THIAZOLIDINEDIONES REPRESS OB GENE-EXPRESSION IN RODENTS VIA ACTIVATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA

The ob gene product, leptin, is a signaling factor regulating body wei ght and energy balance, ob gene expression in rodents is increased in obesity and is regulated by feeding patterns and hormones, such as ins ulin and glucocorticoids, In humans with gross obesity, ob mRNA levels are higher, but other modulators of human ob expression are unknown, In view of the importance of peroxisome proliferator-activated recepto r gamma (PPAR gamma) in adipocyte differentiation, we analyzed whether ob gene expression is subject to regulation by factors activating PPA Rs, Treatment of rats with the PPAR alpha activator fenofibrate did no t change adipose tissue and body weight and had no significant effect on ob mRNA levels, However, administration of the thiazolidinedione BR L49653, a PPAR gamma ligand, increased food intake and adipose tissue weight while reducing ob mRNA levels in rats in a dose-dependent manne r, The inhibitory action of the thiazolidinedione BRL49653 on ob mRNA levels was also observed in vitro, Thiazolidinediones reduced the expr ession of the human ob promoter in primary adipocytes, however, in und ifferentiated 3T3-L1 preadipocytes lacking endogenous PPAR gamma, cotr ansfection of PPAR gamma was required to observe the decrease, In conc lusion, these data suggest that PPAR gamma activators reduce ob mRNA l evels through an effect of PPAR gamma on the ob promoter.