15-deoxy-Δ12,14 prostaglandin J2:: A putative endogenous promoter of adipogenesis suppresses the ob gene

Leptin is considered a key factor in the regulation of appetite and energy expenditure, but little is known about the control of its synthesis and release. Thiazolidinediones (TZDs) have recently been shown to downregulate leptin expression, and it has been speculated that downregulation of the ob gene occurs through activation of the transcription factor, peroxisome proliferator-activated receptor gamma (PPAR gamma). However, there are no studies using an endogenous PPAR gamma ligand. We examined the effect of 15-deoxy-Delta(12,14) prostaglandin J(2) (15d-PGJ(2)), a putative natural ligand of PPAR gamma, on ob gene expression in fully differentiated 3T3-L1 adipocytes and compared its effect with that of two other PPAR gamma activators, the TZD troglitazone (Trog) and indomethacin (Indo). 15d-PGJ(2), Trog, and Indo all inhibited leptin expression at concentrations at which they activate PPAR gamma. The inhibition of leptin expression of PPAR gamma activators was surprising, since PPAR gamma is known to induce adipogenesis during which the ob gene is expressed. To address the possibility that PPAR gamma plays different roles before and after the induction of adipogenesis, we examined the effects of the three PPAR gamma ligands on the expression of leptin and the glucose transporter protein GLUT4, both of which are expressed during differentiation of 3T3-L1 preadipocytes to adipocytes. In the absence of PPAR gamma ligands, leptin and GLUT4 synthesis increased from day 3 to day 9 or 10 during differentiation. However, in the presence of any of the three PPAR gamma ligands, GLUT4 expression was unaffected, while ob gene expression was inhibited. We hypothesize that PPAR gamma may be essential for induction of adipocyte differentiation but then needs to be inactivated to allow expression of the ob gene. Copyright (C) 1999 by W.B. Saunders Company.