Up-Regulation of Peroxisome Proliferator-Activated Receptors (PPAR- ) and PPAR- Messenger Ribonucleic Acid Expression in the Liver in Murine Obesity: Troglitazone Induces Expression of PPAR- -Responsive Adipose Tissue-Specific Genes in the Liver of Obese Diabetic Mice

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Abstract
Peroxisome proliferator-activated receptors (PPARs) are tran- scription factors that play an important role in the regulation of genes involved in lipid utilization and storage, lipoprotein metabolism, adi- pocyte differentiation, and insulin action. The three isoforms of the PPAR family, i.e. a, d, and g, have distinct tissue distribution pat- terns. PPAR-a is predominantly present in the liver, and PPAR-g in adipose tissue, whereas PPAR-d is ubiquitously expressed. A recent study reported increased PPAR-g messenger RNA (mRNA) expres- sion in the liver in ob/ob mice; however, it is not known whether increased PPAR-g expression in the liver has any functional conse- quences. The expression of PPAR-a and -d in the liver in obesity has not been determined. We have now examined the mRNA levels of PPAR-a ,- d, and -g in three murine models of obesity, namely, ob/ob (leptin-deficient), db/db (leptin-receptor deficient), and serotonin 5-HT2c receptor (5-HT2cR) mutant mice. 5-HT2cR mutant mice de- velop a late-onset obesity that is associated with higher plasma leptin levels. Our results show that PPAR-a mRNA levels in the liver are increased by 2- to 3-fold in all three obese models, whereas hepatic PPAR-g mRNA levels are increased by 7- to 9-fold in ob/ob and db/db mice and by 2-fold in obese 5-HT2cR mutant mice. PPAR-d mRNA expression is not altered in ob/ob or db/db mice. To determine whether increased PPAR-g expression in the liver has any functional consequences, we examined the effect of troglitazone treatment on the hepatic mRNA levels of several PPAR-g-responsive adipose tissue- specific genes that have either no detectable or very low basal ex- pression in the liver. The treatment of lean control mice with trogli- tazone significantly increased the expression of adipocyte fatty acid- binding protein (aP2) and fatty acid translocase (FAT/CD36) in the liver. This troglitazone-induced increase in the expression of aP2 and FAT/CD36 was markedly enhanced in the liver in ob/ob mice. Tro- glitazone also induced a pronounced 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 expression of aP2, FAT/CD36, and uncoupling protein-2 in adipose tissue in lean or ob/ob mice. Taken together, our results suggest that the effects of PPAR-g acti- vators on lipid metabolism and energy homeostasis in obesity and type 2 diabetes may be partly mediated through their effects on PPAR-g in the liver. (Endocrinology 141: 4021- 4031, 2000)

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