Document Detail


Prevention of obesity in mice by antisense oligonucleotide inhibitors of stearoyl-CoA desaturase-1.
MedLine Citation:
PMID:  15761499     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Effective therapies for the treatment of obesity, a key element of metabolic syndrome, are urgently needed but currently lacking. Stearoyl-CoA desaturase-1 (SCD1) is the rate-limiting enzyme catalyzing the conversion of saturated long-chain fatty acids into monounsaturated fatty acids, which are major components of triglycerides. In the current study, we tested the efficacy of pharmacological inhibition of SCD1 in controlling lipogenesis and body weight in mice. SCD1-specific antisense oligonucleotide inhibitors (ASOs) reduced SCD1 expression, reduced fatty acid synthesis and secretion, and increased fatty acid oxidization in primary mouse hepatocytes. Treatment of mice with SCD1 ASOs resulted in prevention of diet-induced obesity with concomitant reductions in SCD1 expression and the ratio of oleate to stearoyl-CoA in tissues and plasma. These changes correlated with reduced body adiposity, hepatomegaly and steatosis, and postprandial plasma insulin and glucose levels. Furthermore, SCD1 ASOs reduced de novo fatty acid synthesis, decreased expression of lipogenic genes, and increased expression of genes promoting energy expenditure in liver and adipose tissues. Thus, SCD1 inhibition represents a new target for the treatment of obesity and related metabolic disorders.
Authors:
Guoqiang Jiang; Zhihua Li; Franklin Liu; Kenneth Ellsworth; Qing Dallas-Yang; Margaret Wu; John Ronan; Christine Esau; Cain Murphy; Deborah Szalkowski; Raynald Bergeron; Thomas Doebber; Bei B Zhang
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Publication Detail:
Type:  Journal Article     Date:  2005-03-10
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  115     ISSN:  0021-9738     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2005 Apr 
Date Detail:
Created Date:  2005-04-20     Completed Date:  2005-06-28     Revised Date:  2012-05-24    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1030-8     Citation Subset:  AIM; IM    
Affiliation:
Metabolic Disorders - Diabetes and Comparative Medicine, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
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MeSH Terms
Descriptor/Qualifier:
Adipose Tissue / cytology,  metabolism
Animals
Blood Glucose / metabolism
Body Weight
Cells, Cultured
Diet
Fatty Acids / chemistry,  metabolism
Hepatocytes / cytology,  metabolism
Insulin / metabolism
Liver / cytology,  enzymology
Mice
Mice, Inbred Strains
Motor Activity
Obesity / metabolism,  prevention & control*
Oligonucleotides, Antisense / genetics,  metabolism*
Oxidation-Reduction
Oxygen Consumption
Stearoyl-CoA Desaturase* / antagonists & inhibitors,  genetics,  metabolism
Chemical
Reg. No./Substance:
0/Blood Glucose; 0/Fatty Acids; 0/Insulin; 0/Oligonucleotides, Antisense; EC 1.14.19.1/Scd1 protein, mouse; EC 1.14.19.1/Stearoyl-CoA Desaturase
Comments/Corrections
Comment In:
J Clin Invest. 2006 Jun;116(6):1478-81   [PMID:  16741573 ]
Erratum In:
J Clin Invest. 2005 Aug;115(8):2297

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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