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Sander Kersten - One of the best experts on this subject based on the ideXlab platform.
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Peroxisome Proliferator activated receptor alpha target genes
Ppar Research, 2010Co-Authors: Maryam Rakhshandehroo, Michael Muller, Bianca Knoch, Sander KerstenAbstract:The Peroxisome Proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPARα serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPARα binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPARα governs biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPARα is directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPARα in lipid metabolism and other pathways through a detailed analysis of the different known or putative PPARα target genes. The emphasis is on gene regulation by PPARα in liver although many of the results likely apply to other organs and tissues as well.
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Peroxisome Proliferator activated receptor α target genes
Cellular and Molecular Life Sciences, 2004Co-Authors: Stephane Mandard, Michael Muller, Sander KerstenAbstract:Peroxisome Proliferator-activated receptors (PPARs) are nuclear proteins that belong to the superfamily of nuclear hormone receptors. They mediate the effects of small lipophilic compounds such as long-chain fatty acids and their derivatives on transcription of genes commonly called PPAR target genes. Here we review the involvement of PPARα in peroxisomal and mitochondrial fatty acid oxidation, microsomal fatty acid hydroxylation, lipoprotein, bile and amino acid metabolism, glucose homeostasis, biotransformation, inflammation control, hepato-carcinogenesis and other pathways, through a detailed analysis of the different known or putative PPARα target genes.
Johan Auwerx - One of the best experts on this subject based on the ideXlab platform.
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international union of pharmacology lxi Peroxisome Proliferator activated receptors
Pharmacological Reviews, 2006Co-Authors: Liliane Michalik, Paul Grimaldi, Johan Auwerx, Christopher K. Glass, Mitchell A Lazar, Frank J. Gonzalez, Joel P Berger, Krishna V Chatterjee, Takashi Kadowaki, Stephen OrahillyAbstract:The three Peroxisome Proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. They share a high degree of structural homology with all members of the superfamily, particularly in the DNA-binding domain and ligand- and cofactor-binding domain. Many cellular and systemic roles have been attributed to these receptors, reaching far beyond the stimulation of Peroxisome proliferation in rodents after which they were initially named. PPARs exhibit broad, isotype-specific tissue expression patterns. PPARalpha is expressed at high levels in organs with significant catabolism of fatty acids. PPARbeta/delta has the broadest expression pattern, and the levels of expression in certain tissues depend on the extent of cell proliferation and differentiation. PPARgamma is expressed as two isoforms, of which PPARgamma2 is found at high levels in the adipose tissues, whereas PPARgamma1 has a broader expression pattern. Transcriptional regulation by PPARs requires heterodimerization with the retinoid X receptor (RXR). When activated by a ligand, the dimer modulates transcription via binding to a specific DNA sequence element called a Peroxisome Proliferator response element (PPRE) in the promoter region of target genes. A wide variety of natural or synthetic compounds was identified as PPAR ligands. Among the synthetic ligands, the lipid-lowering drugs, fibrates, and the insulin sensitizers, thiazolidinediones, are PPARalpha and PPARgamma agonists, respectively, which underscores the important role of PPARs as therapeutic targets. Transcriptional control by PPAR/RXR heterodimers also requires interaction with coregulator complexes. Thus, selective action of PPARs in vivo results from the interplay at a given time point between expression levels of each of the three PPAR and RXR isotypes, affinity for a specific promoter PPRE, and ligand and cofactor availabilities.
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intestinal antiinflammatory effect of 5 aminosalicylic acid is dependent on Peroxisome Proliferator activated receptor gamma
Journal of Experimental Medicine, 2005Co-Authors: Christel Rousseaux, Johan Auwerx, W Wahli, Beatrice Desvergne, Bruno Lefebvre, Laurent Dubuquoy, Philippe Lefebvre, O Romano, Daniel Metzger, Gian Carlo NaccariAbstract:5-aminosalicylic acid (5-ASA) is an antiinflammatory drug widely used in the treatment of inflammatory bowel diseases. It is known to inhibit the production of cytokines and inflammatory mediators, but the mechanism underlying the intestinal effects of 5-ASA remains unknown. Based on the common activities of Peroxisome Proliferator-activated receptor-gamma (PPAR-gamma) ligands and 5-ASA, we hypothesized that this nuclear receptor mediates 5-ASA therapeutic action. To test this possibility, colitis was induced in heterozygous PPAR-gamma(+/-) mice and their wild-type littermates, which were then treated with 5-ASA. 5-ASA treatment had a beneficial effect on colitis only in wild-type and not in heterozygous mice. In epithelial cells, 5-ASA increased PPAR-gamma expression, promoted its translocation from the cytoplasm to the nucleus, and induced a modification of its conformation permitting the recruitment of coactivators and the activation of a Peroxisome-Proliferator response element-driven gene. Validation of these results was obtained with organ cultures of human colonic biopsies. These data identify PPAR-gamma as a target of 5-ASA underlying antiinflammatory effects in the colon.
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Expression of Peroxisome Proliferator-activated receptor gamma (PPARgamma) in normal human pancreatic islet cells.
Diabetologia, 2000Co-Authors: Mathilde Dubois, Francois Pattou, Julie Kerr-conte, Valery Gmyr, B. Vandewalle, Pierre Desreumaux, Johan Auwerx, Kristina Schoonjans, Lefebvre JAbstract:AIMS/HYPOTHESIS: Thiazolidinediones are reported to improve pancreatic islet morphology and beta-cell function in rodents, supporting the hypothesis of a direct action of thiazolidinediones on endocrine islet cells. In this study we examined the expression of the Peroxisome Proliferator-activated receptor gamma, a nuclear receptor that is activated by naturally occurring fatty acids and synthetic thiazolidinediones, in normal human endocrine pancreatic cells. METHODS: Human islets were isolated from pancreata harvested in ten brain-dead lean non-diabetic adult donors. We analysed the gene and protein expression of the human Peroxisome Proliferator-activated receptor gamma and evaluated the effects of Peroxisome Proliferator-activated receptor gamma agonist on insulin secretion in human islet preparations. RESULTS: The RT-PCR carried out on total RNA from four distinct human islet preparations demonstrated the presence of Peroxisome Proliferator-activated receptor gamma mRNA. Western blot analysis showed the consistent expression of Peroxisome Proliferator-activated receptor gamma protein. Peroxisome Proliferator-activated receptor gamma was shown to be present in all three endocrine cell types studied (alpha, beta and delta cells) by immunohistochemistry. CONCLUSION/INTERPRETATION: We found that Peroxisome Proliferator-activated receptor gamma is highly expressed in human islet endocrine cells, both at the mRNA and protein levels. These results support the hypothesis of a direct influence of Peroxisome Proliferator-activated receptor gamma agonist on human pancreatic endocrine cells.
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Peroxisome Proliferator-activated receptors: mediators of a fast food impact on gene regulation.
Current Opinion in Clinical Nutrition and Metabolic Care, 1999Co-Authors: Laurent Gelman, Johan AuwerxAbstract:Peroxisome Proliferator-activated receptors are nuclear receptors with pleiotropic effects on intra- and extracellular lipid metabolism, glucose homeostasis, inflammation control, and cell proliferation. This review addresses the respective roles of the different Peroxisome Proliferator-activated receptor isoforms in these different processes.
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Peroxisome Proliferator activated receptors orphans with ligands and functions
Current Opinion in Lipidology, 1997Co-Authors: Kristina Schoonjans, Bart Staels, Genevieve Martin, Johan AuwerxAbstract:The three Peroxisome Proliferator-activated receptors (PPARs), PPAR alpha, delta and gamma, form a subfamily of the nuclear hormone receptor gene family. PPAR alpha has been shown to bind and be activated by leukotriene B4 and fibrates, whereas prostaglandin J2 derivatives and the antidiabetic thiazolidinediones, respectively, are natural and synthetic ligands for PPAR gamma. The availability of ligands and activators for PPAR alpha and PPAR gamma allowed an initial assessment of their respective functions. PPAR alpha and PPAR gamma are shown to function as important regulators in lipid and glucose metabolism, adipocyte differentiation, inflammatory response and energy homeostasis. PPAR alpha seems to mediate its pleiotropic effects mainly through the stimulation of oxidation of lipids, whereas PPAR gamma is a key mediator of lipid storage. The next few years will be very exciting as additional studies will refine our current knowledge about PPAR alpha and PPAR gamma and may reveal a ligand and role for the lonesome orphan among the PPARs, PPAR delta.
Steven A Kliewer - One of the best experts on this subject based on the ideXlab platform.
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structural determinants of ligand binding selectivity between the Peroxisome Proliferator activated receptors
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: H E Xu, Millard H Lambert, V G Montana, Kelli D Plunket, Linda B Moore, Jon L Collins, J A Oplinger, Steven A Kliewer, R T Gampe, David D MckeeAbstract:The Peroxisome Proliferator-activated receptors (PPARs) are transcriptional regulators of glucose, lipid, and cholesterol metabolism. We report the x-ray crystal structure of the ligand binding domain of PPARα (NR1C1) as a complex with the agonist ligand GW409544 and a coactivator motif from the steroid receptor coactivator 1. Through comparison of the crystal structures of the ligand binding domains of the three human PPARs, we have identified molecular determinants of subtype selectivity. A single amino acid, which is tyrosine in PPARα and histidine in PPARγ, imparts subtype selectivity for both thiazolidinedione and nonthiazolidinedione ligands. The availability of high-resolution cocrystal structures of the three PPAR subtypes will aid the design of drugs for the treatments of metabolic and cardiovascular diseases.
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adipose tissue resistin expression is severely suppressed in obesity and stimulated by Peroxisome Proliferator activated receptor γ agonists
Journal of Biological Chemistry, 2001Co-Authors: Cem Z Gorgun, Steven A Kliewer, Qiang Tong, Teoman K Uysal, Kathleen K Brown, Wallace W Harrington, William R Oliver, Timothy M Willson, Gokhan S HotamisligilAbstract:Abstract Elevated levels of the hormone resistin, which is secreted by fat cells, are proposed to cause insulin resistance and to serve as a link between obesity and type 2 diabetes. In this report we show that resistin expression is significantly decreased in the white adipose tissue of several different models of obesity including the ob/ob, db/db, tub/tub, and KKAy mice compared with their lean counterparts. Furthermore, in response to several different classes of antidiabetic Peroxisome Proliferator-activated receptor γ agonists, adipose tissue resistin expression is increased in both ob/ob mice and Zucker diabetic fatty rats. These data demonstrate that experimental obesity in rodents is associated with severely defective resistin expression, and decreases in resistin expression are not required for the antidiabetic actions of Peroxisome Proliferator-activated receptor γ agonists.
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Peroxisome Proliferator activated receptor γ and metabolic disease
Annual Review of Biochemistry, 2001Co-Authors: Timothy M Willson, Millard H Lambert, Steven A KliewerAbstract:▪ Abstract The nuclear Peroxisome Proliferator–activated receptor γ (PPARγ) is a transcription factor that is activated by polyunsaturated fatty acids and their metabolites and is essential for fat cell formation. Although obesity is a strong risk factor for type 2 diabetes mellitus and other metabolic diseases, potent PPARγ activators such as the glitazone drugs lower glucose and lipid levels in patients with type 2 diabetes and also have antiatherosclerotic and antihypertensive effects. We review recent studies providing insight into the paradoxical relationship between PPARγ and metabolic disease. We also review recent advances in understanding the structural basis for PPARγ activation by ligands. The unusual ligand-binding properties of PPARγ suggest that it will be possible to discover new chemical classes of receptor “modulators” with distinct pharmacological activities for the treatment of type 2 diabetes and other metabolic diseases.
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differential expression and activation of a family of murine Peroxisome Proliferator activated receptors
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Steven A Kliewer, Barry M Forman, Bruce Blumberg, Uwe Borgmeyer, David J Mangelsdorf, Kazuhiko Umesono, Ronald M EvansAbstract:Abstract To gain insight into the function of Peroxisome Proliferator-activated receptor (PPAR) isoforms in mammals, we have cloned and characterized two PPAR alpha-related cDNAs (designated PPAR gamma and -delta, respectively) from mouse. The three PPAR isoforms display widely divergent patterns of expression during embryogenesis and in the adult. Surprisingly, PPAR gamma and -delta are not activated by pirinixic acid (Wy 14,643), a potent Peroxisome Proliferator and activator of PPAR alpha. However, PPAR gamma and -delta are activated by the structurally distinct Peroxisome Proliferator LY-171883 and linoleic acid, respectively, indicating that each of the isoforms can act as a regulated activator of transcription. These data suggest that tissue-specific responsiveness to Peroxisome Proliferators, including certain fatty acids, is in part a consequence of differential expression of multiple, pharmacologically distinct PPAR isoforms.
Frank J. Gonzalez - One of the best experts on this subject based on the ideXlab platform.
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Influence of Peroxisome Proliferator-activated Receptor aa on Ubiquinone Biosynthesis
2020Co-Authors: Mikael Turunen, Jeffrey M Peters, Frank J. Gonzalez, Sophia Schedin, Gustav DallnerAbstract:The control of ubiquinone biosynthesis by Peroxisome Proliferators was investigated using Peroxisome Proliferator activated receptor a (PPARa)null mice. Administration of 2-(diethylhexyl)phthalate to control mice resulted in elevated ubiquinone levels in the liver, while dolichol, dolichyl-P and cholesterol concentrations remained unchanged. In PPARanull mice, the level of these lipids were similar to control levels and administration of the Peroxisome Proliferator did not increase the levels of ubiquinone. The increase in ubiquinone levels was the result of increased synthesis. Induction was most pronounced in liver, kidney and heart, which have relatively high levels of PPARa. When the tissue concentration of hydrogen peroxide was elevated by inhibition of catalase activity with aminotriazole, the amount of ubiquinone was not increased, suggesting that the induction of ubiquinone synthesis occured through a direct mechanism. The activities of branch-point enzymes FPP-synthase, squalene synthase, cis-prenyltransferase, trans-prenyltransferase and NPHB-transferase were substantially increased in control but not in PPARa-null mice after treatment with Peroxisome Proliferators. These data suggest that the induction of ubiquinone biosynthesis after administration of Peroxisome Proliferators is dependent on the PPARa through regulation of some of the mevalonate pathway enzymes. # 2000 Academic Press
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the role of Peroxisome Proliferator activated receptors in carcinogenesis and chemoprevention
Nature Reviews Cancer, 2012Co-Authors: Jeffrey M Peters, Yatrik M Shah, Frank J. GonzalezAbstract:Abstract Peroxisome Proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in regulating glucose and lipid homeostasis, inflammation, proliferation and differentiation. Although all of these functions might contribute to the influence of PPARs in carcinogenesis, there is a distinct need for a review of the literature and additional experimentation to determine the potential for targeting PPARs for cancer therapy and cancer chemoprevention. As PPAR agonists include drugs that are used for the treatment of metabolic diseases, a more complete understanding of the roles of PPARs in cancer will aid in determining any increased cancer risk for patients undergoing therapy with PPAR agonists.
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international union of pharmacology lxi Peroxisome Proliferator activated receptors
Pharmacological Reviews, 2006Co-Authors: Liliane Michalik, Paul Grimaldi, Johan Auwerx, Christopher K. Glass, Mitchell A Lazar, Frank J. Gonzalez, Joel P Berger, Krishna V Chatterjee, Takashi Kadowaki, Stephen OrahillyAbstract:The three Peroxisome Proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. They share a high degree of structural homology with all members of the superfamily, particularly in the DNA-binding domain and ligand- and cofactor-binding domain. Many cellular and systemic roles have been attributed to these receptors, reaching far beyond the stimulation of Peroxisome proliferation in rodents after which they were initially named. PPARs exhibit broad, isotype-specific tissue expression patterns. PPARalpha is expressed at high levels in organs with significant catabolism of fatty acids. PPARbeta/delta has the broadest expression pattern, and the levels of expression in certain tissues depend on the extent of cell proliferation and differentiation. PPARgamma is expressed as two isoforms, of which PPARgamma2 is found at high levels in the adipose tissues, whereas PPARgamma1 has a broader expression pattern. Transcriptional regulation by PPARs requires heterodimerization with the retinoid X receptor (RXR). When activated by a ligand, the dimer modulates transcription via binding to a specific DNA sequence element called a Peroxisome Proliferator response element (PPRE) in the promoter region of target genes. A wide variety of natural or synthetic compounds was identified as PPAR ligands. Among the synthetic ligands, the lipid-lowering drugs, fibrates, and the insulin sensitizers, thiazolidinediones, are PPARalpha and PPARgamma agonists, respectively, which underscores the important role of PPARs as therapeutic targets. Transcriptional control by PPAR/RXR heterodimers also requires interaction with coregulator complexes. Thus, selective action of PPARs in vivo results from the interplay at a given time point between expression levels of each of the three PPAR and RXR isotypes, affinity for a specific promoter PPRE, and ligand and cofactor availabilities.
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The Peroxisome Proliferator-activated receptor alpha (PPARalpha): role in hepatocarcinogenesis.
Molecular and cellular endocrinology, 2002Co-Authors: Frank J. GonzalezAbstract:The Peroxisome Proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear receptor superfamily and mediates most of the known biological effects of Peroxisome Proliferators. The latter represents a large group of chemicals that include the fibrate hyperlipidemic drugs, the pthalate plasticizers, various solvents and degreasing agents, and endogenous hormones and fatty acids. Peroxisome Proliferators are classical members of the nongenotoxic group of chemical carcinogens that do not require metabolic activation to electrophiles in order to exert their harmful effects. These chemicals are of particular concern to regulatory agencies since they can only be detected by long-term carcinogen bioassays using rodents. The mechanism of the carcinogenic action of Peroxisome Proliferators is beginning to emerge. PPARalpha-null mice are resistant to hepatocarcinogenesis indicating that this receptor is necessary for cancer. However, recent studies indicate that Kupffer cells, in a PPARalpha independent manor, are required for the major effects of Peroxisome Proliferators on cell proliferation. An interaction between PPARalpha and estrogen carcinogenesis has also been elucidated.
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The Peroxisome Proliferator-activated receptor α (PPARα): role in hepatocarcinogenesis
Molecular and Cellular Endocrinology, 2002Co-Authors: Frank J. GonzalezAbstract:Abstract The Peroxisome Proliferator-activated receptor α (PPARα) is a member of the nuclear receptor superfamily and mediates most of the known biological effects of Peroxisome Proliferators. The latter represents a large group of chemicals that include the fibrate hyperlipidemic drugs, the pthalate plasticizers, various solvents and degreasing agents, and endogenous hormones and fatty acids. Peroxisome Proliferators are classical members of the nongenotoxic group of chemical carcinogens that do not require metabolic activation to electrophiles in order to exert their harmful effects. These chemicals are of particular concern to regulatory agencies since they can only be detected by long-term carcinogen bioassays using rodents. The mechanism of the carcinogenic action of Peroxisome Proliferators is beginning to emerge. PPARα-null mice are resistant to hepatocarcinogenesis indicating that this receptor is necessary for cancer. However, recent studies indicate that Kupffer cells, in a PPARα independent manor, are required for the major effects of Peroxisome Proliferators on cell proliferation. An interaction between PPARα and estrogen carcinogenesis has also been elucidated.
Bruce M Spiegelman - One of the best experts on this subject based on the ideXlab platform.
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Peroxisome Proliferator activated receptor γ coactivator 1 coactivators energy homeostasis and metabolism
Endocrine Reviews, 2006Co-Authors: Christophe Handschin, Bruce M SpiegelmanAbstract:Many biological programs are regulated at the transcriptional level. This is generally achieved by the concerted actions of several transcription factors. Recent findings have shown that, in many cases, transcriptional coactivators coordinate the overall regulation of the biological programs. One of the best-studied examples of coactivator control of metabolic pathways is the Peroxisome Proliferator-activated receptor γ coactivator 1 (PGC-1) family. These proteins are strong activators of mitochondrial function and are thus dominant regulators of oxidative metabolism in a variety of tissues. The PGC-1 coactivators themselves are subject to powerful regulation at the transcriptional and posttranslational levels. Recent studies have elucidated the function of the PGC-1 coactivators in different tissues and have highlighted the implications of PGC-1 dysregulation in diseases such as diabetes, obesity, cardiomyopathy, or neurodegeneration.
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induction of solid tumor differentiation by the Peroxisome Proliferator activated receptor γ ligand troglitazone in patients with liposarcoma
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: George D Demetri, Pasha Sarraf, Ryan Naujoks, Natalee Campbell, Elisabetta Mueller, Bruce M Spiegelman, Christopher D.m. Fletcher, Samuel SingerAbstract:Agonist ligands for the nuclear receptor Peroxisome Proliferator-activated receptor-γ have been shown to induce terminal differentiation of normal preadipocytes and human liposarcoma cells in vitro. Because the differentiation status of liposarcoma is predictive of clinical outcomes, modulation of the differentiation status of a tumor may favorably impact clinical behavior. We have conducted a clinical trial for treatment of patients with advanced liposarcoma by using the Peroxisome Proliferator-activated receptor-γ ligand troglitazone, in which extensive correlative laboratory studies of tumor differentiation were performed. We report here the results of three patients with intermediate to high-grade liposarcomas in whom troglitazone administration induced histologic and biochemical differentiation in vivo. Biopsies of tumors from each of these patients while on troglitazone demonstrated histologic evidence of extensive lipid accumulation by tumor cells and substantial increases in NMR-detectable tumor triglycerides compared with pretreatment biopsies. In addition, expression of several mRNA transcripts characteristic of differentiation in the adipocyte lineage was induced. There was also a marked reduction in immunohistochemical expression of Ki-67, a marker of cell proliferation. Together, these data indicate that terminal adipocytic differentiation was induced in these malignant tumors by troglitazone. These results indicate that lineage-appropriate differentiation can be induced pharmacologically in a human solid tumor.
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Peroxisome Proliferator-activated receptor gamma and the control of adipogenesis.
Current Opinion in Lipidology, 1997Co-Authors: Regina P. Brun, Erding Hu, Bruce M SpiegelmanAbstract:: The adipose cell is now known to play a complex role in energy homeostasis, storing energy and signaling to other tissues concerning the state of energy balance. The past several years have seen an explosive increase in our knowledge of the transcriptional basis of adipocyte differentiation. This review describes the role of Peroxisome Proliferator-activated receptor gamma in this process, and describes how other transcription factors may affect adipogenesis by modulating the amount or activity of Peroxisome Proliferator-activated receptor gamma. Furthermore, Peroxisome Proliferator-activated receptor gamma and other adipogenic transcription factors provide a focus for beginning to understand how various hormones and metabolites influence the development of this tissue in vivo.