Activated PPARβ/δ Protects Pancreatic β Cells in Type 2 Diabetic Goto-Kakizaki Rats from Lipoapoptosis via GPR40.

GW501516-activated peroxisome proliferator-activated receptor (PPAR) β/δ and G-protein-coupled receptor (GPR) 40 were shown to protect pancreatic β cells against lipoapoptosis. Therefore, this study aimed to investigate whether activated PPARβ/δ could protect type 2 diabetic rats from lipoapoptosis through regulation of GPR40 and to compare the protective effects of activated PPARβ/δ and PPARγ. We made an animal model of type 2 diabetic lipoapoptosis by feeding spontaneously type 2 diabetic Goto-Kakizaki (GK) rats with a high-fat diet (HFD) to evaluate the effects of PPARβ/δ on islet β cell apoptosis. And, treated INS-1 cells with 0.5 mM palmitate (PAM) in the absence/presence of GW501516 (a specific agonist of PPAR β/δ) and with/without transfection of GPR40 siRNA to explore the underlying molecular mechanism. HFD aggravated GK rats' poorer INSR30, lower mass, greater apoptosis of β cells, lower mass, and lower expression of GPR40, which were similarly improved by GW501516 at 3 or 6 mg/kg day and pioglitazone. Compared with pioglitazone, GW501516 caused more weight loss and had no effect on insulin resistance. GW501516 protected INS-1 cells from PAM-induced apoptosis by upregulating GPR40 and activating Akt/Bcl-2/caspase-3. Activated extracellular regulated protein kinases (ERK) was relevant to the lipoapoptosis in INS-1 cells, but was not involved in the antilipoapoptotic effect of GW501516. These results showed that the PPARβ/δ agonist GW501516 protected β cells from lipoapoptosis and improved β cell mass by upregulating GPR40 and activating the Akt/Bcl-2/caspase-3 pathway, but not the ERK-signaling pathway.

Li J ，Xu S ，Liu Y ，Yan Z ，Zhang F ，Lv Q ，Tong N ... -  《-》

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)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.

Yang Y ，Tong Y ，Gong M ，Lu Y ，Wang C ，Zhou M ，Yang Q ，Mao T ，Tong N ... -  《-》

Activation of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) increases the expression of prostaglandin E2 receptor subtype EP4. The roles of phosphatidylinositol 3-kinase and CCAAT/enhancer-binding protein beta.

Han S ，Ritzenthaler JD ，Wingerd B ，Roman J ... -  《JOURNAL OF BIOLOGICAL CHEMISTRY》

PPARβ/δ Agonist Provides Neuroprotection by Suppression of IRE1α-Caspase-12-Mediated Endoplasmic Reticulum Stress Pathway in the Rotenone Rat Model of Parkinson's Disease.

Tong Q ，Wu L ，Gao Q ，Ou Z ，Zhu D ，Zhang Y ... -  《-》

Protective Role of PPARdelta in Lipoapoptosis of Pancreatic β Cells.

Yang Y ，Ren J ，Tong Y ，Hu X ，Lv Q ，Tong N ... -  《-》