Opposite regulation of PPAR-alpha and -gamma gene expression by both theirligands 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 a dipocyte differentiation. Little is known, however, about the control of th e expression of the genes encoding each of all three receptor subtypes: alp ha, delta, and gamma. We have addressed this question in the brown adipocyt e, the only cell type that co-expresses high levels of the three PPAR subty pes. Differentiation of brown adipocytes is associated with enhanced expres sion of PPAR genes. However, whereas PPAR gamma and PPAR delta genes are al ready expressed in preadipocytes, the mRNA for PPAR alpha appears suddenly in association with the acquisition of the terminally differentiated phenot ype. 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 i nhibition of PPAR gamma mRNA expression depends on protein synthesis, excep t when its specific ligand prostaglandin J(2) is used. Our results indicate a strictly opposite autoregulation of PPAR subtypes, which supports specif ic physiological roles for them in controlling brown fat differentiation an d thermogenic activity. (C) 1999 Elsevier Science Ireland Ltd. All rights r eserved.