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Cell Signal. 2014 Feb;26(2):268-78. doi: 10.1016/j.cellsig.2013.11.019. Epub 2013 Nov 21.

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

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Division of Endocrinology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
West China School of Medicine, Sichuan University, Chengdu, Sichuan, China.
Laboratory of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
Laboratory of Transplantation Engineering, West China Hospital of Sichuan University, Chengdu, China.
Division of Endocrinology, West China Hospital of Sichuan University, Chengdu, Sichuan, China. Electronic address:


We previously showed that activated peroxisome proliferator-activated receptor (PPAR)β/δ can protect pancreatic β 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 β cells. In the present study, we aimed to investigate the underlying molecular mechanisms that PPARβ/δ activation suppressed apoptosis and improved β 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 PPARβ/δ agonist GW501516 (GW) in the presence or absence of palmitate (PA) and transfected with siRNA for PPARβ/δ or treated with the PPARβ/δ 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 PPARβ/δ activation decreased apoptosis in β cells and robustly stimulated GLP-1R expression under lipotoxic conditions. GW enhanced glucose-stimulated insulin secretion (GSIS) impaired by PA through stimulation of GLP-1R expression in β cells. Moreover, SREBP-1c/Caveolin-1 signaling was involved in PPARβ/δ-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 PPARβ/δ activation may represent a new therapeutic method for protecting pancreatic β cells from lipotoxicity.


Apoptosis; ELISA; Ex; FBS; FDA; FFA; FITC; G protein coupled receptor; GLP-1R; GPCR; GSIS; GW; GW501516; HBSS; Hanks' balanced salt solution; KRBH; PA; PI; PPARβ/δ; Palmitate; Pancreatic β cells; SREBP-1c; T2D; enzyme-linked immunosorbent assay; exendin-4; fetal bovine serum; fluorescein diacetate; fluorescein isothiocyanate; free fatty acid; glucagon-like peptide-1 receptor; glucose-free Krebs–Ringer bicarbonate HEPES buffer; glucose-stimulated insulin secretion; palmitate; peroxisome proliferator-activated receptor β/δ; propidium iodide; qPCR; quantitative polymerase chain reaction; sterol regulatory element binding protein-1c; type 2 diabetes

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