague-Dawley Signal Transduction/physiology Stearoyl-CoA Desaturase/genetics,metabolism
Chemicals
Dietary Fats Insulin Isoenzymes Oligonucleotides, Antisense Stearoyl-CoA Desaturase Proto-Oncogene Proteins c-akt Glucose-6-Phosphatase Phosphoenolpyruvate Carboxykinase (GTP) Glucose
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Gutiérrez-Juárez Roger
Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA.
Pocai Alessandro
Mulas Claudia
Ono Hiraku
Bhanot Sanjay
Monia Brett P
Rossetti Luciano
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI26991
Published
2006-06-00
Pages
1686-95
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1464900
Subset
IM
Grants
NIDDK NIH HHS · R01 DK045024 · United States
NIA NIH HHS · P01 AG021654 · United States
NIDDK NIH HHS · DK 48321 · United States
NIDDK NIH HHS · DK 45024 · United States
NIDDK NIH HHS · R01 DK048321 · United States
NIDDK NIH HHS · P30 DK020541 · United States
NIA NIH HHS · AG 21654 · United States
NIDDK NIH HHS · P60 DK020541 · United States
NIDDK NIH HHS · DK 20541 · United States
NIDDK NIH HHS · R37 DK048321 · United States
Corrections
CommentIn
PMID: 16741573
External Links
PubMed source DOI: 10.1172/JCI26991 PMC Full Text View journal details
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