Sustained Action of Ceramide on the Insulin Signaling Pathway in Muscle Cells: IMPLICATION OF THE DOUBLE-STRANDED RNA-ACTIVATED PROTEIN KINASE
In vivo, ectopic accumulation of fatty acids in muscles leads to alterations in insulin signaling at both the IRS1 and Akt steps. However, in vitro treatments with saturated fatty acids or their derivative ceramide demonstrate an effect only at the Akt step. In this study, we adapted our experimenta...
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| Published in: | The Journal of biological chemistry Vol. 291; no. 6; p. 3019 |
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| Main Authors: | , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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05.02.2016
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| ISSN: | 1083-351X, 1083-351X |
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| Abstract | In vivo, ectopic accumulation of fatty acids in muscles leads to alterations in insulin signaling at both the IRS1 and Akt steps. However, in vitro treatments with saturated fatty acids or their derivative ceramide demonstrate an effect only at the Akt step. In this study, we adapted our experimental procedures to mimic the in vivo situation and show that the double-stranded RNA-dependent protein kinase (PKR) is involved in the long-term effects of saturated fatty acids on IRS1. C2C12 or human muscle cells were incubated with palmitate or directly with ceramide for short or long periods, and insulin signaling pathway activity was evaluated. PKR involvement was assessed through pharmacological and genetic studies. Short-term treatments of myotubes with palmitate, a ceramide precursor, or directly with ceramide induce an inhibition of Akt, whereas prolonged periods of treatment show an additive inhibition of insulin signaling through increased IRS1 serine 307 phosphorylation. PKR mRNA, protein, and phosphorylation are increased in insulin-resistant muscles. When PKR activity is reduced (siRNA or a pharmacological inhibitor), serine phosphorylation of IRS1 is reduced, and insulin-induced phosphorylation of Akt is improved. Finally, we show that JNK mediates ceramide-activated PKR inhibitory action on IRS1. Together, in the long term, our results show that ceramide acts at two distinct levels of the insulin signaling pathway (IRS1 and Akt). PKR, which is induced by both inflammation signals and ceramide, could play a major role in the development of insulin resistance in muscle cells. |
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| AbstractList | In vivo, ectopic accumulation of fatty acids in muscles leads to alterations in insulin signaling at both the IRS1 and Akt steps. However, in vitro treatments with saturated fatty acids or their derivative ceramide demonstrate an effect only at the Akt step. In this study, we adapted our experimental procedures to mimic the in vivo situation and show that the double-stranded RNA-dependent protein kinase (PKR) is involved in the long-term effects of saturated fatty acids on IRS1. C2C12 or human muscle cells were incubated with palmitate or directly with ceramide for short or long periods, and insulin signaling pathway activity was evaluated. PKR involvement was assessed through pharmacological and genetic studies. Short-term treatments of myotubes with palmitate, a ceramide precursor, or directly with ceramide induce an inhibition of Akt, whereas prolonged periods of treatment show an additive inhibition of insulin signaling through increased IRS1 serine 307 phosphorylation. PKR mRNA, protein, and phosphorylation are increased in insulin-resistant muscles. When PKR activity is reduced (siRNA or a pharmacological inhibitor), serine phosphorylation of IRS1 is reduced, and insulin-induced phosphorylation of Akt is improved. Finally, we show that JNK mediates ceramide-activated PKR inhibitory action on IRS1. Together, in the long term, our results show that ceramide acts at two distinct levels of the insulin signaling pathway (IRS1 and Akt). PKR, which is induced by both inflammation signals and ceramide, could play a major role in the development of insulin resistance in muscle cells. In vivo, ectopic accumulation of fatty acids in muscles leads to alterations in insulin signaling at both the IRS1 and Akt steps. However, in vitro treatments with saturated fatty acids or their derivative ceramide demonstrate an effect only at the Akt step. In this study, we adapted our experimental procedures to mimic the in vivo situation and show that the double-stranded RNA-dependent protein kinase (PKR) is involved in the long-term effects of saturated fatty acids on IRS1. C2C12 or human muscle cells were incubated with palmitate or directly with ceramide for short or long periods, and insulin signaling pathway activity was evaluated. PKR involvement was assessed through pharmacological and genetic studies. Short-term treatments of myotubes with palmitate, a ceramide precursor, or directly with ceramide induce an inhibition of Akt, whereas prolonged periods of treatment show an additive inhibition of insulin signaling through increased IRS1 serine 307 phosphorylation. PKR mRNA, protein, and phosphorylation are increased in insulin-resistant muscles. When PKR activity is reduced (siRNA or a pharmacological inhibitor), serine phosphorylation of IRS1 is reduced, and insulin-induced phosphorylation of Akt is improved. Finally, we show that JNK mediates ceramide-activated PKR inhibitory action on IRS1. Together, in the long term, our results show that ceramide acts at two distinct levels of the insulin signaling pathway (IRS1 and Akt). PKR, which is induced by both inflammation signals and ceramide, could play a major role in the development of insulin resistance in muscle cells.In vivo, ectopic accumulation of fatty acids in muscles leads to alterations in insulin signaling at both the IRS1 and Akt steps. However, in vitro treatments with saturated fatty acids or their derivative ceramide demonstrate an effect only at the Akt step. In this study, we adapted our experimental procedures to mimic the in vivo situation and show that the double-stranded RNA-dependent protein kinase (PKR) is involved in the long-term effects of saturated fatty acids on IRS1. C2C12 or human muscle cells were incubated with palmitate or directly with ceramide for short or long periods, and insulin signaling pathway activity was evaluated. PKR involvement was assessed through pharmacological and genetic studies. Short-term treatments of myotubes with palmitate, a ceramide precursor, or directly with ceramide induce an inhibition of Akt, whereas prolonged periods of treatment show an additive inhibition of insulin signaling through increased IRS1 serine 307 phosphorylation. PKR mRNA, protein, and phosphorylation are increased in insulin-resistant muscles. When PKR activity is reduced (siRNA or a pharmacological inhibitor), serine phosphorylation of IRS1 is reduced, and insulin-induced phosphorylation of Akt is improved. Finally, we show that JNK mediates ceramide-activated PKR inhibitory action on IRS1. Together, in the long term, our results show that ceramide acts at two distinct levels of the insulin signaling pathway (IRS1 and Akt). PKR, which is induced by both inflammation signals and ceramide, could play a major role in the development of insulin resistance in muscle cells. |
| Author | Ferré, Pascal Hainault, Isabelle Hage Hassan, Rima Pacheco de Sousa, Ana Catarina Blachnio-Zabielska, Agnieszka Foufelle, Fabienne Bourron, Olivier Mahfouz, Rana Hajduch, Eric Koskas, Fabien Górski, Jan |
| Author_xml | – sequence: 1 givenname: Rima surname: Hage Hassan fullname: Hage Hassan, Rima organization: From INSERM, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France – sequence: 2 givenname: Ana Catarina surname: Pacheco de Sousa fullname: Pacheco de Sousa, Ana Catarina organization: From INSERM, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France – sequence: 3 givenname: Rana surname: Mahfouz fullname: Mahfouz, Rana organization: From INSERM, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France – sequence: 4 givenname: Isabelle surname: Hainault fullname: Hainault, Isabelle organization: From INSERM, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France – sequence: 5 givenname: Agnieszka surname: Blachnio-Zabielska fullname: Blachnio-Zabielska, Agnieszka organization: Department of Physiology, Medical University of Bialystok, 15-222 Bialystok, Poland, Assistance Publique-Hôpitaux de Paris – sequence: 6 givenname: Olivier surname: Bourron fullname: Bourron, Olivier organization: From INSERM, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, Département de Diabétologie et Maladies Métaboliques and – sequence: 7 givenname: Fabien surname: Koskas fullname: Koskas, Fabien organization: Service de Chirurgie Vasculaire,Hôpital Pitié-Salpêtrière, 75013 Paris, France – sequence: 8 givenname: Jan surname: Górski fullname: Górski, Jan organization: Department of Physiology, Medical University of Bialystok, 15-222 Bialystok, Poland, Assistance Publique-Hôpitaux de Paris – sequence: 9 givenname: Pascal surname: Ferré fullname: Ferré, Pascal organization: From INSERM, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France – sequence: 10 givenname: Fabienne surname: Foufelle fullname: Foufelle, Fabienne organization: From INSERM, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France – sequence: 11 givenname: Eric surname: Hajduch fullname: Hajduch, Eric email: eric.hajduch@crc.jussieu.fr organization: From INSERM, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Unité Mixte de Recherche_S 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, eric.hajduch@crc.jussieu.fr |
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| Keywords | protein kinase RNA-activated (PKR) ceramide insulin signaling type 2 diabetes Akt PKB skeletal muscle |
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| SubjectTerms | Animals Cell Line Ceramides - genetics Ceramides - metabolism eIF-2 Kinase - genetics eIF-2 Kinase - metabolism Humans Insulin - genetics Insulin - metabolism Insulin Receptor Substrate Proteins - genetics Insulin Receptor Substrate Proteins - metabolism Insulin Resistance - physiology Male MAP Kinase Kinase 4 - genetics MAP Kinase Kinase 4 - metabolism Mice Muscle, Skeletal - cytology Muscle, Skeletal - metabolism Phosphorylation Proto-Oncogene Proteins c-akt Signal Transduction - physiology |
| Title | Sustained Action of Ceramide on the Insulin Signaling Pathway in Muscle Cells: IMPLICATION OF THE DOUBLE-STRANDED RNA-ACTIVATED PROTEIN KINASE |
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