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

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 Wdr13Lepr db/db and Wdr13Lepr 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.

Implication of Genetic Deletion of Wdr13 in Mice: Mild Anxiety, Better Performance in Spatial Memory Task, with Upregulation of Multiple Synaptic Proteins

“…Similarly, RAB3A is important for synaptic transmission, learning and memory (Yang et al, 2007). CAMK2A belongs to the CaM-kinase II family of proteins-known for their significant role in synaptic plasticity, long term potentiation (LTP), and learning and memory (Soderling, 1993). Levels of Vesicular glutamate transporter 1 (VGLUT1)—an important molecule for excitatory synapse and for maintaining LTP (Balschun et al, 2010) was also found to be increased in Wdr13 −/0 mice.…”

Impaired liver regeneration and lipid homeostasis in CCl4 treated WDR13 deficient mice

“…Cellular hyperproliferation due to downregulation of p21 in absence of WDR13, has also been reported [11]. We have also demonstrated that the introgression of Wdr13 -null mutation in obese and diabetic Lepr db/db mouse model resulted in reduction of serum free-fatty acids, liver triglyceride and systemic inflammation [12]. Cell proliferative phenotype in pancreas and amelioration of fatty liver, prompted us to study the response of Wdr13 -/0 mice to direct liver injury induced by chronic CCl 4 administration and regeneration therein.…”

“…Since our previous study [12] indicated amelioration of fatty liver phenotype upon deletion of Wdr13 in Lepr db/db mice, we analysed liver triglyceride levels in the present study. In contrast to our earlier study, we observed higher triglycerides level in the liver of CCl 4 administered Wdr13 -/0 mice as compared to that in CCl 4 treated wildtypes (Fig.…”

“…WDR13, a member of the WD repeat protein family, is present in most of the mouse tissues, with relatively higher abundance in pancreas, liver, testis and ovary [9]. Previous studies have shown that Wdr13 -/0 mice have age-dependent mild obesity, enhanced pancreatic β-cell proliferation [10–12], hyperinsulinemia and better glucose clearance [10,12]. Cellular hyperproliferation due to downregulation of p21 in absence of WDR13, has also been reported [11].…”

WDR13 promotes the differentiation of bovine skeletal muscle‐derived satellite cells by affecting PI3K/AKT signaling

“…WDR13 was originally discovered by Singh on human X chromosomes Xp11.23 and is highly conserved in vertebrates, where it is prominently expressed in the brain, pancreas, ovary, and testis (Singh et al, ; Suresh et al, ). More recent studies have shown that mice lacking the Wdr13 gene develop mild obesity, hyperinsulinemia, and increased islet β cell proliferation (Singh et al, ; Singh et al, ; Singh et al, ), suggesting a potential role in diabetes. Moreover, we previously demonstrated a significant increase in WDR13 expression during differentiation of bovine myogenic satellite cells (MDSCs) (Tong et al, ).…”