Recent evidence indicates that decreased oxidative capacity, lipotoxicity, and mitochondrial aberrations contribute to the development of insulin resistance and type 2 diabetes. The goal of this study was to investigate the effects of peroxisome proliferator-activated receptor delta (PPAR delta) activation on lipid oxidation, mitochondrial function, and insulin secretion in pancreatic beta-cells. After HIT-T15 cells (a beta-cell line) were exposed to high concentrations of palmitate and GW501516 (GW; a selective agonist of PPAR delta), we found that administration of GW increased the expression of PPAR delta mRNA. GW-induced activation of PPAR delta up-regulated carnitine palmitoyltransferase 1 (CPT1), long-chain acyl-CoA dehydrogenase (LCAD), pyruvate dehydrogenase kinase 4 (PDK4), and uncoupling protein 2 (UCP2); alleviated mitochondrial swelling; attenuated apoptosis: and reduced basal insulin secretion induced by increased palmitate in HIT cells. These results suggest that activation of PPAR delta plays an important role in protecting pancreatic beta-cells against aberrations caused by lipotoxicity in metabolic syndrome and diabetes. (c) 2009 Elsevier Inc. All rights reserved.