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The Journal of Lipid Research, Vol. 40, 1177-1184, July 1999
Copyright © 1999 by Lipid Research, Inc.

Original Article

Rosiglitazone (BRL49653), a PPAR-selective agonist, causes peroxisome proliferator-like liver effects in obese mice

Correspondence to: Björn Dahllöf

The PPAR (peroxisome proliferator activated receptor) transcription factors are ligand-activated nuclear receptors that regulate genes involved in lipid metabolism and homeostasis. PPAR is preferentially expressed in liver and PPAR preferentially in adipose tissue. Activation of PPAR leads to peroxisome proliferation and increased ß-oxidation of fatty acids in rodents. PPAR-activation leads to adipocyte differentiation and improved insulin signaling of mature adipocytes. Both PPAR receptors are believed to be functional targets for treatment of hyperlipidemia in man. We have treated obese diabetic mice (ob/ob), which have highly elevated levels of plasma triglycerides, glucose and insulin, for 1 week with WY14,643 (180 µmol/kg/day), a selective PPAR agonist, or rosiglitazone (BRL49653; 2.5 µmol/kg/day), a selective PPAR agonist. The doses used produce a similar therapeutic effect in both treatment groups (lowering of triglycerides and glucose). High resolution two-dimensional gel electrophoresis of livers showed that WY14,643 and rosiglitazone both produced changes in expression pattern of many proteins involved in peroxisomal fatty acid ß-oxidation. However, similar experiments performed in lean mice showed significant up-regulation of these proteins only with WY14,643 treatment. Furthermore, the proteins up-regulated by the drugs in obese mice had a higher basal expression in obese controls compared to the lean littermates. Liver PPAR mRNA levels were determined and we observed that PPAR2 mRNA levels were elevated in obese mice compared to lean littermates. As PPAR and PPAR recognize similar DNA response elements, it is likely that the effects of rosiglitazone on PPAR responsive genes in livers of the ob/ob mice are mediated by PPAR2. — Edvardsson, U., M. Bergström, M. Alexandersson, K. Bamberg, B. Ljung, and B. Dahllöf. Rosiglitazone (BRL49653), a PPAR-selective agonist, causes peroxisome proliferator-like liver effects in obese mice. J. Lipid Res. 1999. 40: 1177;–1184.

Supplementary key words: BRL49653, WY14,643, peroxisome proliferation, PPAR, proteomics, ob/ob, obese mice, insulin resistance, two-dimensional gel electrophoresis

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