title: Short Term Palmitate Supply Impairs Intestinal Insulin Signaling via Ceramide Production.
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.
authors.affiliation: 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.
authors.forename: Thi Thu Trang
authors.initials: TT
authors.lastname: Tran
authors.affiliation: 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.
authors.forename: Bárbara Graziela
authors.initials: BG
authors.lastname: Postal
authors.affiliation: 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.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Demignot
authors.affiliation: 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.
authors.forename: Agnès
authors.initials: A
authors.lastname: Ribeiro
authors.affiliation: 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.
authors.forename: Céline
authors.initials: C
authors.lastname: Osinski
authors.affiliation: INSERM UMR866, Université de Bourgogne, F-21070 Dijon, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Pais de Barros
authors.affiliation: Medical University of Bialystok, P-15-089 Bialystok, Poland, and.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Blachnio-Zabielska
authors.affiliation: 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.
authors.forename: Armelle
authors.initials: A
authors.lastname: Leturque
authors.affiliation: 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.
authors.forename: Monique
authors.initials: M
authors.lastname: Rousset
authors.affiliation: 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.
authors.forename: Pascal
authors.initials: P
authors.lastname: Ferré
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Hajduch
authors.affiliation: 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.
authors.forename: Véronique
authors.initials: V
authors.lastname: Carrière
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002518:Ceramides / Q000096:biosynthesis*; D020895:Enterocytes / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D000073878:Palm Oil; D019308:Palmitic Acid / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010938:Plant Oils / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002518:Ceramides; D007328:Insulin; D010938:Plant Oils; D019308:Palmitic Acid; D000073878:Palm Oil; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt PKB; ceramide; fatty acid; insulin; intestine; lipid; palmitic acid; signaling