BMB reports 679 http://bmbreports.org BMB reports *Corresponding author. Tel: 34-91-372.47.60; Fax: 34-91-351.04.96; E-mail: carbocos@ceu.es Received 4 May 2009, Accepted 30 May 2009 Keywords: Adipose tissue, Fenofibrate, mRNA levels, Pregnancy, Rat Fenofibrate reduces adiposity in pregnant and virgin rats but through different mechanisms María del Carmen González 1 , Hubert Vidal 2 , Emilio Herrera 1 & Carlos Bocos 1, * 1 Facultades de Farmacia y Medicina, Universidad CEU San Pablo, Montepríncipe, Boadilla del Monte, Madrid, Spain, 2 University of Lyon, INSERM Unit 870, INRA 1235, Faculty of Medicine Lyon-Sud, Fr-69600 Oullins, France Fenofibrate has been proven to reduce adiposity. Since gestation produces an increase in white adipose tissue (WAT) mass, we comparatively studied this drug-effect in virgin and pregnant rats. Fenofibrate reduced lumbar WAT weight in both pregnant and virgin rats. Fenofibrate treatment did not modify plasma free fatty acid (FFA) concentration in virgin rats, it greatly in- creased it in pregnant animals. Remarkable differences be- tween the two groups were obtained for two proteins related to fatty acid oxidation and esterification and storing. Respectively, the mRNA levels of carnitine palmitoyltransferase I (CPT-I) were increased by the fenofibrate only in the virgin rats and a similar finding was observed for the expression of phosphoe- nolpyruvate carboxykinase (PEPCK). These findings indicate that fenofibrate reduces adiposity in pregnant and virgin rats through different mechanisms: a) in virgin rats, by promoting fatty acid oxidation; and b) in pregnant rats, by enhancing fatty acid output. [BMB reports 2009; 42(10): 679-684] INTRODUCTION Fibrates have been effectively used to reduce plasma triacyl- glycerol levels under conditions of hypertriacylglycerolemia (1). The molecular bases for the action of fibrates on lipid metabo- lism have been elucidated (2, 3) and involve the activation of transcriptional factors, known as peroxisome proliferator-activated receptors (PPAR), principally the PPARα form. However, there are still aspects of the effects of fibrates on lipid metabolism that re- main to be understood. Some fibrates have also been shown to have opposite effects on plasma and liver lipids in rats depend- ing on the degree of hypertriacylglycerolemia (4), and have also been shown to have different regulatory effects on gene ex- pression in rodents versus humans (for a review, 3, 5). During late pregnancy hypertriacylglycerolemia is consistently developed (6) as a consequence of enhanced white adipose tis- sue (WAT) lipolytic activity (7), enhanced liver production of VLDL (8), and decreased extrahepatic lipoprotein lipase activity (9). Moreover, hyperinsulinemia and insulin resistance also de- velop during late pregnancy (10), these being responsible for most of the changes in maternal lipid metabolism (11). Thus, the hypertriacylglycerolemia present during late pregnancy may be comparable to that normally seen in Type 2 diabetic patients, in which the use of fibrates is recommended (12). In a previous work (13), we showed that fenofibrate, a PPARα agonist, was unable to maintain its hypotriacylglycerolemic ef- fect beyond two days in pregnant rats, whereas in virgin rats it efficiently produced the expected reduction on plasma tri- acylglycerol throughout its treatment. Such inefficiency of feno- fibrate on the triacylglycerolemia of pregnant rats was ascribed to the elevated amount of FFA which reached the liver in treated pregnant rats and which were not sufficiently oxidized and/or stored, and therefore had to be canalized back to the plasma as triacylglycerols (13, 14). This implies that WAT in treated preg- nant rats would be releasing fatty acids into the plasma. It has been reported that fenofibrate can reduce body weight gain in animal models of diabetes (15), obesity (16), and insulin resistance such as seen in obese Zucker rats (17) and high fat fed C57BL/6 mice (18), as well as in normal rats (19). This effect of fe- nofibrate on body weight gain and on the reduction of WAT mass has been ascribed to increased fat catabolism in liver mainly through the induction of target enzymes involved in hepatic fatty acid oxidation (16, 18). In fact, it has been proposed that PPARα activators reduce insulin resistance and WAT depots secondary to their effects on liver. Curiously, no effects were reported in WAT (18). Although there are authors who only determined the hepatic expression of PPARα target genes (20), in spite of having found reductions in adiposity after fenofibrate treatment, recent works indicate that PPARα is also expressed in WAT, where it is able to regulate genes involved in fatty acid oxidation (21). Due to the above mentioned different responses to fenofi- brate in liver of pregnant and virgin animals (13,14), the aim of the present work was to determine the expression of PPAR and related genes in WAT of pregnant and virgin rats receiving or not such treatment. Moreover, since fenofibrate has been pro- ven to reduce adiposity (16-19) and gestation produces an in- crease in WAT mass (22), we comparatively studied this drug-effect in virgin and pregnant rats. Thus, we found that fe-