Short Term Palmitate Supply Impairs Intestinal Insulin Signaling via Ceramide Production
The worldwide prevalence of metabolic diseases is increasing, and there are global recommendations to limit consumption of certain nutrients, especially saturated lipids. Insulin resistance, a common trait occurring in obesity and type 2 diabetes, is associated with intestinal lipoprotein overproduc...
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| Veröffentlicht in: | The Journal of biological chemistry Jg. 291; H. 31; S. 16328 |
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| Sprache: | Englisch |
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29.07.2016
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| Abstract | The worldwide prevalence of metabolic diseases is increasing, and there are global recommendations to limit consumption of certain nutrients, especially saturated lipids. Insulin resistance, a common trait occurring in obesity and type 2 diabetes, is associated with intestinal lipoprotein overproduction. However, the mechanisms by which the intestine develops insulin resistance in response to lipid overload remain unknown. Here, we show that insulin inhibits triglyceride secretion and intestinal microsomal triglyceride transfer protein expression in vivo in healthy mice force-fed monounsaturated fatty acid-rich olive oil but not in mice force-fed saturated fatty acid-rich palm oil. Moreover, when mouse intestine and human Caco-2/TC7 enterocytes were treated with the saturated fatty acid, palmitic acid, the insulin-signaling pathway was impaired. We show that palmitic acid or palm oil increases ceramide production in intestinal cells and that treatment with a ceramide analogue partially reproduces the effects of palmitic acid on insulin signaling. In Caco-2/TC7 enterocytes, ceramide effects on insulin-dependent AKT phosphorylation are mediated by protein kinase C but not by protein phosphatase 2A. Finally, inhibiting de novo ceramide synthesis improves the response of palmitic acid-treated Caco-2/TC7 enterocytes to insulin. These results demonstrate that a palmitic acid-ceramide pathway accounts for impaired intestinal insulin sensitivity, which occurs within several hours following initial lipid exposure. |
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| AbstractList | The worldwide prevalence of metabolic diseases is increasing, and there are global recommendations to limit consumption of certain nutrients, especially saturated lipids. Insulin resistance, a common trait occurring in obesity and type 2 diabetes, is associated with intestinal lipoprotein overproduction. However, the mechanisms by which the intestine develops insulin resistance in response to lipid overload remain unknown. Here, we show that insulin inhibits triglyceride secretion and intestinal microsomal triglyceride transfer protein expression in vivo in healthy mice force-fed monounsaturated fatty acid-rich olive oil but not in mice force-fed saturated fatty acid-rich palm oil. Moreover, when mouse intestine and human Caco-2/TC7 enterocytes were treated with the saturated fatty acid, palmitic acid, the insulin-signaling pathway was impaired. We show that palmitic acid or palm oil increases ceramide production in intestinal cells and that treatment with a ceramide analogue partially reproduces the effects of palmitic acid on insulin signaling. In Caco-2/TC7 enterocytes, ceramide effects on insulin-dependent AKT phosphorylation are mediated by protein kinase C but not by protein phosphatase 2A. Finally, inhibiting de novo ceramide synthesis improves the response of palmitic acid-treated Caco-2/TC7 enterocytes to insulin. These results demonstrate that a palmitic acid-ceramide pathway accounts for impaired intestinal insulin sensitivity, which occurs within several hours following initial lipid exposure.The worldwide prevalence of metabolic diseases is increasing, and there are global recommendations to limit consumption of certain nutrients, especially saturated lipids. Insulin resistance, a common trait occurring in obesity and type 2 diabetes, is associated with intestinal lipoprotein overproduction. However, the mechanisms by which the intestine develops insulin resistance in response to lipid overload remain unknown. Here, we show that insulin inhibits triglyceride secretion and intestinal microsomal triglyceride transfer protein expression in vivo in healthy mice force-fed monounsaturated fatty acid-rich olive oil but not in mice force-fed saturated fatty acid-rich palm oil. Moreover, when mouse intestine and human Caco-2/TC7 enterocytes were treated with the saturated fatty acid, palmitic acid, the insulin-signaling pathway was impaired. We show that palmitic acid or palm oil increases ceramide production in intestinal cells and that treatment with a ceramide analogue partially reproduces the effects of palmitic acid on insulin signaling. In Caco-2/TC7 enterocytes, ceramide effects on insulin-dependent AKT phosphorylation are mediated by protein kinase C but not by protein phosphatase 2A. Finally, inhibiting de novo ceramide synthesis improves the response of palmitic acid-treated Caco-2/TC7 enterocytes to insulin. These results demonstrate that a palmitic acid-ceramide pathway accounts for impaired intestinal insulin sensitivity, which occurs within several hours following initial lipid exposure. The worldwide prevalence of metabolic diseases is increasing, and there are global recommendations to limit consumption of certain nutrients, especially saturated lipids. Insulin resistance, a common trait occurring in obesity and type 2 diabetes, is associated with intestinal lipoprotein overproduction. However, the mechanisms by which the intestine develops insulin resistance in response to lipid overload remain unknown. Here, we show that insulin inhibits triglyceride secretion and intestinal microsomal triglyceride transfer protein expression in vivo in healthy mice force-fed monounsaturated fatty acid-rich olive oil but not in mice force-fed saturated fatty acid-rich palm oil. Moreover, when mouse intestine and human Caco-2/TC7 enterocytes were treated with the saturated fatty acid, palmitic acid, the insulin-signaling pathway was impaired. We show that palmitic acid or palm oil increases ceramide production in intestinal cells and that treatment with a ceramide analogue partially reproduces the effects of palmitic acid on insulin signaling. In Caco-2/TC7 enterocytes, ceramide effects on insulin-dependent AKT phosphorylation are mediated by protein kinase C but not by protein phosphatase 2A. Finally, inhibiting de novo ceramide synthesis improves the response of palmitic acid-treated Caco-2/TC7 enterocytes to insulin. These results demonstrate that a palmitic acid-ceramide pathway accounts for impaired intestinal insulin sensitivity, which occurs within several hours following initial lipid exposure. |
| Author | Postal, Bárbara Graziela Ferré, Pascal Ribeiro, Agnès Carrière, Véronique Blachnio-Zabielska, Agnieszka Pais de Barros, Jean-Paul Leturque, Armelle Tran, Thi Thu Trang Osinski, Céline Demignot, Sylvie Hajduch, Eric Rousset, Monique |
| Author_xml | – sequence: 1 givenname: Thi Thu Trang surname: Tran fullname: Tran, Thi Thu Trang organization: From the Centre de Recherche des Cordeliers, INSERM, UPMC Univ Paris 06, Sorbonne Universités, Université Paris Descartes, Sorbonne Paris Cité, Ecole Pratique des Hautes Etudes (EPHE), Université Paris Sciences et Lettres, Université Paris Diderot, CNRS, Institute of Cardiometabolism and Nutrition, F-75006 Paris, France – sequence: 2 givenname: Bárbara Graziela surname: Postal fullname: Postal, Bárbara Graziela organization: From the Centre de Recherche des Cordeliers, INSERM, UPMC Univ Paris 06, Sorbonne Universités, Université Paris Descartes, Sorbonne Paris Cité, Ecole Pratique des Hautes Etudes (EPHE), Université Paris Sciences et Lettres, Université Paris Diderot, CNRS, Institute of Cardiometabolism and Nutrition, F-75006 Paris, France – sequence: 3 givenname: Sylvie surname: Demignot fullname: Demignot, Sylvie organization: From the Centre de Recherche des Cordeliers, INSERM, UPMC Univ Paris 06, Sorbonne Universités, Université Paris Descartes, Sorbonne Paris Cité, Ecole Pratique des Hautes Etudes (EPHE), Université Paris Sciences et Lettres, Université Paris Diderot, CNRS, Institute of Cardiometabolism and Nutrition, F-75006 Paris, France – sequence: 4 givenname: Agnès surname: Ribeiro fullname: Ribeiro, Agnès organization: From the Centre de Recherche des Cordeliers, INSERM, UPMC Univ Paris 06, Sorbonne Universités, Université Paris Descartes, Sorbonne Paris Cité, Ecole Pratique des Hautes Etudes (EPHE), Université Paris Sciences et Lettres, Université Paris Diderot, CNRS, Institute of Cardiometabolism and Nutrition, F-75006 Paris, France – sequence: 5 givenname: Céline surname: Osinski fullname: Osinski, Céline organization: From the Centre de Recherche des Cordeliers, INSERM, UPMC Univ Paris 06, Sorbonne Universités, Université Paris Descartes, Sorbonne Paris Cité, Ecole Pratique des Hautes Etudes (EPHE), Université Paris Sciences et Lettres, Université Paris Diderot, CNRS, Institute of Cardiometabolism and Nutrition, F-75006 Paris, France – sequence: 6 givenname: Jean-Paul surname: Pais de Barros fullname: Pais de Barros, Jean-Paul organization: INSERM UMR866, Université de Bourgogne, F-21070 Dijon, France – sequence: 7 givenname: Agnieszka surname: Blachnio-Zabielska fullname: Blachnio-Zabielska, Agnieszka organization: Medical University of Bialystok, P-15-089 Bialystok, Poland, and – sequence: 8 givenname: Armelle surname: Leturque fullname: Leturque, Armelle organization: From the Centre de Recherche des Cordeliers, INSERM, UPMC Univ Paris 06, Sorbonne Universités, Université Paris Descartes, Sorbonne Paris Cité, Ecole Pratique des Hautes Etudes (EPHE), Université Paris Sciences et Lettres, Université Paris Diderot, CNRS, Institute of Cardiometabolism and Nutrition, F-75006 Paris, France – sequence: 9 givenname: Monique surname: Rousset fullname: Rousset, Monique organization: From the Centre de Recherche des Cordeliers, INSERM, UPMC Univ Paris 06, Sorbonne Universités, Université Paris Descartes, Sorbonne Paris Cité, Ecole Pratique des Hautes Etudes (EPHE), Université Paris Sciences et Lettres, Université Paris Diderot, CNRS, Institute of Cardiometabolism and Nutrition, F-75006 Paris, France – sequence: 10 givenname: Pascal surname: Ferré fullname: Ferré, Pascal organization: INSERM UMRS 1138, Sorbonne Universités, UPMC Univ Paris 06, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Institute of Cardiometabolism and Nutrition (ICAN), Centre de Recherche des Cordeliers, F-75006 Paris, France – sequence: 11 givenname: Eric surname: Hajduch fullname: Hajduch, Eric organization: INSERM UMRS 1138, Sorbonne Universités, UPMC Univ Paris 06, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Institute of Cardiometabolism and Nutrition (ICAN), Centre de Recherche des Cordeliers, F-75006 Paris, France – sequence: 12 givenname: Véronique surname: Carrière fullname: Carrière, Véronique email: veronique.carriere@crc.jussieu.fr organization: From the Centre de Recherche des Cordeliers, INSERM, UPMC Univ Paris 06, Sorbonne Universités, Université Paris Descartes, Sorbonne Paris Cité, Ecole Pratique des Hautes Etudes (EPHE), Université Paris Sciences et Lettres, Université Paris Diderot, CNRS, Institute of Cardiometabolism and Nutrition, F-75006 Paris, France, veronique.carriere@crc.jussieu.fr |
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| Keywords | ceramide intestine signaling insulin fatty acid Akt PKB lipid palmitic acid |
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| SubjectTerms | Animals Caco-2 Cells Ceramides - biosynthesis Enterocytes - metabolism Humans Insulin - metabolism Intestinal Mucosa - metabolism Mice Palm Oil Palmitic Acid - metabolism Palmitic Acid - pharmacology Phosphorylation - drug effects Plant Oils - pharmacology Proto-Oncogene Proteins c-akt - metabolism Signal Transduction |
| Title | Short Term Palmitate Supply Impairs Intestinal Insulin Signaling via Ceramide Production |
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