Lack of Wdr13 Gene in Mice Leads to Enhanced Pancreatic Beta Cell Proliferation, Hyperinsulinemia and Mild Obesity

Singh, Vijay Pratap; Lakshmi, B. Jyothi; Singh, Shalu; Shah, Vanya; Goel, Sandeep; Sarathi, D. Partha; Kumar, Satish

doi:10.1371/journal.pone.0038685

Cited by 12 publications

(45 citation statements)

References 49 publications

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“…Lepr db/db mice might have been a reflection of a lower birthweight of Wdr13-knockout mice [15], or Wdr13 deletion per se might have prevented body weight gain in the Wdr13…”

Section: Discussionmentioning

confidence: 99%

“…Animals were genotyped using PCR. Body weight, food intake, glucose and insulin tolerance testing and insulin measurements were performed as described previously [15]. Circulating triacylglycerol was measured using the glycerol-3-phosphate oxidase/phenol+aminophenazone (GPO/PAP) method (Coral Clinical Systems, Goa, India).…”

Section: Methodsmentioning

confidence: 99%

“…Histology western blot analysis and real-time PCR Histology and western blot analysis were performed as described [15]. All the tissues for histology, western blot and real-time PCR analyses were collected from mice fasted for 16 h. Haematoxylin and eosin (H&E) staining and immunostaining were carried out on 4 μm sections, mounted on positively charged slides, from tissues fixed overnight in 4% paraformaldehyde and embedded in paraffin.…”

Section: Methodsmentioning

confidence: 99%

“…For Oil Red O (Sigma-Aldrich, Bangalore, India) staining, liver tissues were frozen in OCT compound (Sigma-Aldrich) and 8 μm sections were mounted on slides and stained with 0.5% Oil Red O solution. Western blots were performed using antibodies to nuclear factor of κ light polypeptide gene enhancer in B cells inhibitor, alpha (IκBα) ( Apoptotic assay Tissue sections were prepared as described previously [15]. TUNEL assays were performed using the DeadEnd Fluorometric TUNEL System (Promega).…”

Section: Methodsmentioning

confidence: 99%

“…Wdr13-knockout mice have increased pancreatic beta cell proliferation, which leads to increased islet mass, hyperinsulinaemia and better glucose clearance, notwithstanding mild obesity at a later age [15]. 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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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.

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“…Lepr db/db mice might have been a reflection of a lower birthweight of Wdr13-knockout mice [15], or Wdr13 deletion per se might have prevented body weight gain in the Wdr13…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2014

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

Tong

et al. 2019

Cell Biology International

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Muscle satellite cells are usually at rest, and when externally stimulated or regulated, they can be further differentiated by cell fusion to form new myotubes and muscle fibers. WD repeat domain 13 (WDR13) is highly conserved in vertebrates. Studies have shown that mice lacking the Wdr13 gene develop mild obesity, hyperinsulinemia, and increased islet β cell proliferation. However, the role of WDR13 in bovine cells is unclear. Here, we investigated the effect of WDR13 on bovine skeletal muscle‐derived satellite cells (MDSCs). We found that WDR13 was upregulated in bovine MDSCs using western blotting and immunofluorescence experiments. Moreover, activation and inhibition of WDR13 expression increased and decreased cell differentiation, respectively, suggesting that WDR13 promotes bovine MDSC differentiation. To further understand the mechanism of action of WDR13, we examined changes in the PI3K/AKT signaling pathway following WDR13 activation or inhibition. In addition, cells were treated with a phosphoinositide kinase 3 (PI3K) inhibitor, LY294004, to observe cell differentiation. The results showed that activation of WDR13 inhibited the PI3K/AKT signaling pathway and enhanced cell differentiation. These data suggest that WDR13 can promote the differentiation of bovine MDSCs by affecting the PI3K/AKT signaling pathway.

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Wdr13 and streptozotocin-induced diabetes

et al. 2018

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Type I diabetes, though contributes to only 5–10% of total diabetes cases, is a rising concern in today’s world. Our previous studies have shown that the absence of WDR13 in mouse results in pancreatic β-cell hyper-proliferation. Also, amelioration of the diabetic phenotype on introgression of Wdr13-null (Wdr13-/0) mutation in genetically diabetic mice (Leprdb/db) [type II diabetes] was observed. It was thus, interesting to see the role of WDR13 in streptozotocin-mediated diabetes in mice, a model for type I diabetes. Wdr13-/0 mice along with its wild type (Wdr13+/0 mice) littermates were administered streptozotocin intraperitoneally for 5 consecutive days. Blood glucose levels and body weights of these mice were monitored for subsequent 5 weeks and then they were sacrificed for physiological and histological analyses. Results showed that Wdr13-/0 mice exhibited higher serum insulin levels, better glucose clearance and significantly higher number of proliferating β-cells; reiterating the finding that absence of WDR13 helps in β-cell hyper-proliferation and recovery from diabetes; further underscoring WDR13 as a key target molecule for diabetes treatment/amelioration.

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Lack of Wdr13 Gene in Mice Leads to Enhanced Pancreatic Beta Cell Proliferation, Hyperinsulinemia and Mild Obesity

Cited by 12 publications

References 49 publications

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

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

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

Wdr13 and streptozotocin-induced diabetes

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