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Published online July 23, 2007
Diabetes 56:2467-2475, 2007
DOI: 10.2337/db06-1465
© 2007 by the American Diabetes Association
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The Transcriptional Coactivator Peroxisome Proliferator–Activated Receptor (PPAR){gamma} Coactivator-1{alpha} and the Nuclear Receptor PPAR{alpha} Control the Expression of Glycerol Kinase and Metabolism Genes Independently of PPAR{gamma} Activation in Human White Adipocytes

Anne Mazzucotelli1,2, Nathalie Viguerie1,2,3, Claire Tiraby1,2, Jean-Sébastien Annicotte4, Aline Mairal1,2, Eva Klimcakova1,2,3, Emmanuelle Lepin1,2, Paul Delmar5, Sébastien Dejean6, Geneviève Tavernier1,2, Corinne Lefort1,2, Juan Hidalgo7, Thierry Pineau8, Lluis Fajas4, Karine Clément9, and Dominique Langin1,2,3,10

1 Institut National de la Santé et de la Recherche Médicale (INSERM) U858, Obesity Research Laboratory, Toulouse, F-31432, France
2 Paul Sabatier University, Louis Bugnard Institute, Institut Fédératif de Recherche 31, Toulouse, F-31432, France
3 INSERM, Franco-Czech Laboratory for Clinical Research on Obesity, Prague, CZ-10100, Czech Republic
4 INSERM U834, Metabolism and Cancer Laboratory, Montpellier, F-34090, France
5 Mathématiques Appliquées aux Systémes Laboratory, Ecole Centrale Paris, Chatenay Malabry, F-92295, France
6 Centre National de la Recherche Scientifique, Statistics and Probality Laboratory, Paul Sabatier University, Toulouse, F-31400, France
7 Institute of Neurosciences, Department of Cellular Biology, Physiology and Immunology, Faculty of Sciences, Autonomous University of Barcelona, Barcelona, 08193, Spain
8 Institut National de la Recherche Agronomique, Pharmacology and Toxicology Laboratory, Toulouse, France
9 INSERM U872, Human Research Center on Nutrition, Hôtel Dieu, Paris, F-75181, France
10 Centre Hospitalier Universitaire de Toulouse, Biochemistry Laboratory, Biology Institute of Purpan, Toulouse, F-31059, France

Address correspondence and reprint requests to Dominique Langin, INSERM U858, IFR31 Institute, BP 84225, 31432 Toulouse Cedex 4, France. E-mail: langin{at}toulouse.inserm.fr

Abbreviations: BAT, brown adipose tissue; GFP, green fluorescent protein; GSEA, Gene Set Enrichment Analysis; GyK, glycerol kinase; PANTHER, Protein Analysis Through Evolutionary Relationships; PGC-1{alpha}, peroxisome proliferator–activated receptor {gamma} coactivator 1{alpha}; PPAR, peroxisome proliferator–activated receptor; PPRE, PPAR responsive element; ROS, reactive oxygen species; RXR{alpha}, retinoic acid X receptor-{alpha}; SLC25A4, solute carrier family 25 member 4; UCP, uncoupling protein; WAT, white adipose tissue

OBJECTIVE—The purpose of this work was to determine the pattern of genes regulated by peroxisome proliferator–activated receptor (PPAR) {gamma} coactivator 1{alpha} (PGC-1{alpha}) in human adipocytes and the involvement of PPAR{alpha} and PPAR{gamma} in PGC-1{alpha} transcriptional action.

RESEARCH DESIGN AND METHODS—Primary cultures of human adipocytes were transduced with a PGC-1{alpha} adenovirus and treated with PPAR{gamma} and PPAR{alpha} agonists. Variation in gene expression was assessed using pangenomic microarrays and quantitative RT-PCR. To investigate glycerol kinase (GyK), a target of PGC-1{alpha}, we measured enzymatic activity and glycerol incorporation into triglycerides. In vivo studies were performed on wild-type and PPAR{alpha}–/– mice. The GyK promoter was studied using chromatin immunoprecipitation and promoter reporter gene assays.

RESULTS—Among the large number of genes regulated by PGC-1{alpha} independently of PPAR{gamma}, new targets involved in metabolism included the gene encoding GyK. The induction of GyK by PGC-1{alpha} was observed at the levels of mRNA, enzymatic activity, and glycerol incorporation into triglycerides. PPAR{alpha} was also upregulated by PGC-1{alpha}. Its activation led to an increase in GyK expression and activity. PPAR{alpha} was shown to bind and activate the GyK promoter. Experiments in mice confirmed the role of PGC-1{alpha} and PPAR{alpha} in the regulation of GyK in vivo.

CONCLUSIONS—This work uncovers novel pathways regulated by PGC-1{alpha} and reveals that PPAR{alpha} controls gene expression in human white adipocytes. The induction of GyK by PGC-1{alpha} and PPAR{alpha} may promote a futile cycle of triglyceride hydrolysis and fatty acid reesterification.


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Copyright © 2007 by the American Diabetes Association.