Protective Role of PPARdelta in Lipoapoptosis of Pancreatic β Cells

Abstract Lipoapoptosis plays an important role in the pathogenesis of type 2 diabetes. Peroxisome proliferator‐activated receptor delta (PPARdelta), a vital regulator of glucose and lipid metabolism, may reduce fatty acid‐induced pancreatic β cell lipotoxicity in diabetes. However, the detailed molecular mechanisms underlying this process are not fully understood. In this study, we investigated the effect of activation of PPARdelta on palmitate‐induced β cell apoptosis, and we explored the potential mechanism of the antiapoptotic effect. The cell apoptosis was determined by DNA fragmentation analysis and Hoechst 33342 staining. The expressing of glucagon‐like peptide‐1 receptor (GLP‐1R) in INS‐1 cells was assessed by Western blotting, quantification of PCR, and was further confirmed by immunofluorescence staining. The potential of PPARdelta to interact with homologous PPRE in the GLP‐1R gene was determined by Chromatin immunoprecipitation (ChIP). Our results showed that exposure of INS‐1 cells to palmitate for 24 h caused a significant increase in cell apoptosis, which was inhibited by GW501516. PPARdelta exerted anti‐apoptotic effects in pancreatic β cells via the PI3 K/PKB/FoxO1 signaling pathway. Moreover, PPARdelta upregulated the GLP‐1R expression under lipotoxic conditions. The ChIP assay revealed a direct binding of PPARdelta to a noncanonical PPRE motif of the GLP‐1R gene in INS‐1 cells. Our study suggested that the anti‐apoptotic action of PPARdelta may involve its transcriptional regulation of GLP‐1R and PI3 K/PKB/FoxO1 signaling. GW501516 and possible other GW‐based strategies may confer additional benefit beyond improved glycemic control.