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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 Mice¹

Departments of Medicine and Psychiatry (L.H.T., K.N.), University of California, San Francisco, California 94143; and Metabolism Section, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, California 94121

Address all correspondence and requests for reprints to: Riaz A. Memon, Ph.D., Department of Veterans Affairs Medical Center, Metabolism Section 111F, 4150 Clement Street, San Francisco, California 94121. E-mail: rmemon{at}itsa.ucsf.edu

Peroxisome proliferator-activated receptors (PPARs) are transcription factors 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. , , and , have distinct tissue distribution patterns. PPAR- is predominantly present in the liver, and PPAR- in adipose tissue, whereas PPAR- is ubiquitously expressed. A recent study reported increased PPAR- messenger RNA (mRNA) expression in the liver in ob/ob mice; however, it is not known whether increased PPAR- expression in the liver has any functional consequences. The expression of PPAR- and - in the liver in obesity has not been determined. We have now examined the mRNA levels of PPAR-, -, and - 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 develop a late-onset obesity that is associated with higher plasma leptin levels. Our results show that PPAR- mRNA levels in the liver are increased by 2- to 3-fold in all three obese models, whereas hepatic PPAR- 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- mRNA expression is not altered in ob/ob or db/db mice. To determine whether increased PPAR- expression in the liver has any functional consequences, we examined the effect of troglitazone treatment on the hepatic mRNA levels of several PPAR--responsive adipose tissue-specific genes that have either no detectable or very low basal expression in the liver. The treatment of lean control mice with troglitazone 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. Troglitazone 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- activators on lipid metabolism and energy homeostasis in obesity and type 2 diabetes may be partly mediated through their effects on PPAR- in the liver.

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