title: Phenotypic Characterization of Mice Carrying Homozygous Deletion of KLF11, a Gene in Which Mutations Cause Human Neonatal and MODY VII Diabetes.
abstract: We have previously shown that amino acid changes in the human Kruppel-Like Factor (KLF) 11 protein is associated with the development of maturity onset diabetes of the young VII, whereas complete inactivation of this pathway by the -331 human insulin mutation causes neonatal diabetes mellitus. Here, we report that Klf11-/- mice have decreased circulating insulin levels, alterations in the control of blood glucose and body weight, as well as serum dyslipidemia, but do not develop diabetes. Functional assays using ex vivo liver tissue sections demonstrate that Klf11-/- mice display increased insulin sensitivity. Genome-wide experiments validated by pathway-specific quantitative PCR arrays reveal that the Klf11-/- phenotype associates to alterations in the regulation of gene networks involved in lipid metabolism, in particular those regulated by peroxisome proliferator-activated receptor-γ. Combined, these results demonstrate that the major phenotype given by the whole-body deletion of Klf11 in mouse is not diabetes but increased insulin sensitivity, likely due to altered transcriptional regulation in target tissues. The absence of diabetes in the Klf11-/- mouse either indicates an interspecies difference for the role of this transcription factor in metabolic homeostasis between mouse and humans, or potentially highlights the fact that other molecular factors can compensate for its absence. Nevertheless, the data of this study, gathered at the whole-organism level, further support a role for KLF11 in metabolic processes like insulin sensitivity, which regulation is critical in several forms of diabetes.
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics (A.M., A.S., W.A.F., N.B., G.L., R.U.), Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, Medicine, Epigenomics Translation Program Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905; Metabolic Diseases and Aging Laboratory (C.E.), Institut Pasteur Montevideo, Montevideo 11400, Uruguay; Department of Anesthesia and Robert and Arlene Kogod Center on Aging (C.E., T.W., E.N.C.), Mayo Clinic, Rochester, Minnesota 55905; Endocrinology and Nephrology (E.C.), Centre Hospitalier Universitaire de Québec Research Center and Laval University, Québec, Québec, G1V 4G2, Canada; Lieber Institute for Brain Development (S.S.), Baltimore, Maryland 21205; and Centre de Recherche en Cancérologie de Marseille (J.I.), INSERM U1068, Centre Nationale de la Recherche Scientifique Unité Mixte de Recherche 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, 13288, France.
authors.forename: Angela
authors.initials: A
authors.lastname: Mathison
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics (A.M., A.S., W.A.F., N.B., G.L., R.U.), Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, Medicine, Epigenomics Translation Program Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905; Metabolic Diseases and Aging Laboratory (C.E.), Institut Pasteur Montevideo, Montevideo 11400, Uruguay; Department of Anesthesia and Robert and Arlene Kogod Center on Aging (C.E., T.W., E.N.C.), Mayo Clinic, Rochester, Minnesota 55905; Endocrinology and Nephrology (E.C.), Centre Hospitalier Universitaire de Québec Research Center and Laval University, Québec, Québec, G1V 4G2, Canada; Lieber Institute for Brain Development (S.S.), Baltimore, Maryland 21205; and Centre de Recherche en Cancérologie de Marseille (J.I.), INSERM U1068, Centre Nationale de la Recherche Scientifique Unité Mixte de Recherche 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, 13288, France.
authors.forename: Carlos
authors.initials: C
authors.lastname: Escande
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics (A.M., A.S., W.A.F., N.B., G.L., R.U.), Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, Medicine, Epigenomics Translation Program Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905; Metabolic Diseases and Aging Laboratory (C.E.), Institut Pasteur Montevideo, Montevideo 11400, Uruguay; Department of Anesthesia and Robert and Arlene Kogod Center on Aging (C.E., T.W., E.N.C.), Mayo Clinic, Rochester, Minnesota 55905; Endocrinology and Nephrology (E.C.), Centre Hospitalier Universitaire de Québec Research Center and Laval University, Québec, Québec, G1V 4G2, Canada; Lieber Institute for Brain Development (S.S.), Baltimore, Maryland 21205; and Centre de Recherche en Cancérologie de Marseille (J.I.), INSERM U1068, Centre Nationale de la Recherche Scientifique Unité Mixte de Recherche 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, 13288, France.
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Calvo
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics (A.M., A.S., W.A.F., N.B., G.L., R.U.), Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, Medicine, Epigenomics Translation Program Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905; Metabolic Diseases and Aging Laboratory (C.E.), Institut Pasteur Montevideo, Montevideo 11400, Uruguay; Department of Anesthesia and Robert and Arlene Kogod Center on Aging (C.E., T.W., E.N.C.), Mayo Clinic, Rochester, Minnesota 55905; Endocrinology and Nephrology (E.C.), Centre Hospitalier Universitaire de Québec Research Center and Laval University, Québec, Québec, G1V 4G2, Canada; Lieber Institute for Brain Development (S.S.), Baltimore, Maryland 21205; and Centre de Recherche en Cancérologie de Marseille (J.I.), INSERM U1068, Centre Nationale de la Recherche Scientifique Unité Mixte de Recherche 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, 13288, France.
authors.forename: Seungmae
authors.initials: S
authors.lastname: Seo
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics (A.M., A.S., W.A.F., N.B., G.L., R.U.), Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, Medicine, Epigenomics Translation Program Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905; Metabolic Diseases and Aging Laboratory (C.E.), Institut Pasteur Montevideo, Montevideo 11400, Uruguay; Department of Anesthesia and Robert and Arlene Kogod Center on Aging (C.E., T.W., E.N.C.), Mayo Clinic, Rochester, Minnesota 55905; Endocrinology and Nephrology (E.C.), Centre Hospitalier Universitaire de Québec Research Center and Laval University, Québec, Québec, G1V 4G2, Canada; Lieber Institute for Brain Development (S.S.), Baltimore, Maryland 21205; and Centre de Recherche en Cancérologie de Marseille (J.I.), INSERM U1068, Centre Nationale de la Recherche Scientifique Unité Mixte de Recherche 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, 13288, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: White
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics (A.M., A.S., W.A.F., N.B., G.L., R.U.), Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, Medicine, Epigenomics Translation Program Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905; Metabolic Diseases and Aging Laboratory (C.E.), Institut Pasteur Montevideo, Montevideo 11400, Uruguay; Department of Anesthesia and Robert and Arlene Kogod Center on Aging (C.E., T.W., E.N.C.), Mayo Clinic, Rochester, Minnesota 55905; Endocrinology and Nephrology (E.C.), Centre Hospitalier Universitaire de Québec Research Center and Laval University, Québec, Québec, G1V 4G2, Canada; Lieber Institute for Brain Development (S.S.), Baltimore, Maryland 21205; and Centre de Recherche en Cancérologie de Marseille (J.I.), INSERM U1068, Centre Nationale de la Recherche Scientifique Unité Mixte de Recherche 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, 13288, France.
authors.forename: Ann
authors.initials: A
authors.lastname: Salmonson
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics (A.M., A.S., W.A.F., N.B., G.L., R.U.), Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, Medicine, Epigenomics Translation Program Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905; Metabolic Diseases and Aging Laboratory (C.E.), Institut Pasteur Montevideo, Montevideo 11400, Uruguay; Department of Anesthesia and Robert and Arlene Kogod Center on Aging (C.E., T.W., E.N.C.), Mayo Clinic, Rochester, Minnesota 55905; Endocrinology and Nephrology (E.C.), Centre Hospitalier Universitaire de Québec Research Center and Laval University, Québec, Québec, G1V 4G2, Canada; Lieber Institute for Brain Development (S.S.), Baltimore, Maryland 21205; and Centre de Recherche en Cancérologie de Marseille (J.I.), INSERM U1068, Centre Nationale de la Recherche Scientifique Unité Mixte de Recherche 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, 13288, France.
authors.forename: William A
authors.initials: WA
authors.lastname: Faubion
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics (A.M., A.S., W.A.F., N.B., G.L., R.U.), Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, Medicine, Epigenomics Translation Program Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905; Metabolic Diseases and Aging Laboratory (C.E.), Institut Pasteur Montevideo, Montevideo 11400, Uruguay; Department of Anesthesia and Robert and Arlene Kogod Center on Aging (C.E., T.W., E.N.C.), Mayo Clinic, Rochester, Minnesota 55905; Endocrinology and Nephrology (E.C.), Centre Hospitalier Universitaire de Québec Research Center and Laval University, Québec, Québec, G1V 4G2, Canada; Lieber Institute for Brain Development (S.S.), Baltimore, Maryland 21205; and Centre de Recherche en Cancérologie de Marseille (J.I.), INSERM U1068, Centre Nationale de la Recherche Scientifique Unité Mixte de Recherche 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, 13288, France.
authors.forename: Navtej
authors.initials: N
authors.lastname: Buttar
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics (A.M., A.S., W.A.F., N.B., G.L., R.U.), Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, Medicine, Epigenomics Translation Program Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905; Metabolic Diseases and Aging Laboratory (C.E.), Institut Pasteur Montevideo, Montevideo 11400, Uruguay; Department of Anesthesia and Robert and Arlene Kogod Center on Aging (C.E., T.W., E.N.C.), Mayo Clinic, Rochester, Minnesota 55905; Endocrinology and Nephrology (E.C.), Centre Hospitalier Universitaire de Québec Research Center and Laval University, Québec, Québec, G1V 4G2, Canada; Lieber Institute for Brain Development (S.S.), Baltimore, Maryland 21205; and Centre de Recherche en Cancérologie de Marseille (J.I.), INSERM U1068, Centre Nationale de la Recherche Scientifique Unité Mixte de Recherche 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, 13288, France.
authors.forename: Juan
authors.initials: J
authors.lastname: Iovanna
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics (A.M., A.S., W.A.F., N.B., G.L., R.U.), Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, Medicine, Epigenomics Translation Program Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905; Metabolic Diseases and Aging Laboratory (C.E.), Institut Pasteur Montevideo, Montevideo 11400, Uruguay; Department of Anesthesia and Robert and Arlene Kogod Center on Aging (C.E., T.W., E.N.C.), Mayo Clinic, Rochester, Minnesota 55905; Endocrinology and Nephrology (E.C.), Centre Hospitalier Universitaire de Québec Research Center and Laval University, Québec, Québec, G1V 4G2, Canada; Lieber Institute for Brain Development (S.S.), Baltimore, Maryland 21205; and Centre de Recherche en Cancérologie de Marseille (J.I.), INSERM U1068, Centre Nationale de la Recherche Scientifique Unité Mixte de Recherche 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, 13288, France.
authors.forename: Gwen
authors.initials: G
authors.lastname: Lomberk
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics (A.M., A.S., W.A.F., N.B., G.L., R.U.), Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, Medicine, Epigenomics Translation Program Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905; Metabolic Diseases and Aging Laboratory (C.E.), Institut Pasteur Montevideo, Montevideo 11400, Uruguay; Department of Anesthesia and Robert and Arlene Kogod Center on Aging (C.E., T.W., E.N.C.), Mayo Clinic, Rochester, Minnesota 55905; Endocrinology and Nephrology (E.C.), Centre Hospitalier Universitaire de Québec Research Center and Laval University, Québec, Québec, G1V 4G2, Canada; Lieber Institute for Brain Development (S.S.), Baltimore, Maryland 21205; and Centre de Recherche en Cancérologie de Marseille (J.I.), INSERM U1068, Centre Nationale de la Recherche Scientifique Unité Mixte de Recherche 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, 13288, France.
authors.forename: Eduardo N
authors.initials: EN
authors.lastname: Chini
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics (A.M., A.S., W.A.F., N.B., G.L., R.U.), Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, Medicine, Epigenomics Translation Program Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905; Metabolic Diseases and Aging Laboratory (C.E.), Institut Pasteur Montevideo, Montevideo 11400, Uruguay; Department of Anesthesia and Robert and Arlene Kogod Center on Aging (C.E., T.W., E.N.C.), Mayo Clinic, Rochester, Minnesota 55905; Endocrinology and Nephrology (E.C.), Centre Hospitalier Universitaire de Québec Research Center and Laval University, Québec, Québec, G1V 4G2, Canada; Lieber Institute for Brain Development (S.S.), Baltimore, Maryland 21205; and Centre de Recherche en Cancérologie de Marseille (J.I.), INSERM U1068, Centre Nationale de la Recherche Scientifique Unité Mixte de Recherche 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, 13288, France.
authors.forename: Raul
authors.initials: R
authors.lastname: Urrutia
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001786:Blood Glucose / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D050171:Dyslipidemias / Q000097:blood / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D059467:Transcriptome
chemical_list: D051017:Apoptosis Regulatory Proteins; D001786:Blood Glucose; D004268:DNA-Binding Proteins; D007328:Insulin; C506460:KLF11 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors