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Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance
- Source :
- Nature medicine. 13(10)
- Publication Year :
- 2007
-
Abstract
- Insulin resistance is often associated with obesity and can precipitate type 2 diabetes. To date, most known approaches that improve insulin resistance must be preceded by the amelioration of obesity and hepatosteatosis. Here, we show that this provision is not mandatory; insulin resistance and hyperglycemia are improved by the modification of hepatic fatty acid composition, even in the presence of persistent obesity and hepatosteatosis. Mice deficient for Elovl6, the gene encoding the elongase that catalyzes the conversion of palmitate to stearate, were generated and shown to become obese and develop hepatosteatosis when fed a high-fat diet or mated to leptin-deficient ob/ob mice. However, they showed marked protection from hyperinsulinemia, hyperglycemia and hyperleptinemia. Amelioration of insulin resistance was associated with restoration of hepatic insulin receptor substrate-2 and suppression of hepatic protein kinase C epsilon activity resulting in restoration of Akt phosphorylation. Collectively, these data show that hepatic fatty acid composition is a new determinant for insulin sensitivity that acts independently of cellular energy balance and stress. Inhibition of this elongase could be a new therapeutic approach for ameliorating insulin resistance, diabetes and cardiovascular risks, even in the presence of a continuing state of obesity.
- Subjects :
- Male
medicine.medical_specialty
Carcinoma, Hepatocellular
Time Factors
Insulin Receptor Substrate Proteins
Fatty Acid Elongases
Type 2 diabetes
Protein Kinase C-epsilon
General Biochemistry, Genetics and Molecular Biology
Mice
Insulin resistance
Acetyltransferases
Diabetes mellitus
Internal medicine
Cell Line, Tumor
medicine
Hyperinsulinemia
Animals
Insulin
Obesity
RNA, Messenger
Phosphorylation
Mice, Knockout
biology
business.industry
Body Weight
Liver Neoplasms
Intracellular Signaling Peptides and Proteins
General Medicine
medicine.disease
Phosphoproteins
Dietary Fats
Transplantation
Insulin receptor
Endocrinology
biology.protein
Diet, Atherogenic
Metabolic syndrome
Insulin Resistance
business
Proto-Oncogene Proteins c-akt
Gene Deletion
Signal Transduction
Subjects
Details
- ISSN :
- 10788956
- Volume :
- 13
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Nature medicine
- Accession number :
- edsair.doi.dedup.....2b8c7c5592ac727bc0ce45c03d2ab2f7