Unknown,Transcriptomics,Genomics,Proteomics

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GW7647 and Rosiglitazone treated human differentiated adipocytes

ABSTRACT: Objective : This work aimed at characterizing PPARα involvement in metabolism regulation and at comparing PPARα and PPARγ roles in human white adipocytes. Research Design and Methods : Profiling of gene expression alterations was assessed with microarrays and RT-qPCR. Primary cultures of human adipocytes were treated with PPARα agonist GW7647 or PPARγ agonist Rosiglitazone. Western blot were used to determine protein level modifications. Metabolic changes were evaluated with palmitate and glucose oxidation studies and with metabolite measurements. Results : GW7647 induces an upregulation of β-oxidation gene expression and increases palmitate oxidation. Unexpectedly glycolysis was strongly reduced at transcriptional and functional levels by GW7647 while the overall glucose oxidation remains unaltered, leading to a decrease in pyruvate and lactate production. Moreover lipogenesis was downregulated by GW7647 inhibiting triglyceride esterification and de novo lipogenesis. GW7647 induced alterations were abolished by a PPARα antagonist treatment and were clearly different from Rosiglitazone effects. Rosiglitazone had no major impact on glycolysis and β-oxidation but increased glucose incorporation into glycerol backbone of triglycerides. Conclusions : Altogether these results show that PPARα can upregulate β-oxidation in human white adipocytes. Its pharmacological activation may be used to oxidize fatty acids in situ when lipolysis is activated thus preventing their release into systemic circulation. We treated four adipocyte cultures, each one coming from different subjects, with GW7647, Rosiglitazone (ROSI) or DMSO. DMSO treated cells are control samples. Thus we have four paired sample groups for each treatment (GW7647 and ROSI).

ORGANISM(S): Homo sapiens

SUBMITTER: Nathalie Viguerie

PROVIDER: E-GEOD-15862 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Peroxisome proliferator-activated receptor-alpha control of lipid and glucose metabolism in human white adipocytes.

Ribet Carole C Montastier Emilie E Valle Carine C Bezaire Véronic V Mazzucotelli Anne A Mairal Aline A Viguerie Nathalie N Langin Dominique D

Endocrinology 20091103 1

This work aimed at characterizing the role of peroxisome proliferator-activated receptors (PPAR)alpha in human white adipocyte metabolism and at comparing PPAR alpha and PPAR gamma actions in these cells. Primary cultures of human fat cells were treated with the PPAR alpha agonist GW7647 or the PPAR gamma agonist rosiglitazone. Changes in gene expression were determined using DNA microarrays and quantitative RT-PCR. Western blot and metabolic studies were performed to identify the biological eff ...[more]

PMID: 19887568

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Project description:Nuclear receptor activation in liver leads to coordinated alteration of the expression of multiple gene products with attendant phenotypic changes of hepatocytes. Peroxisome proliferators including endogenous fatty acids, environmental chemicals, and drugs induce a multi-enzyme metabolic response that affects lipid and fatty acid processing. We studied the signaling network for the peroxisome proliferator-associated receptor alpha (PPARα) in primary human hepatocytes using the selective PPARα ligand, GW7647. We measured gene expression over multiple concentrations and times and conducted ChIP-seq studies at 2 and 24 hours to assess genomic binding of PPARα. Over all treatments there were 192 genes differentially expressed. Of these only 51% showed evidence of PPARα binding – either directly at PPARα response elements or via alternative mechanisms. Almost half of regulated genes had no PPARα binding. We then developed two novel bioinformatics methods to visualize the dose-dependent activation of both the transcription factor circuitry for PPARα and the downstream metabolic network in relation to functional annotation categories. Available databases identified several key transcription factors involved with the non-genomic targets after GW7647 treatment, including SP1, STAT1, ETS1, ERα, and HNF4α. The linkage from PPARα binding through gene expression likely requires intermediate protein kinases to activate these transcription factors. We found enrichment of functional annotation categories for organic acid metabolism and cell lipid metabolism among the differentially expressed genes. Lipid transport processes showed enrichment at the highest concentration of GW7647 (10μM). While our strategy for mapping transcriptional networks is evolving, these approaches are necessary in moving from toxicogenomic methods that derive signatures of activity to methods that establish pathway structure, showing the coordination of the activated nuclear receptor with other signaling pathways. Primary hepatocytes from four donors were exposed to 0, 0.001, 0.01, 0.1, 1.0, or 10.0μM GW7647 for 2, 6, 12, 24, or 72 hours.

Dataset Information

GW7647 and Rosiglitazone treated human differentiated adipocytes

Publications

Peroxisome proliferator-activated receptor-alpha control of lipid and glucose metabolism in human white adipocytes.

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