Opposite regulation of PPAR-α and -γ gene expression by both their ligands and retinoic acid in brown adipocytes

The peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors involved in the regulation of lipid metabolism and adipocyte differentiation. Little is known, however, about the control of the expression of the genes encoding each of all three receptor subtypes: alpha, delta, and gamma. We have addressed this question in the brown adipocyte, the only cell type that co-expresses high levels of the three PPAR subtypes. Differentiation of brown adipocytes is associated with enhanced expression of PPAR genes. However, whereas PPAR gamma and PPAR delta genes are already expressed in preadipocytes, the mRNA for PPAR alpha appears suddenly in association with the acquisition of the terminally differentiated phenotype. Both retinoic acid isomers and PPAR agonists, specific for either PPAR alpha or PPAR gamma, regulate expression of each PPAR subtype gene in the opposite way: they up-regulate PPAR alpha and down-regulate PPAR gamma. The effects on PPAR alpha mRNA are independent of protein synthesis, whereas inhibition of PPAR gamma mRNA expression depends on protein synthesis, except when its specific ligand prostaglandin J(2) is used. Our results indicate a strictly opposite autoregulation of PPAR subtypes, which supports specific physiological roles for them in controlling brown fat differentiation and thermogenic activity. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.