Activation of PPARβ/δ protects pancreatic β cells from palmitate-induced apoptosis by upregulating the expression of GLP-1 receptor

We previously showed that activated peroxisome proliferator-activated receptor (PPAR)beta/delta can protect pancreatic beta cells against lipotoxic apoptosis. However, the molecular mechanism remained unclear. Glucagon-like peptide-1 receptor (GLP-1R) has been reported to exhibit a protective effect against lipotoxic apoptosis in pancreatic beta cells. In the present study, we aimed to investigate the underlying molecular mechanisms that PPAR beta/delta activation suppressed apoptosis and improved beta cell function impaired by fatty acids, focusing on contribution of GLP-1R. Isolated rat islets and rat insulin-secreting INS-1 cells were treated with the PPAR beta/delta agonist GW501516 (GW) in the presence or absence of palmitate (PA) and transfected with siRNA for PPAR beta/delta or treated with the PPAR beta/delta antagonist GSK0660. Apoptosis was assessed by DNA fragmentation, Hoechst 33342 staining and flow cytometry. GLP-1R expression in INS-1 cells and islets was assayed by immunoblotting, quantitative PCR (qPCR) and immunofluorescence staining. SREBP-1c, Caveolin-1, Akt, Bcl-2, Bcl-xl and caspase-3 expression was measured using immunoblotting and qPCR Our results showed that PPAR beta/delta activation decreased apoptosis in beta cells and robustly stimulated GLP-1R expression under lipotoxic conditions. GW enhanced glucosestimulated insulin secretion (GSIS) impaired by PA through stimulation of GLP-1R expression in beta cells. Moreover, SREBP-1c/Caveolin-1 signaling was involved in PPAR beta/delta-regulated GLP-1R expression. Finally, GW exerted anti-apoptotic effects via interfering with GLP-1R-dependent Akt/Bcl-2 and Bcl-xl/caspase-3 signaling pathways. Our study suggested that the anti-apoptotic action of GW may involve its transcriptional regulation of GLP-1R, and PPAR beta/delta activation may represent a new therapeutic method for protecting pancreatic beta cells from lipotoxicity. (C) 2013 Elsevier Inc All rights reserved.