A High-Fat/High-Sucrose Diet Induces WNT4 Expression in Mouse Pancreatic ß-cells.

ABSTRACT

Aims/Introduction: Several lines of evidence suggest that dysregulation of the WNT signaling pathway is involved in the pathogenesis of type 2 diabetes. This study was performed to elucidate the effects of a high-fat/high-sucrose (HF/HS) diet on pancreatic islet functions in relation to modulation of WNT ligand expression in ß-cells. MATERIALS AND METHODS: Mice were fed either standard mouse chow or a HF/HS diet from 8 weeks of age. At 20 weeks of age, intraperitoneal glucose tolerance tests were performed in both groups of mice, followed by euthanasia and isolation of pancreatic islets. WNT-related gene expression in islets and MIN6 cells was measured by quantitative real-time RT-PCR. To explore the direct effects of WNT signals on pancreatic ß-cells, MIN6 cells were exposed to recombinant mouse WNT4 protein (rmWNT4) for 48 h, and glucose-induced insulin secretion was measured. Furthermore, Wnt4 siRNAs were transfected into MIN6 cells, and cell viability and insulin secretion were measured in control and Wnt4 siRNA-transfected MIN6 cells. RESULTS: Mice fed the HF/HS diet were heavier and their plasma glucose and insulin levels were higher compared with mice fed standard chow. Wnt4, Wnt5b, Ror1, and Ror2 expression was upregulated, while Fzd4, Fzd5, Fzd6, Lrp5, and Lrp6 expression was downregulated in the islets of mice fed the HF/HS diet. Wnt4 was the most abundantly expressed WNT ligand in ß-cells, and its expression was increased by the HF/HS diet. Although exposure to recombinant mouse WNT4 protein for 48 h did not alter glucose-induced insulin secretion, it was significantly reduced by knockdown of Wnt4 in MIN6 cells. CONCLUSIONS: We demonstrated that the HF/HS diet-induced increase of WNT4 signaling in ß-cells is involved in augmentation of glucose-induced insulin secretion and impaired ß-cell proliferation. These results strongly indicate an essential role of WNT4 in the regulation of ß-cell functions in mouse pancreatic islets.