Gene Expression Profile of Adipocyte Differentiation and Its Regulation by Peroxisome Proliferator-Activated Receptor- Agonists (original) (raw)
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Endocrinology, 2002
PPAR␥ is an adipocyte-specific nuclear hormone receptor. Agonists of PPAR␥, such as thiazolidinediones (TZDs), promote adipocyte differentiation and have insulin-sensitizing effects in animals and diabetic patients. Affymetrix oligonucleotide arrays representing 6347 genes were employed to profile the gene expression responses of mature 3T3-L1 adipocytes and differentiating preadipocytes to a TZD PPAR␥ agonist in vitro. The expression of 579 genes was significantly up-or down-regulated by more than 1.5-fold during differentiation and/or by treatment with TZD, and these genes were organized into 32 clusters that demonstrated concerted changes in expression of genes controlling cell growth or lipid metabolism. Quantitative PCR was employed to further characterize gene expression and led to the identification of -catenin as a new PPAR␥ target gene. Both mRNA and protein levels for -catenin were down-regulated in 3T3-L1 adipocytes compared with fibroblasts and were further decreased by treatment of adipocytes with PPAR␥ agonists. Treatment of db/db mice with a PPAR␥ agonist also resulted in reduction of -catenin mRNA levels in adipose tissue. These results suggest that -catenin plays an important role in the regulation of adipogenesis. Thus, the transcriptional patterns revealed in this study further the understanding of adipogenesis process and the function of PPAR␥ activation.
Endocrinology, 2002
PPAR gamma is an adipocyte-specific nuclear hormone receptor. Agonists of PPAR gamma, such as thiazolidinediones (TZDs), promote adipocyte differentiation and have insulin-sensitizing effects in animals and diabetic patients. Affymetrix oligonucleotide arrays representing 6347 genes were employed to profile the gene expression responses of mature 3T3-L1 adipocytes and differentiating preadipocytes to a TZD PPAR gamma agonist in vitro. The expression of 579 genes was significantly up- or down-regulated by more than 1.5-fold during differentiation and/or by treatment with TZD, and these genes were organized into 32 clusters that demonstrated concerted changes in expression of genes controlling cell growth or lipid metabolism. Quantitative PCR was employed to further characterize gene expression and led to the identification of beta-catenin as a new PPAR gamma target gene. Both mRNA and protein levels for beta-catenin were down-regulated in 3T3-L1 adipocytes compared with fibroblasts a...
Journal of Biological Chemistry, 2000
While searching for natural ligands for the peroxisome proliferator-activated receptor (PPAR) ␥, we identified a synthetic compound that binds to this receptor. Bisphenol A diglycidyl ether (BADGE) is a ligand for PPAR␥ with a K d(app) of 100 M. This compound has no apparent ability to activate the transcriptional activity of PPAR␥; however, BADGE can antagonize the ability of agonist ligands such as rosiglitazone to activate the transcriptional and adipogenic action of this receptor. BADGE also specifically blocks the ability of natural adipogenic cell lines such as 3T3-L1 and 3T3-F442A cells to undergo hormone-mediated cell differentiation. These results provide the first pharmacological evidence that PPAR␥ activity is required for the hormonally induced differentiation of adipogenic cells.
A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation
Proceedings of the National Academy of Sciences, 1999
The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate glucose and lipid homeostasis. The PPARγ subtype plays a central role in the regulation of adipogenesis and is the molecular target for the 2,4-thiazolidinedione class of antidiabetic drugs. Structural studies have revealed that agonist ligands activate the PPARs through direct interactions with the C-terminal region of the ligand-binding domain, which includes the activation function 2 helix. GW0072 was identified as a high-affinity PPARγ ligand that was a weak partial agonist of PPARγ transactivation. X-ray crystallography revealed that GW0072 occupied the ligand-binding pocket by using different epitopes than the known PPAR agonists and did not interact with the activation function 2 helix. In cell culture, GW0072 was a potent antagonist of adipocyte differentiation. These results establish an approach to the design of PPAR ligands with modified biological activities.
Journal of Biological Chemistry, 2014
Background: Tudor-SN has been observed in lipid droplets, but its role in lipid homeostasis remains unclear. Results: Tudor-SN and PPAR␥ are both regulated by C/EBP during adipogenesis and significantly influence the regulation of PPAR␥ target genes. Conclusion: Tudor-SN functions as a co-activator of PPAR␥ in adipogenesis. Significance: The study has elucidated a new functional mechanism for the regulation of adipogenesis.
2006
Thiazolidinediones (TZDs) are insulin-sensitizing drugs currently used to treat type 2 diabetes. They are activators of peroxisome proliferator-activated receptor (PPAR)-␥, and adipose tissue constitutes a major site for their biological effects. PPAR coactivator (PGC)-1␣ is a transcriptional coactivator of PPAR␥ and other transcription factors. It is involved in the control of mitochondrial biogenesis, and its activity has been linked to insulin sensitization. Here we report that PGC-1␣ gene expression in brown and white adipocytes is a direct target of TZDs via PPAR␥ activation. Activators of the retinoid X receptor also induce PGC-1␣ gene expression. This is due to the presence of a PPAR␥-responsive element in the distal region of the PGC-1␣ gene promoter that binds PPAR␥/retinoid X receptor heterodimers. Moreover, there is a positive autoregulatory loop of control of the PGC-1␣ gene through coactivation of PPAR␥ responsiveness to TZDs by PGC-1␣ itself. These data indicate that some of the effects of TZDs, especially promotion of mitochondrial biogenesis and oxidative pathways in adipose depots, entail PGC-1␣ up-regulation via enhanced transcription of the PGC-1␣ gene. (Endocrinol