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

The PPAR (peroxisome proliferator activated receptor) transcription factors are ligand-activated nuclear receptors that regulate genes involved in lip id metabolism and homeostasis, PPAR alpha is preferentially expressed in li ver and PPAR gamma preferentially in adipose tissue. Activation of PPAR alp ha leads to peroxisome proliferation and increased beta-oxidation of fatty acids in rodents. PPAR gamma-activation leads to adipocyte differentiation and improved insulin signaling of mature adipocytes, Both PPAR receptors ar e believed to be functional targets for treatment of hyperlipidemia in man. We have treated obese diabetic mice (ob/ob), which have highly elevated le vels of plasma triglycerides, glucose and insulin, for I week with WY14,643 (180 mu mol/kg/day), a selective PPAR alpha agonist, or rosiglitazone (BRL 49653; 2.5 mu mol/kg/day), a selective PPAR gamma agonist, The doses used p roduce a similar therapeutic effect in both treatment groups (lowering of t riglycerides and glucose). High resolution two-dimensional gel electrophore sis of livers showed that WY14,643 and rosiglitazone both produced changes in expression pattern of many proteins involved in peroxisomal fatty acid b eta-oxidation, However, similar experiments performed in lean mice showed s ignificant upregulation of these proteins only with WY14,643 treatment. Fur thermore, 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 gamma mRNA levels were determined and we observed that PPAR gamma 2 m RNA levels were elevated in obese mice compared to lean littermates. As PPA R alpha and PPAR gamma recognize similar DNA response elements, it is likel y that the effects of rosiglitazone on PPAR alpha responsive genes in liver s of the ob/ob mice are mediated by PPAR gamma 2.