Activation of PPARd and RXRa stimulates fatty acid oxidatin and insulin secretion inpancreatic beta-cells

ACTIVATION OF PPARd AND RXRa STIMULATES FATTY ACID OXIDATION AND INSULIN SECRETION IN PANCREATIC b-CELLS

Michael Boergesen¹, Kim Ravnskjaer², Francesca Frigerio³, Allan E. Karlsen⁴, Pierre Maechler³ and Susanne Mandrup¹

¹ Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark; ² Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; ³ Department of Cell Physiology and Metabolism, University Medical Centre, CH-1211 Geneva 4, Switzerland; ⁴ Novo Nordisk, Denmark

Synthetic agonists of the peroxisome proliferator-activated receptor (PPAR) ? and PPARa have long been used as insulin-sensitizing and lipid-lowering drugs, respectively. The availability of agonists specific of PPARd has recently promoted great interest in also this third PPAR subtype as a target for treatment of metabolic diseases. Thus, in animal models of obesity PPARd agonists display a modest insulin sensitizing action and a marked improvement of the plasma lipid profile by reducing circulating free fatty acids and triglycerides and raising HDL-cholesterol. The lipid-lowering effect of PPARd-activation correlates with increased oxidation and dissipation of lipids particularly in skeletal muscle.

Here we show that PPARd at the RNA as well as protein level is the most abundant PPAR subtype in the rat pancreatic ß-cell line INS-1E and in isolated rat pancreatic islets. In keeping with that, a large number of PPAR target genes are most potently activated by agonists specific of PPARd rather than by agonists of other PPAR subtypes, and this activation is highly synergistic with agonists of retinoid X receptor (RXR). Activation of PPARd and RXR in INS-1E cells and isolated rat pancreatic islets increases the expression of genes involved in fatty acid uptake and oxidation. This correlates with a 5-fold induction of ¹⁴C-Oleate ß-oxidation when INS-1E cells are exposed to PPARd and RXR agonists. Notably, culture of INS-1E cells with oleate and other unsaturated fatty acids in the presence of an RXR agonist induces the same subset of genes as PPARd specific agonists and stimulates ß-oxidation. Importantly, oleate-induction of gene expression and ß-oxidation in INS-1E cells is abolished by knock-down of PPARd using adenoviral transfer of shRNA. Thus, PPARd appears to be a central regulator of fatty acid metabolism as well as a central effector of unsaturated fatty acids in pancreatic ß-cells.

Interestingly, activation of PPARd increases basal as well as glucose-stimulated insulin secretion of INS-1E cells. This increase is further potentiated by RXR agonists.

This observation suggests that PPARd may mediate some of the positive effects of fatty acids on insulin secretion.

The work is supported by the Danish Health Science Council and the Danish Diabetes Association.