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Phenotypic Characterization of Mice Carrying Homozygous Deletion of KLF11, a Gene in Which Mutations Cause Human Neonatal and MODY VII Diabetes. Endocrinology 2015 Oct;156(10):3581-95 PMID: 26248217 PMCID: PMC4588811

Pubmed ID

26248217

DOI

10.1210/en.2015-1145

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.

Author List

Mathison A, Escande C, Calvo E, Seo S, White T, Salmonson A, Faubion WA Jr, Buttar N, Iovanna J, Lomberk G, Chini EN, Urrutia R

Authors

Gwen Lomberk PhD Associate Professor in the Surgery department at Medical College of Wisconsin
Angela Mathison PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin




Scopus

2-s2.0-84943616432   3 Citations

MESH terms used to index this publication - Major topics in bold

Analysis of Variance
Animals
Blood Glucose
DNA-Binding Proteins
Diabetes Mellitus, Type 2
Dyslipidemias
Energy Metabolism
Female
Gene Deletion
Homozygote
Humans
Infant, Newborn
Insulin
Insulin Resistance
Liver
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Oligonucleotide Array Sequence Analysis
Phenotype
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors
Transcriptome
jenkins-FCD Prod-310 bff9d975ec7f2d302586822146c2801dd4449aad