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.
Abstract
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. RESEARCH DESIGN AND 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.