Peroxisome proliferator-activated receptor α (PPARα) induces PPARγ coactivator 1α (PGC-1α) gene expression and contributes to thermogenic activation of brown fat: involvement of PRDM16.
Peroxisome proliferator activated receptor α (PPARα) is a distinctive marker of the brown fat phenotype that has been proposed to coordinate the transcriptional activation of genes for lipid oxidation and for thermogenic uncoupling protein 1 in brown adipose tissue. Here, we investigated the involvement of PPARα in the transcriptional control of the PPARγ coactivator (PGC)-1α gene. Treatment with PPARα agonists induced PGC-1α mRNA expression in brown fat in vivo and in primary brown adipocytes. This enhancement of PGC-1α transcription was mediated by PPARα binding to a PPAR-responsive element in the distal PGC-1α gene promoter. PGC-1α gene expression was decreased in PPARα-null brown fat, both under basal conditions and in response to thermogenic activation. Moreover, PPARα- and cAMP-mediated pathways interacted to control PGC-1α transcription. PRDM16 (PRD1-BF1-RIZ1 homologous domain-containing 16) promoted PPARα induction of PGC-1α gene transcription, especially under conditions in which protein kinase A pathways were activated. This enhancement was associated with the interaction of PRDM16 with the PGC-1α promoter at the PPARα-binding site. In addition, PPARα promoted the expression of the PRDM16 gene in brown adipocytes, and activation of PPARα in human white adipocytes led to the appearance of a brown adipocyte pattern of gene expression, including induction of PGC-1α and PRDM16. Collectively, these results suggest that PPARα acts as a key component of brown fat thermogenesis by coordinately regulating lipid catabolism and thermogenic gene expression via induction of PGC-1α and PRDM16.
Department of Biochemistry and Molecular Biology and Institute of Biomedicine, University of Barcelona, and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Catalonia, Spain.
Elayne
E
Hondares
Meritxell
M
Rosell
Julieta
J
Díaz-Delfín
Yolanda
Y
Olmos
Maria
M
Monsalve
Roser
R
Iglesias
Francesc
F
Villarroya
Marta
M
Giralt
D052437:Adipocytes, Brown / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D022722:Thermogenesis / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C521133:Prdm16 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors