The peroxisome proliferator-activated receptors (PPARs) are a family of transcription factors belonging to the nuclear

This article is available online at http://www.jlr.org The peroxisome proliferator-activated receptors (PPARs) are a family of transcription factors belonging to the nuclear receptor superfamily. The PPAR family consists of three subtypes, PPAR , PPAR , and PPAR / , all of which are regulated by fatty acids and their derivatives. The PPARs bind to peroxisome proliferator response elements (PPREs) as heterodimers with the retinoid-X-receptor (RXR). Upon ligand binding, the PPAR-RXR heterodimers stimulate expression of each their subset of genes involved in glucose and fatty acid metabolism, insulin signaling, cell differentiation, or cell proliferation (reviewed in Ref. 1 ). The PPAR subtypes have distinct transactivation characteristics and display preference for distinct subsets of target genes ( 2–4 ). All three PPAR subtypes are expressed in pancreatic -cells ( 5, 6 ). We previously reported that PPAR governs -cell fatty acid catabolism, while activation of PPAR primarily directs fatty acids toward esterifi cation and accumulation as triglycerides ( 7 ). These specifi c roles are refl ected in the metabolic control of PPAR and PPAR expression. Under hypoglycemic fasting conditions, where there is increased demand for energy production from nonglucose substrates, PPAR is most abundant, whereas PPAR is upregulated in -cells under hyperglycemic and hyperlipidemic conditions ( 6, 8, 9 ). PPAR is widely expressed in mammalian tissues and cell types; however, until recently, the function of PPAR in metabolic regulation has been elusive. Evidence now accumulates in favor of a pivotal role for PPAR in basal lipid oxidation. The importance of PPAR in lipid catabolism has been described for metabolically important tisAbstract The peroxisome proliferator-activated receptor (PPAR ) is implicated in regulation of mitochondrial processes in a number of tissues, and PPAR activation is associated with decreased susceptibility to ectopic lipid deposition and metabolic disease. Here, we show that PPAR is the PPAR subtype expressed at the highest level in insulinoma cells and rat pancreatic islets. Furthermore, PPAR displays high transcriptional activity and acts in pronounced synergy with retinoid-X-receptor (RXR). Interestingly, unsaturated fatty acids mimic the effects of synthetic PPAR 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 . Activation of PPAR increases the fatty acid oxidation capacity in INS-1E -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 is a fatty acid sensor that adapts  -cell mitochondrial function to longterm changes in unsaturated fatty acid levels. As maintenance of mitochondrial metabolism is essential to preserve -cell function, these data indicate that dietary or pharmacological activation of PPAR and RXR may be benefi cial in the prevention of -cell dysfunction. —Ravnskjaer, K., F. Frigerio, M. Boergesen, T. Nielsen, P. Maechler, and S. Mandrup. PPAR 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.