BioPAX pathway converted from "Transcriptional regulation of white adipocyte differentiation" in the Reactome database. Transcriptional regulation of white adipocyte differentiation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT Formation of PPARG:RXRA heterodimer (ARF6 complex) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> RXRA RXRA A0A1D5P2B5 Reactome DB_ID: 10584330 nucleoplasm GENE ONTOLOGY GO:0005654 UniProt:A0A1D5P2B5 RXRA Gallus gallus NCBI Taxonomy 9031 UniProt A0A1D5P2B5 1 EQUAL 462 EQUAL Reactome Database ID Release 82 10584330 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10584330 Reactome R-GGA-381319 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-381319.1 Reactome http://www.reactome.org PPARG PPARG A0A3Q3ACW5 Reactome DB_ID: 10591519 UniProt:A0A3Q3ACW5 PPARG UniProt A0A3Q3ACW5 1 EQUAL 505 EQUAL Reactome Database ID Release 82 10591519 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10591519 Reactome R-GGA-446172 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-446172.1 PPARG:RXRA Heterodimer Reactome DB_ID: 10593446 1 1 Reactome Database ID Release 82 10593446 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10593446 Reactome R-GGA-381281 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-381281.1 Reactome Database ID Release 82 10593448 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10593448 Reactome R-GGA-381262 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-381262.1 PPARG binds the Retinoic acid X Receptor RXRA to form a heterodimer that has transcriptional acivation activity. The complex was initially called ARF6 when discovered. PPARG binds RXRA via the C-terminus and AF-2 regions of PPARG. 17011499 Pubmed 2006 Transcriptional control of adipocyte formation Farmer, SR Cell Metab 4:263-73 19043829 Pubmed 2008 Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA Chandra, V Huang, P Hamuro, Y Raghuram, S Wang, Y Burris, TP Rastinejad, F Nature 456:350-6 17980149 Pubmed 2008 Effect of heterodimer partner RXRalpha on PPARgamma activation function-2 helix in solution Lu, J Chen, M Stanley, SE Li, E Biochem Biophys Res Commun 365:42-6 inferred from electronic annotation EVIDENCE CODE ECO:0000203 LEFT-TO-RIGHT PPARG binds PPARG agonists This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome PPARG agonists Reactome DB_ID: 9732650 rosiglizole rosiglitazone Avandia&reg; Reactome DB_ID: 9732641 rosiglitazone [Guide to Pharmacology:1056] rosiglitazone Avandia&reg; rosiglizole Guide to Pharmacology 1056 Reactome Database ID Release 82 9732641 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9732641 Reactome R-ALL-9732641 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9732641.1 U-72107A pioglitazone Actos&reg; Glustin&reg; pioglitazone HCl Reactome DB_ID: 9732611 pioglitazone [Guide to Pharmacology:2694] pioglitazone Actos&reg; Glustin&reg; pioglitazone HCl U-72107A Guide to Pharmacology 2694 Reactome Database ID Release 82 9732611 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9732611 Reactome R-ALL-9732611 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9732611.1 CS-045 troglitazone Rezulin&reg; Reactome DB_ID: 9732670 troglitazone [Guide to Pharmacology:2693] troglitazone CS-045 Rezulin&reg; Guide to Pharmacology 2693 Reactome Database ID Release 82 9732670 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9732670 Reactome R-ALL-9732670 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9732670.1 Reactome Database ID Release 82 9732650 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9732650 Reactome R-ALL-9732650 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9732650.1 PPARG:RXRA:Corepressor Complex Reactome DB_ID: 10658496 Ghost homologue of NCOR1 Reactome DB_ID: 10658494 Reactome Database ID Release 82 10658494 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10658494 Reactome R-GGA-442501 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442501.1 1 HDAC3 F1NH59 Reactome DB_ID: 10590115 UniProt:F1NH59 UniProt F1NH59 1 EQUAL 428 EQUAL Reactome Database ID Release 82 10590115 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590115 Reactome R-GGA-442464 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442464.1 1 1 NCOR2 NCOR2 A0A3Q2UH07 Reactome DB_ID: 10590097 UniProt:A0A3Q2UH07 NCOR2 UniProt A0A3Q2UH07 1 EQUAL 2525 EQUAL Reactome Database ID Release 82 10590097 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590097 Reactome R-GGA-442469 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-442469.1 1 Reactome Database ID Release 82 10658496 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10658496 Reactome R-GGA-381226 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-381226.1 PPARG:PPARG agonists Reactome DB_ID: 10658498 cytosol GENE ONTOLOGY GO:0005829 1 1 Reactome Database ID Release 82 10658498 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10658498 Reactome R-GGA-9732600 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-9732600.1 Reactome Database ID Release 82 10658500 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10658500 Reactome R-GGA-9732629 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-9732629.1 Peroxisome proliferator-activated receptor gamma (PPARG) is expressed mainly in fat tissue, where it regulates genes involved in fat cell (adipocyte) differentiation, fatty acid uptake and storage, and glucose uptake. PPARG is a nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, PPARG binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes. PPARG can regulate peroxisomal fatty acid beta-oxidation, adipocyte differentiation and glucose homeostasis.<br><br>Thiazolidinediones (TZDs, glitazones) are a family of drugs acting as insulin sensitizers and are only approved for the treatment of type 2 diabetes mellitus (T2DM). TZDs are PPARG agonists and act via PPARG to make cells more responsive to insulin. TZDs used to manage T2DM are rosiglitazone (Henke et al. 1998, Young et al. 1998), pioglitazone (Sakamoto et al. 2000) and troglitazone (Henke et al. 1998). Troglitazone was withdrawn in 2000 due to risk of hepatotoxicity (Graham et al. 2001) but has since been extensively studied using a variety of in vivo, in vitro and computational methods (Kassahun et al. 2001). 11497537 Pubmed 2001 Liver enzyme monitoring in patients treated with troglitazone Graham, D J Drinkard, C R Shatin, D Tsong, Y Burgess, M J JAMA 286:831-3 11095972 Pubmed 2000 Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone Sakamoto, J Kimura, H Moriyama, S Odaka, H Momose, Y Sugiyama, Y Sawada, H Biochem Biophys Res Commun 278:704-11 9454824 Pubmed 1998 Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisomal proliferator-activated receptor gamma Young, P W Buckle, D R Cantello, B C Chapman, H Clapham, J C Coyle, P J Haigh, D Hindley, R M Holder, J C Kallender, H Latter, A J Lawrie, K W Mossakowska, D Murphy, G J Roxbee Cox, L Smith, S A J Pharmacol Exp Ther 284:751-9 9836620 Pubmed 1998 N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents Henke, B R Blanchard, S G Brackeen, M F Brown, K K Cobb, J E Collins, J L Harrington, W W Hashim, M A Hull-Ryde, E A Kaldor, I Kliewer, S A Lake, D H Leesnitzer, L M Lehmann, J M Lenhard, J M Orband-Miller, L A Miller, J F Mook, R A Noble, S A Oliver, W Parks, D J Plunket, K D Szewczyk, J R Willson, T M J Med Chem 41:5020-36 11170509 Pubmed 2001 Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission Kassahun, K Pearson, P G Tang, W McIntosh, I Leung, K Elmore, C Dean, D Wang, R Doss, G Baillie, T A Chem Res Toxicol 14:62-70 Reactome Database ID Release 82 10660608 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10660608 Reactome R-GGA-381340 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-381340.1 Adipogenesis is the process of cell differentiation by which preadipocytes become adipocytes. During this process the preadipocytes cease to proliferate, begin to accumulate lipid droplets and develop morphologic and biochemical characteristics of mature adipocytes such as hormone responsive lipogenenic and lipolytic programs. The most intensively studied model system for adipogenesis is differentiation of the mouse 3T3-L1 preadipocyte cell line by an induction cocktail of containing mitogens (insulin/IGF1), glucocorticoid (dexamethasone), an inducer of cAMP (IBMX), and fetal serum (Cao et al. 1991, reviewed in Farmer 2006). More recently additional cellular models have become available to study adipogenesis that involve almost all stages of development (reviewed in Rosen and MacDougald 2006). In vivo knockout mice lacking putative adipogenic factors have also been extensively studied. Human pathways are traditionally inferred from those discovered in mouse but are now beginning to be validated in cellular models derived from human adipose progenitors (Fischer-Posovszky et al. 2008, Wdziekonski et al. 2011).<br>Adipogenesis is controlled by a cascade of transcription factors (Yeh et al. 1995, reviewed in Farmer 2006, Gesta et al. 2007). One of the first observable events during adipocyte differentiation is a transient increase in expression of the CEBPB (CCAAT/Enhancer Binding Protein Beta, C/EBPB) and CEBPD (C/EBPD) transcription factors (Cao et al. 1991, reviewed in Lane et al. 1999). This occurs prior to the accumulation of lipid droplets. However, it is the subsequent inductions of CEBPA and PPARG that are critical for morphological, biochemical and functional adipocytes.<br>Ectopic expression of CEBPB alone is capable of inducing substantial adipocyte differentiation in fibroblasts while CEBPD has a minimal effect. CEBPB is upregulated in response to intracellular cAMP (possibly via pCREB) and serum mitogens (possibly via Krox20). CEBPD is upregulated in response to glucocorticoids. The exact mechanisms that upregulate the CEBPs are not fully known.<br>CEBPB and CEBPD act directly on the Peroxisome Proliferator-activated Receptor Gamma (PPARG) gene by binding its promoter and activating transcription. CEBPB and CEBPD also directly activate the EBF1 gene (and possibly other EBFs) and KLF5 (Jimenez et al. 2007, Oishi 2005). The EBF1 and KLF5 proteins, in turn bind, and activate the PPARG promoter. Other hormones, such as insulin, affect PPARG expression and other transcription factors, such as ADD1/SREBP1c, bind the PPARG promoter. This is an area of ongoing research.<br>During adipogenesis the PPARG gene is transcribed to yield 2 variants. The adipogenic variant 2 mRNA encodes 30 additional amino acids at the N-terminus compared to the widely expressed variant 1 mRNA.<br>PPARG encodes a type II nuclear hormone receptor (remains in the nucleus in the absence of ligand) that forms a heterodimer with the Retinoid X Receptor Alpha (RXRA). The heterodimer was initially identified as a complex regulating the aP2/FABP4 gene and named ARF6 (Tontonoz et al. 1994).<br>The PPARG:RXRA heterodimer binds a recognition sequence that consists of two hexanucleotide motifs (DR1 motifs) separated by 1 nucleotide. Binding occurs even in the absence of ligands, such as fatty acids, that activate PPARG. In the absence of activating ligands, the PPARG:RXRA complex recruits repressors of transcription such as SMRT/NCoR2, NCoR1, and HDAC3 (Tontonoz and Spiegelman 2008).<br>Each molecule of PPARG can bind 2 molecules of activating ligands. Although, the identity of the endogenous ligands of PPARG is unknown, exogenous activators include fatty acids and the thiazolidinedione class of antidiabetic drugs (reviewed in Berger et al. 2005, Heikkinen et al. 2007, Lemberger et al. 1996). The most potent activators of PPARG in vitro are oxidized derivatives of unsaturated fatty acids.. Upon binding activating ligands PPARG causes a rearrangement of adjacent factors: Corepressors such as SMRT/NCoR2 are lost and coactivators such as TIF2, PRIP, CBP, and p300 are recruited (Tontonoz and Spiegelman). PPARG also binds directly to the TRAP220 subunit of the TRAP/Mediator complex that recruits RNA polymerase II. Thus binding of activating ligand by PPARG causes transcription of PPARG target genes.<br>Targets of PPARG include genes involved in differentiation (PGAR/HFARP, Perilipin, aP2/FABP4, CEBPA), fatty acid transport (LPL, FAT/CD36), carbohydrate metabolism (PEPCK-C, AQP7, GK, GLUT4 (SLC2A4)), and energy homeostasis (LEPTIN and ADIPONECTIN) (Perera et al. 2006).<br>Within 10 days of differentiation CEBPB and CEBPD are no longer located at the PPARG promoter. Instead CEBPA is present. EBF1 and PPARG bind the CEBPA promoter and activate transcription of CEBPA, one of the key transcription factors in adipogenesis. A current hypothesis posits a self-reinforcing loop that maintains PPARG expression and the differentiated state: PPARG activates CEBPA and CEBPA activates PPARG. Additionally EBF1 (and possibly other EBFs) activates CEBPA, CEBPA activates EBF1, and EBF1 activates PPARG. 18518822 Pubmed 2008 Fat and beyond: the diverse biology of PPARgamma Tontonoz, P Spiegelman, BM Annu Rev Biochem 77:289-312 7838715 Pubmed 1994 Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPAR gamma and RXR alpha Tontonoz, P Graves, RA Budavari, AI Erdjument-Bromage, H Lui, M Hu, E Tempst, P Spiegelman, BM Nucleic Acids Res 22:5628-34 1840554 Pubmed 1991 Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells Cao, Z Umek, RM McKnight, SL Genes Dev 5:1538-52 7531665 Pubmed 1995 Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins Yeh, WC Cao, Z Classon, M McKnight, SL Genes Dev 9:168-81 17956727 Pubmed 2007 Developmental origin of fat: tracking obesity to its source Gesta, S Tseng, YH Kahn, CR Cell 131:242-56 8970730 Pubmed 1996 Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology Lemberger, T Desvergne, B Wahli, W Annu Rev Cell Dev Biol 12:335-63 16380219 Pubmed 2006 Identification of novel PPARgamma target genes in primary human adipocytes Perera, RJ Marcusson, EG Koo, S Kang, X Kim, Y White, N Dean, NM Gene 369:90-9 15860371 Pubmed 2005 PPARs: therapeutic targets for metabolic disease Berger, JP Akiyama, TE Meinke, PT Trends Pharmacol Sci 26:244-51 10603305 Pubmed 1999 Role of the CCAAT enhancer binding proteins (C/EBPs) in adipocyte differentiation Lane, MD Tang, QQ Jiang, MS Biochem Biophys Res Commun 266:677-83 17060461 Pubmed 2007 Critical role for Ebf1 and Ebf2 in the adipogenic transcriptional cascade Jimenez, MA Akerblad, P Sigvardsson, M Rosen, ED Mol Cell Biol 27:743-57 20054179 Pubmed 2008 Human SGBS cells - a unique tool for studies of human fat cell biology Fischer-Posovszky, P Newell, FS Wabitsch, M Tornqvist, HE Obes Facts 1:184-9 17139329 Pubmed 2006 Adipocyte differentiation from the inside out Rosen, ED MacDougald, OA Nat Rev Mol Cell Biol 7:885-96 16054042 Pubmed 2005 Kr├╝ppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation Oishi, Y Manabe, I Tobe, K Tsushima, K Shindo, T Fujiu, K Nishimura, G Maemura, K Yamauchi, T Kubota, N Suzuki, R Kitamura, T Akira, Shizuo Kadowaki, T Nagai, R Cell Metab 1:27-39 21082419 Pubmed 2011 The generation and the manipulation of human multipotent adipose-derived stem cells Wdziekonski, B Mohsen-Kanson, T Villageois, P Dani, C Methods Mol Biol 702:419-27 17475546 Pubmed 2007 PPARgamma in human and mouse physiology Heikkinen, S Auwerx, J Argmann, CA Biochim Biophys Acta 1771:999-1013