Erschienen in:
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.