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

Fibrates and thiazolidinediones are used clinically to treat hypertriglycer idemia and hyperglycemia, respectively. Fibrates bind to the peroxisome pro liferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligan ds of PPAR-gamma. These intracellular receptors form heterodimers with reti noid X receptor to modulate gene transcription. To elucidate the target gen es regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF ) for 15 days with a PPAR-alpha -specific compound, fenofibrate, a PPAR-gam ma -specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, GW23 31, and measured the levels of several messenger RNAs (mRNAs) in liver by r eal-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 apolipoprotei n 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 transpo rter 4 and phosphoenolpyruvate carboxykinase in adipose tissue. We identifi ed a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivit y in that tissue by prolonging insulin responses. The results of these stud ies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combin ing actions in hepatic and peripheral tissues. Copyright (C) 2001 by WB. Sa unders Company.