Up-regulation of peroxisome proliferator-activated receptors (PPAR-alpha) and PPAR-gamma messenger ribonucleic acid expression in the liver in murineobesity: Troglitazone induces expression of PPAR-gamma-responsive adipose tissue-specific genes in the liver of obese diabetic mice

Peroxisome proliferator-activated receptors (PPARs) are transcription facto rs that play an important role in the regulation of genes involved in lipid utilization and storage, lipoprotein metabolism, adipocyte differentiation , and insulin action. The three isoforms of the PPAR family, i.e. alpha, de lta, and gamma, have distinct tissue distribution patterns. PPAR-alpha is p redominantly present in the liver, and PPAR-gamma in adipose tissue, wherea s PPAR-delta is ubiquitously expressed. A recent study reported increased P PAR-gamma messenger RNA (mRNA) expression in the liver in ob/ob mice; howev er, it is not known whether increased PPAR-gamma expression in the liver ha s any functional consequences. The expression of PPAR-alpha and -delta in t he liver in obesity has not been determined. We have now examined the mRNA levels of PPAR-alpha, -delta, and -gamma in three murine models of obesity, namely, ob/ob (leptin-deficient), db/db (leptin-receptor deficient), and s erotonin 5-HT2c receptor (5-HT2cR) mutant mice. 5-HT2cR mutant mice develop a late-onset obesity that is associated with higher plasma leptin levels. Our results show that PPAR-alpha mRNA levels in the liver are increased by 2- to 3-fold in all three obese models, whereas hepatic PPAR-gamma mRNA lev els are increased by 7- to 9-fold in ob/ob and db/db mice and by a-fold in obese 5-HT2cR mutant mice. PPAR-delta mRNA expression is not altered in ob/ ob or db/db mice. To determine whether increased PPAR-gamma expression in t he liver has any functional consequences, we examined the effect of troglit azone treatment on the hepatic mRNA levels of several PPAR-gamma -responsiv e adipose tissue-specific genes that have either no detectable or very low basal expression in the liver. The treatment of lean control mice with trog litazone significantly increased the expression of adipocyte fatty acid-bin ding protein (aP2) and fatty acid translocase (FAT/CD36) in the liver. This troglitazone-induced increase in the expression of aP2 and FAT/CD86 was ma rkedly enhanced in the liver in ob/ob mice. Troglitazone also induced a pro nounced increase in the expression of uncoupling protein-2 in the liver in ob/ob mice. In contrast to the liver, troglitazone did not increase the exp ression of aP2, FAT/CD36, and uncoupling protein-2 in adipose tissue in lea n or ob/ob mice. Taken together, our results suggest that the effects of PP AR-gamma activators on lipid metabolism and energy homeostasis in obesity a nd type 2 diabetes may be partly mediated through their effects on PPAR-gam ma in the liver.