Abstract
Brown adipose tissue expresses the thermogenic uncoupling protein-1 (UCP-1), which is positively regulated by peroxisome proliferator-activated receptor (PPAR) agonists and retinoids through the activation of the heterodimers PPAR/retinoid X receptor (RXR) and retinoic acid receptor (RAR)/RXR and binding to specific elements in the ucp-1 enhancer. In this study we show that in fetal rat brown adipocyte primary cultures the PPARgamma agonist rosiglitazone (Rosi), as well as retinoic acids 9-cis-retinoic acid and all-trans-retinoic acid also have "extragenic" effects and induce p44/p42 and p38 mitogen-activated protein kinase (p38MAPK) activation. The latter is involved in UCP-1 gene expression, because inhibition of p38MAPK activity with PD169316 impairs the ability of Rosi and retinoids for UCP-1 induction. The inhibitory effects of PD169316 are mimicked by the antioxidant GSH, suggesting a role for reactive oxygenated species (ROS) generation in the increase of UCP-1 expression in response either to Rosi or 9-cis-retinoic acid. Thus, we propose that Rosi and retinoids act as PPAR/RXR and RAR/RXR agonists and also activate p38MAPK. These two coordinated actions could result in a high increase of transcriptional activity on the ucp-1 enhancer and hence on thermogenesis. PPARalpha and gamma agonists but not retinoids also increase UCP-3 expression in fetal brown adipocytes. However, the regulation of UCP-3, which is not involved in thermogenesis, seems to differ from UCP-1 given the fact that is not affected by p38MAPK inhibition.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adipocytes / drug effects*
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Adipocytes / metabolism
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Adipose Tissue, Brown / cytology
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Adipose Tissue, Brown / embryology
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Adipose Tissue, Brown / metabolism*
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Animals
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism
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Cells, Cultured
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Culture Media, Serum-Free
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Cyclic AMP / analogs & derivatives
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Cyclic AMP / metabolism
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Fetus
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Gene Expression Regulation
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Genes, Reporter
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Glutathione / pharmacology
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Imidazoles / pharmacology
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Ion Channels
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Mitochondrial Proteins
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism*
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Promoter Regions, Genetic
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Rats
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Rats, Wistar
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Rosiglitazone
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Thiazoles / pharmacology*
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Thiazolidinediones*
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Tretinoin / chemistry
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Tretinoin / pharmacology*
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Uncoupling Agents / metabolism*
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Uncoupling Protein 1
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p38 Mitogen-Activated Protein Kinases
Substances
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Carrier Proteins
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Culture Media, Serum-Free
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Enzyme Inhibitors
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Imidazoles
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Ion Channels
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Membrane Proteins
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Mitochondrial Proteins
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Recombinant Fusion Proteins
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Thiazoles
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Thiazolidinediones
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Ucp1 protein, rat
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Uncoupling Agents
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Uncoupling Protein 1
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Rosiglitazone
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Tretinoin
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Cyclic AMP
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Cyclic AMP-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Glutathione
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2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole