The Transcriptional Coactivator PGC-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

doi:10.2337/db06-1465

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Original Research

The Transcriptional Coactivator PGC-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 Mazzucotelli^1,^,2, Nathalie Viguerie^1,^,2,^,3, Claire Tiraby^1,^,2, Jean-Sébastien Annicotte⁴, Aline Mairal^1,^,2, Eva Klimcakova^1,^,2,^,3, Emmanuelle Lepin^1,^,2, Paul Delmar⁵, Sébastien Dejean⁶, Geneviève Tavernier^1,^,2, Corinne Lefort^1,^,2, Juan Hidalgo⁷, Thierry Pineau⁸, Lluis Fajas⁴, Karine Clément⁹, and Dominique Langin^1,^,2,^,3,^,10

From the ¹Inserm, U858, Obesity Research Laboratory, Toulouse, F-31432 France;
²Paul Sabatier University, Louis Bugnard Institute, IFR31, Toulouse, F-31432 France;
³Inserm, Franco-Czech Laboratory for Clinical Research on Obesity, Prague, CZ-10100 Czech Republic;
⁴Inserm, U834, Metabolism and Cancer Laboratory, Montpellier, F-34090, France;
⁵MAS laboratory, Ecole Centrale Paris, Chatenay Malabry, F-92295, France;
⁶CNRS, Statistics and Probality Laboratory, Paul Sabatier University, F-31400 Toulouse;
⁷Institute of Neurosciences, Dept. of Cellular Biology, Physiology and Immunology, Faculty of Sciences, Autonomous University of Barcelona, Barcelona, Spain 08193;
⁸INRA, Pharmacology and Toxicology Laboratory, B.P. 3, 31931 Toulouse, France;
⁹Inserm, U872, Human Research Center on Nutrition, Hôtel Dieu, Paris, F-75181 France; and
¹⁰CHU de Toulouse, Biochemistry Laboratory, Biology Institute of Purpan, Toulouse, F-31059 France.

Correspondence: langin{at}toulouse.inserm.fr

Objective :The purpose of the work was to determine the pattern of genesregulated by PGC-1 ${alpha}$ in human adipocytes and the involvement ofPPAR ${alpha}$ and PPAR ${gamma}$ in PGC-1 ${alpha}$ transcriptional action.

Research Design and Methods :Primary cultures of human adipocytes were transduced with aPGC-1 ${alpha}$ adenovirus and treated with PPAR ${gamma}$ and PPAR ${alpha}$ agonists. Variationin gene expression was assessed using pangenomic microarraysand reverse transcription-quantitative polymerase chain reaction.To investigate glycerol kinase (GyK), a target of PGC-1 ${alpha}$ , wemeasured enzymatic activity and glycerol incorporation intotriglycerides. In vivo studies were performed on wild-type andPPAR ${alpha}$ –/– mice. The GyK promoter was studied usingchromatin immunoprecipitation and promoter reporter gene assays.

Results :Among the large number of genes regulated by PGC-1 ${alpha}$ independentlyof PPAR ${gamma}$ , new targets involved in metabolism included the geneencoding GyK. The induction of GyK by PGC-1 ${alpha}$ was observed atthe levels of mRNA, enzymatic activity and glycerol incorporationinto triglycerides. PPAR ${alpha}$ was also upregulated by PGC-1 ${alpha}$ . Itsactivation led to an increase in GyK expression and activity.PPAR ${alpha}$ was shown to bind and activate the GyK promoter. Experimentsin mice confirmed the role of PGC-1 ${alpha}$ and PPAR ${alpha}$ in the regulationof GyK in vivo.

Conclusions :This work uncovers novel pathways regulated by PGC-1 ${alpha}$ and revealsthat PPAR ${alpha}$ controls gene expression in human white adipocytes.The induction of GyK by PGC-1 ${alpha}$ and PPAR ${alpha}$ may promote a futilecycle of triglyceride hydrolysis and fatty acid reesterification.

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