title: Glucose Tolerance Is Improved in Mice Invalidated for the Nuclear Receptor HNF-4γ: A Critical Role for Enteroendocrine Cell Lineage.
abstract: Intestine contributes to energy homeostasis through the absorption, metabolism, and transfer of nutrients to the organism. We demonstrated previously that hepatocyte nuclear receptor-4α (HNF-4α) controls intestinal epithelium homeostasis and intestinal absorption of dietary lipids. HNF-4γ, the other HNF-4 form highly expressed in intestine, is much less studied. In HNF-4γ knockout mice, we detect an exaggerated insulin peak and improvement in glucose tolerance during oral but not intraperitoneal glucose tolerance tests, highlighting the involvement of intestine. Moreover, the enteroendocrine L-type cell lineage is modified, as assessed by the increased expression of transcription factors Isl1, Foxa1/2, and Hnf4a, leading to an increase of both GLP-1-positive cell number and basal and stimulated GLP-1 plasma levels potentiating the glucose-stimulated insulin secretion. Using the GLP-1 antagonist exendin (9-39), we demonstrate a direct effect of GLP-1 on improved glucose tolerance. GLP-1 exerts a trophic effect on pancreatic β-cells, and we report an increase of the β-cell fraction correlated with an augmented number of proliferative islet cells and with resistance to streptozotocin-induced diabetes. In conclusion, the loss of HNF-4γ improves glucose homeostasis through a modulation of the enteroendocrine cell lineage.
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Floriane
authors.initials: F
authors.lastname: Baraille
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Sami
authors.initials: S
authors.lastname: Ayari
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Carrière
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Osinski
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Garbin
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Blondeau
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Guillemain
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Serradas
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Rousset
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Lacasa
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France UMR_S 1158, Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France agnes.ribeiro-pillet@crc.jussieu.fr philippe.cardot@upmc.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Cardot
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France agnes.ribeiro-pillet@crc.jussieu.fr philippe.cardot@upmc.fr.
authors.forename: Agnès
authors.initials: A
authors.lastname: Ribeiro
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D019070:Cell Lineage / Q000502:physiology*; D019858:Enteroendocrine Cells / Q000166:cytology / Q000378:metabolism*; D005951:Glucose Tolerance Test; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D007328:Insulin / Q000097:blood*; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D001786:Blood Glucose; D051557:Hepatocyte Nuclear Factor 4; C496598:Hnf4g protein, mouse; D007328:Insulin