Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat

Metabolism. 2001 Aug;50(8):963-71. doi: 10.1053/meta.2001.24870.


Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, GW2331, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. Fenofibrate and GW2331 induced expression of acyl-coenzyme A (CoA) oxidase and enoyl-CoA hydratase and reduced apolipoprotein C-III and phosphoenolpyruvate carboxykinase mRNAs. Rosiglitazone modestly increased apolipoprotein C-III mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and phosphoenolpyruvate carboxykinase in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues.

MeSH terms

  • Animals
  • Apolipoprotein C-III
  • Apolipoproteins C / genetics
  • Base Sequence
  • Butyrates / pharmacology
  • DNA Primers
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism
  • Fenofibrate / pharmacology
  • Gene Expression Regulation / physiology*
  • Liver / metabolism*
  • Male
  • Phenylurea Compounds / pharmacology
  • Phosphoenolpyruvate Carboxykinase (ATP) / genetics
  • RNA, Messenger / genetics
  • Rats
  • Rats, Zucker
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Transcription Factors / agonists
  • Transcription Factors / chemistry
  • Transcription Factors / physiology*
  • Triglycerides / blood


  • Apolipoprotein C-III
  • Apolipoproteins C
  • Butyrates
  • DNA Primers
  • GW 2331
  • Phenylurea Compounds
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Triglycerides
  • Phosphoenolpyruvate Carboxykinase (ATP)
  • Fenofibrate