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01.02.2015 | Article

Genetic deletion of Wdr13 improves the metabolic phenotype of Lepr ^db/db mice by modulating AP1 and PPARγ target genes

verfasst von: Vijay P. Singh, Chandrashekaran Gurunathan, Sachin Singh, Bhavtaran Singh, B. Jyothi Lakshmi, Arun P. Mishra, Satish Kumar

Erschienen in: Diabetologia | Ausgabe 2/2015

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Abstract

Aim/hypothesis

Type 2 diabetes is a complex disease characterised by hyperglycaemia, hyperinsulinaemia, dyslipidaemia and insulin resistance accompanied by inflammation. Previously, we showed that mice lacking the Wdr13 gene had increased islet mass due to enhanced beta cell proliferation. We hypothesised that introgression of a Wdr13-null mutation, a beta cell-proliferative phenotype, into Lepr ^db/db mice, a beta cell-destructive phenotype, might rescue the diabetic phenotype of the latter.

Methods

Wdr13-deficient mice were crossed with Lepr ^db/db mice to generate mice with the double mutation. We measured various serum metabolic variables of Wdr13 ^+/0 Lepr ^db/db and Wdr13 ^−/0 Lepr ^db/db mice. Further, we analysed the histopathology and gene expression of peroxisome proliferator-activated receptor (PPAR)γ and, activator protein (AP)1 targets in various metabolic tissues.

Results

Lepr ^db/db mice with the Wdr13 deletion had a massively increased islet mass, hyperinsulinaemia and adipocyte hypertrophy. The increase in beta cell mass in Wdr13 ^−/0 Lepr ^db/db mice was due to an increase in beta cell proliferation. Hypertrophy of adipocytes may be the result of increase in transcription of Pparg and its target genes, leading in turn to increased expression of several lipogenic genes. We also observed a significant decrease in the expression of AP1 and nuclear factor κ light chain enhancer of activated B cells (NFκB) target genes involved in inflammation.

Conclusions/interpretation

This study provides evidence that loss of WD repeat domain 13 (WDR13) protein in the Lepr ^db/db mouse model of diabetes is beneficial. Based on these findings, we suggest that WDR13 may be a potential drug target for ameliorating hyperglycaemia and inflammation in diabetic conditions.

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Titel: Genetic deletion of Wdr13 improves the metabolic phenotype of Lepr db/db mice by modulating AP1 and PPARγ target genes
verfasst von: Vijay P. Singh
Chandrashekaran Gurunathan
Sachin Singh
Bhavtaran Singh
B. Jyothi Lakshmi
Arun P. Mishra
Satish Kumar
Publikationsdatum: 01.02.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 2/2015
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-014-3438-y

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Genetic deletion of Wdr13 improves the metabolic phenotype of Lepr ^db/db mice by modulating AP1 and PPARγ target genes

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