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.

MondoA drives muscle lipid accumulation and insulin resistance

“…KLF11 is involved in the regulation of insulin gene expression in pancreatic β cells. In addition, KLF11 deficiency improves HFD-induced obesity by enhancing energy expenditure and insulin sensitivity (39,40). It will be of great interest to delineate the specific mechanisms involved in the control of myocyte insulin action in muscle.…”

Krüppel-Like Factors

“…KLF4 78 , 79 , KLF5 (83) , KLF6 91 , 92 , KLF8 (82) , KLF9 80 , 81 , KLF13 (84) , and KLF15 (85) promote adipocyte differentiation and adipose tissue expansion, whereas KLF2 (89) , KLF3 (87) , KLF7 (88) , and KLF16 (93) have the opposite effect ( Figure 4 ). Moreover, KLF3 (87) , KLF11 (126) , KLF14 (115) , and KLF15 171 , 172 promote weight gain.…”

“…Phenotypic characterization of Klf11 –/– mice revealed defects in glucose homeostasis, resulting in part from β-cell dysfunction. These mice demonstrate impaired insulin production but surprisingly maintain lower blood glucose levels resulting from increased peripheral insulin sensitivity 123 , 126 .…”

SP and KLF Transcription Factors in Digestive Physiology and Diseases

“…Despite evidence showing that disruption of KLF11 function leads to human diabetes mellitus, Klf11 -knockout mice do not develop diabetes 189 . Klf11- knockout mice have lower levels of insulin, but they also develop increased sensitivity to insulin and increased lipid metabolism 189 .…”

“…Klf11- knockout mice have lower levels of insulin, but they also develop increased sensitivity to insulin and increased lipid metabolism 189 . These findings indicate that KLF11 regulates not only insulin production, but also metabolic homeostasis.…”