Chronic exposure to high concentrations of saturated fatty acids, such as palmitic acid (PA), leads to apoptosis of pancreatic beta-cells through the activation of the c-Jun N-terminal kinase (JNK) signaling pathway. This study of beta-cell lipoapoptosis was designed to investigate the roles of pancreatic-derived factor (PANDER), a pro-apoptosis cytokine-like peptide, and exendin-4, a long-acting agonist of the hormone glucagon-like peptide-1 (GLP-1) receptor and anti-apoptosis factor. The glucose-sensitive mouse beta-pancreatic cell line, beta TC6, was used to investigate the mechanisms of PA-induced apoptosis. Twenty-four hours of PA exposure led to increased PANDER expression in a dose- and time-dependent manner, and significantly increased phosphorylation of JNK. Treatment with the JNK-specific inhibitor SP600125 reduced the PA-induced PANDER expression. After the 24 h of PA exposure, cells also underwent marked apoptosis and showed increased activation of the apoptosis protease, caspase-3. The small interfering (si)RNA-mediated silencing of PANDER gene expression significantly reduced both of these effects. When PA-treated beta TC6 cells were exposed to exogenous exendin-4, JNK activation was inhibited, PANDER expression was decreased, and the numbers of apoptotic cells were reduced. Collectively, these results demonstrated that the JNK-mediated signaling mechanism of PA-induced beta-cell apoptosis involves up-regulated expression of PANDER and activation of caspase-3. Exendin-4 may protect against lipoapoptosis by interfering with the JNK-PANDER pathway. (C) 2012 Elsevier Inc. All rights reserved.