Activation of PPARdelta up-regulates fatty acid oxidation and energy uncoupling genes of mitochondria and reduces palmitate-induced apoptosis in pancreatic beta-cells

Biochem Biophys Res Commun. 2010 Jan 15;391(3):1567-72. doi: 10.1016/j.bbrc.2009.12.127. Epub 2009 Dec 27.

Abstract

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 (PPARdelta) 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 PPARdelta), we found that administration of GW increased the expression of PPARdelta mRNA. GW-induced activation of PPARdelta 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 PPARdelta plays an important role in protecting pancreatic beta-cells against aberrations caused by lipotoxicity in metabolic syndrome and diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl-CoA Dehydrogenase, Long-Chain / genetics
  • Animals
  • Carnitine O-Palmitoyltransferase / genetics
  • Cell Line
  • Cricetinae
  • Fatty Acids / metabolism*
  • Gene Expression Regulation*
  • Genes, Mitochondrial*
  • Insulin / metabolism*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / ultrastructure
  • Ion Channels / genetics
  • Microscopy, Electron, Transmission
  • Mitochondria / drug effects
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondrial Proteins / genetics
  • Oxidation-Reduction
  • PPAR delta / agonists
  • PPAR delta / metabolism*
  • Palmitic Acid / pharmacology
  • Protein Kinases / genetics
  • Thiazoles / pharmacology
  • Uncoupling Protein 2
  • Up-Regulation

Substances

  • Fatty Acids
  • GW 501516
  • Insulin
  • Ion Channels
  • Mitochondrial Proteins
  • PPAR delta
  • Thiazoles
  • Uncoupling Protein 2
  • Palmitic Acid
  • Acyl-CoA Dehydrogenase, Long-Chain
  • Carnitine O-Palmitoyltransferase
  • Protein Kinases
  • pyruvate dehydrogenase kinase 4