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

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 beta-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.

SUBMITTER: Solinas G

PROVIDER: S-EPMC1637603 | biostudies-literature | 2006 Oct

REPOSITORIES: biostudies-literature

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

Solinas Giovanni G Naugler Willscott W Galimi Francesco F Lee Myung-Shik MS Karin Michael M

Proceedings of the National Academy of Sciences of the United States of America 20061018 44

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 hepatoc ...[more]

PMID: 17050683

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Project description:IntroductionObesity during pregnancy increases the risk for maternal complications like gestational diabetes, preeclampsia, and maternal inflammation. Maternal obesity also increases the risk of childhood obesity, intrauterine growth restriction (IUGR) and diabetes to the offspring. Increased circulating free fatty acids (FFAs) in obesity due to adipose tissue lipolysis induces lipoapoptosis to hepatocytes, cholangiocytes, and pancreatic-β-cells. During the third trimester of human pregnancy, there is an increase in maternal lipolysis and release of FFAs into the circulation. It is currently unknown if increased FFAs during gestation as a result of maternal obesity cause placental cell lipoapoptosis. Increased exposure of FFAs during maternal obesity has been shown to result in placental lipotoxicity. The objective of the present study is to determine saturated FFA-induced trophoblast lipoapoptosis and also to test the protective role of monounsaturated fatty acids against FFA-induced trophoblast lipoapoptosis using in vitro cell culture model. Here, we hypothesize that saturated FFAs induce placental trophoblast lipoapoptosis, which was prevented by monounsaturated fatty acids.MethodsBiochemical and structural markers of apoptosis by characteristic nuclear morphological changes with DAPI staining, and caspase 3/7 activity was assessed. Cleaved PARP and cleaved caspase 3 were examined by western blot analysis.ResultsTreatment of trophoblast cell lines, JEG-3 and JAR cells with palmitate (PA) or stearate (SA) induces trophoblast lipoapoptosis as evidenced by a significant increase in apoptotic nuclear morphological changes and caspase 3/7 activity. We observed that saturated FFAs caused a concentration-dependent increase in placental trophoblast lipoapoptosis. We also observed that monounsaturated fatty acids like palmitoleate and oleate mitigates placental trophoblast lipoapoptosis caused due to PA exposure.ConclusionWe show that saturated FFAs induce trophoblast lipoapoptosis. Co-treatment of monounsaturated fatty acids like palmitoleate and oleate protects against FFA-induced trophoblast lipoapoptosis.

Dataset Information

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

Publications

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

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