Abstract
The peroxisome proliferator-activated receptor delta (PPARdelta) is implicated in regulation of mitochondrial processes in a number of tissues, and PPARdelta activation is associated with decreased susceptibility to ectopic lipid deposition and metabolic disease. Here, we show that PPARdelta is the PPAR subtype expressed at the highest level in insulinoma cells and rat pancreatic islets. Furthermore, PPARdelta displays high transcriptional activity and acts in pronounced synergy with retinoid-X-receptor (RXR). Interestingly, unsaturated fatty acids mimic the effects of synthetic PPARdelta agonists. Using short hairpin RNA-mediated knockdown, we demonstrate that the ability of unsaturated fatty acids to stimulate fatty acid metabolism is dependent on PPARdelta. Activation of PPARdelta 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 PPARdelta 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 PPARdelta and RXR may be beneficial in the prevention of beta-cell dysfunction.
Highlights
The peroxisome proliferator-activated receptor ␦ (PPAR␦) is implicated in regulation of mitochondrial processes in a number of tissues, and peroxisome proliferatoractivated receptor (PPAR)␦ activation is associated with decreased susceptibility to ectopic lipid deposition and metabolic disease
In keeping with high expression of PPAR␦ in primary cells, PPAR␦ and RXR␣ agonists significantly activated carnitine palmitoyltransferase 1b (CPT-1b) and CD36 expression in isolated rat islets (Fig. 3C). These results indicate that the response to PPAR␦ activation is comparable between primary -cells and INS-1E cells. These results show that PPAR␦ regulates genes involved in fatty acid metabolism in both rat islets and INS-1E -cells and is a probable mediator of transcriptional effects of unsaturated fatty acids
The presence of abundant levels of PPAR␦, mRNA in pancreatic islet is well established [9, 15], but until now, no function has been ascribed to this nuclear receptor in pancreatic -cells
Summary
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. 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 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). We previously reported that PPAR␣ governs -cell fatty acid catabolism, while activation of PPAR␥ primarily directs fatty acids toward esterification and accumulation as triglycerides [7]. These specific roles are reflected in the metabolic control of PPAR␣ and PPAR␥ expression.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
