title: Lipid-rich diet enhances L-cell density in obese subjects and in mice through improved L-cell differentiation.
abstract: The enterohormone glucagon-like peptide-1 (GLP-1) is required to amplify glucose-induced insulin secretion that facilitates peripheral glucose utilisation. Alteration in GLP-1 secretion during obesity has been reported but is still controversial. Due to the high adaptability of intestinal cells to environmental changes, we hypothesised that the density of GLP-1-producing cells could be modified by nutritional factors to prevent the deterioration of metabolic condition in obesity. We quantified L-cell density in jejunum samples collected during Roux-en-Y gastric bypass in forty-nine severely obese subjects analysed according to their fat consumption. In mice, we deciphered the mechanisms by which a high-fat diet (HFD) makes an impact on enteroendocrine cell density and function. L-cell density in the jejunum was higher in obese subjects consuming >30 % fat compared with low fat eaters. Mice fed a HFD for 8 weeks displayed an increase in GLP-1-positive cells in the jejunum and colon accordingly to GLP-1 secretion. The regulation by the HFD appears specific to GLP-1-producing cells, as the number of PYY (peptide YY)-positive cells remained unchanged. Moreover, genetically obese ob/ob mice did not show alteration of GLP-1-positive cell density in the jejunum or colon, suggesting that obesity per se is not sufficient to trigger the mechanism. The higher L-cell density in HFD-fed mice involved a rise in L-cell terminal differentiation as witnessed by the increased expression of transcription factors downstream of neurogenin3 (Ngn3). We suggest that the observed increase in GLP-1-positive cell density triggered by high fat consumption in humans and mice might favour insulin secretion and therefore constitute an adaptive response of the intestine to balance diet-induced insulin resistance.
authors.affiliation: Inserm UMR_S 1138 , Centre de Recherche des Cordeliers ; Sorbonne universités , UPMC Univ Paris 06 ; Sorbonne Cités , UPD Univ Paris 05 ; F-75006 , Paris , France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Aranias
authors.affiliation: Inserm UMR_S 1138 , Centre de Recherche des Cordeliers ; Sorbonne universités , UPMC Univ Paris 06 ; Sorbonne Cités , UPD Univ Paris 05 ; F-75006 , Paris , France ; Institut de Cardiométabolisme et Nutrition , ICAN , Pitié-Salpêtrière Hospital , Paris , France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Grosfeld
authors.affiliation: Institut de Cardiométabolisme et Nutrition , ICAN , Pitié-Salpêtrière Hospital , Paris , France ; Sorbonne universités , UPMC Univ Paris 06 , UMR_S ICAN U1166; Inserm; Nutriomic Team , F-75013 , Paris , France ; Assistance Publique-Hôpitaux de Paris , Pitié-Salpêtrière Hospital , Heart and Metabolism Department , Nutrition Unit , 47-83 Boulevard de l'Hôpital , 75651 Paris Cedex 13 , France.
authors.forename: Christine
authors.initials: C
authors.lastname: Poitou
authors.affiliation: Inserm UMR_S 1138 , Centre de Recherche des Cordeliers ; Sorbonne universités , UPMC Univ Paris 06 ; Sorbonne Cités , UPD Univ Paris 05 ; F-75006 , Paris , France.
authors.forename: Amal Ait
authors.initials: AA
authors.lastname: Omar
authors.affiliation: Inserm UMR_S 1138 , Centre de Recherche des Cordeliers ; Sorbonne universités , UPMC Univ Paris 06 ; Sorbonne Cités , UPD Univ Paris 05 ; F-75006 , Paris , France ; Inserm UMR_S 1149 , DHU Unity , UFR de Médecine Paris Diderot ; Sorbonne Cités , UPD Univ Paris 05 , F-75890 , Paris , France.
authors.forename: Maude
authors.initials: M
authors.lastname: Le Gall
authors.affiliation: INRA UMR 1319 Micalis , Interactions des Commensales et Probiotiques avec l'Hôte , F-78350 Jouy-en-Josas , France ; AgroParisTech , UMR 1319 Micalis , F-78350 Jouy-en-Josas , France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Miquel
authors.affiliation: Inserm UMR_S 1138 , Centre de Recherche des Cordeliers ; Sorbonne universités , UPMC Univ Paris 06 ; Sorbonne Cités , UPD Univ Paris 05 ; F-75006 , Paris , France.
authors.forename: Kévin
authors.initials: K
authors.lastname: Garbin
authors.affiliation: Inserm UMR_S 1138 , Centre de Recherche des Cordeliers ; Sorbonne universités , UPMC Univ Paris 06 ; Sorbonne Cités , UPD Univ Paris 05 ; F-75006 , Paris , France ; Institut de Cardiométabolisme et Nutrition , ICAN , Pitié-Salpêtrière Hospital , Paris , France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Ribeiro
authors.affiliation: Assistance Publique-Hôpitaux de Paris , Surgery Department , Ambroise Paré Hospital , Boulogne-Billancourt , France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Bouillot
authors.affiliation: Inserm UMR_S 1149 , DHU Unity , UFR de Médecine Paris Diderot ; Sorbonne Cités , UPD Univ Paris 05 , F-75890 , Paris , France.
authors.forename: André
authors.initials: A
authors.lastname: Bado
authors.affiliation: Inserm UMR_S 1138 , Centre de Recherche des Cordeliers ; Sorbonne universités , UPMC Univ Paris 06 ; Sorbonne Cités , UPD Univ Paris 05 ; F-75006 , Paris , France ; Institut de Cardiométabolisme et Nutrition , ICAN , Pitié-Salpêtrière Hospital , Paris , France.
authors.forename: Edith
authors.initials: E
authors.lastname: Brot-Laroche
authors.affiliation: Institut de Cardiométabolisme et Nutrition , ICAN , Pitié-Salpêtrière Hospital , Paris , France ; Sorbonne universités , UPMC Univ Paris 06 , UMR_S ICAN U1166; Inserm; Nutriomic Team , F-75013 , Paris , France ; Assistance Publique-Hôpitaux de Paris , Pitié-Salpêtrière Hospital , Heart and Metabolism Department , Nutrition Unit , 47-83 Boulevard de l'Hôpital , 75651 Paris Cedex 13 , France.
authors.forename: Karine
authors.initials: K
authors.lastname: Clément
authors.affiliation: Inserm UMR_S 1138 , Centre de Recherche des Cordeliers ; Sorbonne universités , UPMC Univ Paris 06 ; Sorbonne Cités , UPD Univ Paris 05 ; F-75006 , Paris , France ; Institut de Cardiométabolisme et Nutrition , ICAN , Pitié-Salpêtrière Hospital , Paris , France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Leturque
authors.affiliation: Inserm UMR_S 1149 , DHU Unity , UFR de Médecine Paris Diderot ; Sorbonne Cités , UPD Univ Paris 05 , F-75890 , Paris , France ; Institut Cochin , Inserm UMR_S 1016 , CNRS UMR 8104 , Sorbonne Cités , UPD Univ Paris 05 ; Endocrinology , Metabolism and Diabetes Department , F-75014; Paris , France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Guilmeau
authors.affiliation: Inserm UMR_S 1138 , Centre de Recherche des Cordeliers ; Sorbonne universités , UPMC Univ Paris 06 ; Sorbonne Cités , UPD Univ Paris 05 ; F-75006 , Paris , France ; Institut de Cardiométabolisme et Nutrition , ICAN , Pitié-Salpêtrière Hospital , Paris , France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Serradas
keywords: BrdU, bromodeoxyuridine; CD, control diet; Enteroendocrine cells; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; Gut hormones; HFD, high-fat diet; High-fat diet; Intestine; PYY, peptide YY; foxa1, forkhead box protein A1; foxa2, forkhead box protein A2; isl1, insulin gene enhancer protein-1; ngn3, neurogenin3; pax6, paired box protein-6