PPARδ is a fatty acid sensor that enhances mitochondrial oxidation in insulin-secreting cells and protects against fatty acid-induced dysfunction

The peroxisome proliferator-activated receptor delta (PPAR delta) is implicated in regulation of mitochondrial processes in a number of tissues, and PPAR delta activation is associated with decreased susceptibility to ectopic lipid deposition and metabolic disease. Here, we show that PPAR delta is the PPAR subtype expressed at the highest level in insulinoma cells and rat pancreatic islets. Furthermore, PPAR delta displays high transcriptional activity and acts in pronounced synergy with retinoid-X-receptor (RXR). Interestingly, unsaturated fatty acids mimic the effects of synthetic PPAR delta agonists. Using short hairpin RNA-mediated knockdown, we demonstrate that the ability of unsaturated fatty acids to stimulate fatty acid metabolism is dependent on PPAR delta. Activation of PPAR delta increases the fatty acid oxidation capacity in INS-1E beta-cells, enhances glucose-stimulated insulin secretion (GSIS) from islets, and protects GSIS against adverse effects of prolonged fatty acid exposure. The presented results indicate that the nuclear receptor PPAR delta is a fatty acid sensor that adapts beta-cell mitochondrial function to long-term changes in unsaturated fatty acid levels. As maintenance of mitochondrial metabolism is essential to preserve beta-cell function, these data indicate that dietary or pharmacological activation of PPAR delta and RXR may be beneficial in the prevention of beta-cell dysfunction.-Ravnskjaer, K., F. Frigerio, M. Boergesen, T. Nielsen, P. Maechler, and S. Mandrup. PPAR delta is a fatty acid sensor that enhances mitochondrial oxidation in insulin-secreting cells and protects against fatty acid-induced dysfunction. J. Lipid Res. 2010. 51: 1370-1379.