Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates

Giovanni Solinas, Willscott (Scott) Naugler, Francesco Galimi, Myung Shik Lee, Michael Karin

Research output: Contribution to journalArticle

200 Citations (Scopus)

Abstract

JNKs are attractive targets for treatment of obesity and type-2 diabetes. A sustained increase in JNK activity was observed in dietary and genetic models of obesity in mice, whereas JNK deficiency prevented obesity-induced insulin resistance. A similar insulin-sensitizing effect was seen upon treatment of obese mice with JNK inhibitors. We now demonstrate that treatment with the saturated fatty acid palmitic acid results in sustained JNK activation and insulin resistance in primary mouse hepatocytes and pancreatic β-cells. In the latter, palmitic acid treatment inhibits glucose-induced insulin gene transcription, in part, by interfering with autocrine insulin signaling through phosphorylation of insulin-receptor substrates 1 and 2 at sites that interfere with binding to activated insulin receptors. This mechanism may account for the induction of central insulin resistance by free fatty acids.

Original languageEnglish (US)
Pages (from-to)16454-16459
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number44
DOIs
StatePublished - Oct 31 2006
Externally publishedYes

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Insulin Receptor
Insulin Resistance
Insulin Receptor Substrate Proteins
Fatty Acids
Palmitic Acid
Obesity
Phosphorylation
Insulin
Autocrine Communication
Genes
Obese Mice
Genetic Models
Nonesterified Fatty Acids
Type 2 Diabetes Mellitus
Hepatocytes
Glucose

Keywords

  • Diabetes
  • Insulin gene expression
  • Lipotoxicity
  • Obesity

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. / Solinas, Giovanni; Naugler, Willscott (Scott); Galimi, Francesco; Lee, Myung Shik; Karin, Michael.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 44, 31.10.2006, p. 16454-16459.

Research output: Contribution to journalArticle

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