Synergistic activation of UCP-3 expression in cultured fetal rat brown adipocytes by PPARalpha and PPARgamma ligands.
Rat brown adipocytes express mRNAs for Uncoupling Proteins (UCP) 1, 2 and 3 and the Peroxisome Proliferator Activated Receptors (PPAR) alpha and gamma. We have examined the effects of selective PPARalpha or -gamma activation on changes in UCP-1 and UCP-3 mRNA levels in cultured fetal rat brown adipocytes (FBA). Rosiglitazone (1.0 microM), a selective PPARgamma agonist, elicited 5- and 3-fold increases in UCP-1 and UCP-3, respectively. The PPARalpha ligand, Wy14643 (10.0 microM) increased UCP-3 tenfold, but decreased UCP-1. A synergistic effect on UCP-3 expression (30-fold increase; P < 0. 05) was observed when FBA were exposed to a combination of Wy14643 (10.0 microM) and rosiglitazone (10.0 microM). Thus, activation of PPARgamma increases UCP-1 and UCP-3 levels which are differentially regulated by PPARalpha. A synergistic interaction occurs between PPARalpha and PPARgamma in the regulation of UCP-3 in FBA, probably via co-activator recruitment, suppression of co-repressor proteins or through a direct interaction at the level of the PPRE.
Teruel
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Department of Vascular Biology, SmithKline Beecham Pharmaceuticals, NFSP-N, Third Avenue, Essex, Harlow, CM19 5AW, United Kingdom.
Smith
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Peterson
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Clapham
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JC
D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D007473:Ion Channels; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics; D024101:Mitochondrial Proteins; D020025:Peroxisome Proliferators / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000008:administration & dosage; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3
D002352:Carrier Proteins; D017931:DNA Primers; D007473:Ion Channels; D008024:Ligands; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C000604373:Ucp1 protein, rat; C000604394:Ucp3 protein, rat; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3; D000077154:Rosiglitazone; C006253:pirinixic acid