Phenotypic characterization of mice carrying homozygous deletion of KLF11, a gene in which mutations cause human neonatal and MODY VII diabetes

Angela Mathison, Carlos Escande, Ezequiel Calvo, Seungmae Seo, Thomas White, Ann Salmonson, William Alvis Faubion, Navtej Singh Buttar, Juan Iovanna, Gwen Lomberk, Eduardo Nunes Chini, Raul Urrutia

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3581-3595
Number of pages15
JournalEndocrinology
Volume156
Issue number10
DOIs
StatePublished - Oct 1 2015

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Type 2 Diabetes Mellitus
Mutation
Insulin Resistance
Genes
Kruppel-Like Transcription Factors
Insulin
Phenotype
Peroxisome Proliferator-Activated Receptors
Gene Regulatory Networks
Dyslipidemias
Lipid Metabolism
Blood Glucose
Diabetes Mellitus
Homeostasis
Transcription Factors
Body Weight
Genome
Amino Acids
Polymerase Chain Reaction
Liver

ASJC Scopus subject areas

  • Endocrinology

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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. / Mathison, Angela; Escande, Carlos; Calvo, Ezequiel; Seo, Seungmae; White, Thomas; Salmonson, Ann; Faubion, William Alvis; Buttar, Navtej Singh; Iovanna, Juan; Lomberk, Gwen; Chini, Eduardo Nunes; Urrutia, Raul.

In: Endocrinology, Vol. 156, No. 10, 01.10.2015, p. 3581-3595.

Research output: Contribution to journalArticle

Mathison, Angela ; Escande, Carlos ; Calvo, Ezequiel ; Seo, Seungmae ; White, Thomas ; Salmonson, Ann ; Faubion, William Alvis ; Buttar, Navtej Singh ; Iovanna, Juan ; Lomberk, Gwen ; Chini, Eduardo Nunes ; Urrutia, Raul. / Phenotypic characterization of mice carrying homozygous deletion of KLF11, a gene in which mutations cause human neonatal and MODY VII diabetes. In: Endocrinology. 2015 ; Vol. 156, No. 10. pp. 3581-3595.
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