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.
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 PPARalpha and PPARgamma in PGC-1 alpha transcriptional action.


METHODS
Primary cultures of human adipocytes were transduced with a PGC-1 alpha adenovirus and treated with PPARgamma and PPARalpha 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 PPARalpha(-/-) 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 PPARgamma, 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. PPARalpha was also upregulated by PGC-1 alpha. Its activation led to an increase in GyK expression and activity. PPARalpha was shown to bind and activate the GyK promoter. Experiments in mice confirmed the role of PGC-1 alpha and PPARalpha in the regulation of GyK in vivo.


CONCLUSIONS
This work uncovers novel pathways regulated by PGC-1 alpha and reveals that PPARalpha controls gene expression in human white adipocytes. The induction of GyK by PGC-1 alpha and PPARalpha may promote a futile cycle of triglyceride hydrolysis and fatty acid reesterification.
Mazzucotelli
Anne
A
Institut National de la Santé et de la Recherche Médicale (INSERM) U858, Obesity Research Laboratory, Toulouse, F-31432, France.
Viguerie
Nathalie
N
Tiraby
Claire
C
Annicotte
Jean-Sébastien
JS
Mairal
Aline
A
Klimcakova
Eva
E
Lepin
Emmanuelle
E
Delmar
Paul
P
Dejean
Sébastien
S
Tavernier
Geneviève
G
Lefort
Corinne
C
Hidalgo
Juan
J
Pineau
Thierry
T
Fajas
Lluis
L
Clément
Karine
K
Langin
Dominique
D
D017667:Adipocytes / Q000502:physiology*; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D005991:Glycerol Kinase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D056918:Nuclear Receptor Coactivators; D047493:PPAR alpha / Q000235:genetics* / Q000502:physiology; D047495:PPAR gamma / Q000235:genetics* / Q000502:physiology*
D047908:Intracellular Signaling Peptides and Proteins; C486559:NCOA6 protein, human; D056918:Nuclear Receptor Coactivators; D047493:PPAR alpha; D047495:PPAR gamma; D005991:Glycerol Kinase