Transcriptional regulation of white adipocyte differentiation (Homo sapiens)

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1, 5, 6, 9, 12...17, 20, 322913, 19294, 8, 11, 3714, 18, 31, 3629192827, 4613, 19, 24, 26, 30...19293, 10, 1929192, 19, 30, 44nucleoplasmcytosollipid dropletFAM120BMED31 THRAP3CHD9 MED27 MED18 PCK1 genePLIN1 geneNCOA1 CDK19 MED1 PLIN1PPARG MED12 ALA HDAC3 WNT1,WNT10BPPARGFABP4FABP4:Ligands ofPPARGEGR2KLF5LEPMED16 MED10 TGS1 MED6 TBL1X CARM1 RGZ MED10 SMARCD3 MED23 TNF(77-233)RXRA LINA NFKB1(1-433):RELACEBPBGLUT4 / SLC2A4tetramerSREBF2(1-484) THRAP3 MED17 FABP4 geneMED20 MED30 MED12 EBF1 geneNCOA6 MED6 EP300NCOA3 AA TBL1XR1 13(S')-HODE CEBPD geneMED19 RXRA ADIPOQPPARGC1ACREBBP MED20 NCOA3MED31 9S-HODE NCOR1 MED25 MED22 MED8 RXRACEBPDHELZ2 MED24 Actos MED26 MED24 MED23 CEBPB geneRXRA HDAC3CDK8 CREBBPCREBBP EBF1LEP geneRXRA Mediator Complex(consensus)MED27 PPARG:FattyAcid:RXRA:Mediator:Coactivator ComplexPPARG:RXRA:Corepressor ComplexPCK1MED28 TGFB1MED9 PPARA:RXRACoactivator complexKLF5 geneMED28 NCOR1MED1 9S-HODE LPLMED17 MED16 MED29 NCOA1 4xPalmC-CD36PPARG MED26 CDK8 FABP4 PPARA MED13L NCOA1PPARG CDK19 NCOR2PPARGC1A SLC2A4 gene (GLUT4gene)KLF4ADIPOQ geneMED15 MED14 CDK4MED8 PPARG:RXRAHeterodimerANGPTL geneCCNC MED4 MED30 CEBPAWNT1 CCND3ZNF467CCNC NFKB1(1-433) MED13 EPA MED15 LPL geneNCOA2 FAM120B FABP4SLC2A4 HELZ2 Palm MED9 MED22 ANGPTL4MED4 MED11 Peroxisome Proliferator Receptor Element (PPRE) RELA MED29 13(S')-HODE ADIRFMED13L MED25 MED7 MED21 RGZ MED21 NCOA2 HELZ2MED14 NR2F2EP300 CD36 geneSREBF1-1(1-490) MED7 MED19 PPARG geneActos MED11 ZNF638CEBPA geneMED18 WNT10B NCOR2 MED1 NCOA2SREBF1A,2MED13 16, 432216, 4325, 35, 38745


Description

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).
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.
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.
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.
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.
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).
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).
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.
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).
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. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 381340
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: May, Bruce

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Bibliography

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History

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CompareRevisionActionTimeUserComment
101450view11:32, 1 November 2018ReactomeTeamreactome version 66
100988view21:10, 31 October 2018ReactomeTeamreactome version 65
100524view19:44, 31 October 2018ReactomeTeamreactome version 64
100071view16:28, 31 October 2018ReactomeTeamreactome version 63
99622view15:01, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99229view12:44, 31 October 2018ReactomeTeamreactome version 62
93818view13:38, 16 August 2017ReactomeTeamreactome version 61
93364view11:21, 9 August 2017ReactomeTeamreactome version 61
88360view16:39, 1 August 2016FehrhartOntology Term : 'regulatory pathway' added !
86448view09:18, 11 July 2016ReactomeTeamreactome version 56
83095view09:58, 18 November 2015ReactomeTeamVersion54
81767view10:12, 26 August 2015ReactomeTeamVersion53
76992view08:28, 17 July 2014ReactomeTeamFixed remaining interactions
76697view12:06, 16 July 2014ReactomeTeamFixed remaining interactions
76023view10:08, 11 June 2014ReactomeTeamRe-fixing comment source
75732view11:20, 10 June 2014ReactomeTeamReactome 48 Update
75082view14:03, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74729view08:48, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
13(S')-HODE MetaboliteCHEBI:34154 (ChEBI)
4xPalmC-CD36ProteinP16671 (Uniprot-TrEMBL)
9S-HODE MetaboliteCHEBI:34496 (ChEBI)
AA MetaboliteCHEBI:15843 (ChEBI)
ADIPOQ geneGeneProductENSG00000181092 (Ensembl)
ADIPOQProteinQ15848 (Uniprot-TrEMBL)
ADIRFProteinQ15847 (Uniprot-TrEMBL)
ALA MetaboliteCHEBI:27432 (ChEBI)
ANGPTL geneGeneProductENSG00000167772 (Ensembl)
ANGPTL4ProteinQ9BY76 (Uniprot-TrEMBL)
Actos MetaboliteCHEBI:8228 (ChEBI)
CARM1 ProteinQ86X55 (Uniprot-TrEMBL)
CCNC ProteinP24863 (Uniprot-TrEMBL)
CCND3ProteinP30281 (Uniprot-TrEMBL)
CD36 geneGeneProductENSG00000135218 (Ensembl)
CDK19 ProteinQ9BWU1 (Uniprot-TrEMBL)
CDK4ProteinP11802 (Uniprot-TrEMBL)
CDK8 ProteinP49336 (Uniprot-TrEMBL)
CEBPA geneGeneProductENSG00000245848 (Ensembl)
CEBPAProteinP49715 (Uniprot-TrEMBL)
CEBPB geneGeneProductENSG00000172216 (Ensembl)
CEBPBProteinP17676 (Uniprot-TrEMBL)
CEBPD geneGeneProductENSG00000221869 (Ensembl)
CEBPDProteinP49716 (Uniprot-TrEMBL)
CHD9 ProteinQ3L8U1 (Uniprot-TrEMBL)
CREBBP ProteinQ92793 (Uniprot-TrEMBL)
CREBBPProteinQ92793 (Uniprot-TrEMBL)
EBF1 geneGeneProductENSG00000164330 (Ensembl)
EBF1ProteinQ9UH73 (Uniprot-TrEMBL)
EGR2ProteinP11161 (Uniprot-TrEMBL)
EP300 ProteinQ09472 (Uniprot-TrEMBL)
EP300ProteinQ09472 (Uniprot-TrEMBL)
EPA MetaboliteCHEBI:28364 (ChEBI)
FABP4 ProteinP15090 (Uniprot-TrEMBL)
FABP4 geneGeneProductENSG00000170323 (Ensembl)
FABP4:Ligands of PPARGComplexR-HSA-2026090 (Reactome)
FABP4ProteinP15090 (Uniprot-TrEMBL)
FAM120B ProteinQ96EK7 (Uniprot-TrEMBL)
FAM120BProteinQ96EK7 (Uniprot-TrEMBL)
GLUT4 / SLC2A4 tetramerComplexR-HSA-70384 (Reactome)
HDAC3 ProteinO15379 (Uniprot-TrEMBL)
HDAC3ProteinO15379 (Uniprot-TrEMBL)
HELZ2 ProteinQ9BYK8 (Uniprot-TrEMBL)
HELZ2ProteinQ9BYK8 (Uniprot-TrEMBL)
KLF4ProteinO43474 (Uniprot-TrEMBL)
KLF5 geneGeneProductENSG00000102554 (Ensembl)
KLF5ProteinQ13887 (Uniprot-TrEMBL)
LEP geneGeneProductENSG00000174697 (Ensembl)
LEPProteinP41159 (Uniprot-TrEMBL)
LINA MetaboliteCHEBI:17351 (ChEBI)
LPL geneGeneProductENSG00000175445 (Ensembl)
LPLProteinP06858 (Uniprot-TrEMBL)
MED1 ProteinQ15648 (Uniprot-TrEMBL) MED1 is a component of each of the various Mediator complexes, that function as transcription co-activators. The MED1-containing compolexes include the DRIP, ARC, TRIP and CRSP compllexes.
MED10 ProteinQ9BTT4 (Uniprot-TrEMBL)
MED11 ProteinQ9P086 (Uniprot-TrEMBL)
MED12 ProteinQ93074 (Uniprot-TrEMBL)
MED13 ProteinQ9UHV7 (Uniprot-TrEMBL)
MED13L ProteinQ71F56 (Uniprot-TrEMBL)
MED14 ProteinO60244 (Uniprot-TrEMBL)
MED15 ProteinQ96RN5 (Uniprot-TrEMBL)
MED16 ProteinQ9Y2X0 (Uniprot-TrEMBL)
MED17 ProteinQ9NVC6 (Uniprot-TrEMBL)
MED18 ProteinQ9BUE0 (Uniprot-TrEMBL)
MED19 ProteinA0JLT2 (Uniprot-TrEMBL)
MED20 ProteinQ9H944 (Uniprot-TrEMBL)
MED21 ProteinQ13503 (Uniprot-TrEMBL)
MED22 ProteinQ15528 (Uniprot-TrEMBL)
MED23 ProteinQ9ULK4 (Uniprot-TrEMBL)
MED24 ProteinO75448 (Uniprot-TrEMBL)
MED25 ProteinQ71SY5 (Uniprot-TrEMBL)
MED26 ProteinO95402 (Uniprot-TrEMBL)
MED27 ProteinQ6P2C8 (Uniprot-TrEMBL)
MED28 ProteinQ9H204 (Uniprot-TrEMBL)
MED29 ProteinQ9NX70 (Uniprot-TrEMBL)
MED30 ProteinQ96HR3 (Uniprot-TrEMBL)
MED31 ProteinQ9Y3C7 (Uniprot-TrEMBL)
MED4 ProteinQ9NPJ6 (Uniprot-TrEMBL)
MED6 ProteinO75586 (Uniprot-TrEMBL)
MED7 ProteinO43513 (Uniprot-TrEMBL)
MED8 ProteinQ96G25 (Uniprot-TrEMBL)
MED9 ProteinQ9NWA0 (Uniprot-TrEMBL)
Mediator Complex (consensus)ComplexR-HSA-556786 (Reactome) The Mediator Complex bridges transcription factors and the basal RNA polymerase II complex. Multiple analyses of immunoprecipitated complexes from human cells (HeLa cells) detects 31 subunits. Other complexes with fewer subunits may also exist.
NCOA1 ProteinQ15788 (Uniprot-TrEMBL)
NCOA1ProteinQ15788 (Uniprot-TrEMBL)
NCOA2 ProteinQ15596 (Uniprot-TrEMBL)
NCOA2ProteinQ15596 (Uniprot-TrEMBL)
NCOA3 ProteinQ9Y6Q9 (Uniprot-TrEMBL)
NCOA3ProteinQ9Y6Q9 (Uniprot-TrEMBL)
NCOA6 ProteinQ14686 (Uniprot-TrEMBL)
NCOR1 ProteinO75376 (Uniprot-TrEMBL)
NCOR1ProteinO75376 (Uniprot-TrEMBL)
NCOR2 ProteinQ9Y618 (Uniprot-TrEMBL)
NCOR2ProteinQ9Y618 (Uniprot-TrEMBL)
NFKB1(1-433) ProteinP19838 (Uniprot-TrEMBL)
NFKB1(1-433):RELAComplexR-HSA-194047 (Reactome)
NR2F2ProteinP24468 (Uniprot-TrEMBL)
PCK1 geneGeneProductENSG00000124253 (Ensembl)
PCK1ProteinP35558 (Uniprot-TrEMBL)
PLIN1 geneGeneProductENSG00000166819 (Ensembl)
PLIN1ProteinO60240 (Uniprot-TrEMBL)
PPARA ProteinQ07869 (Uniprot-TrEMBL)
PPARA:RXRA Coactivator complexComplexR-HSA-400154 (Reactome)
PPARG ProteinP37231 (Uniprot-TrEMBL)
PPARG geneGeneProductENSG00000132170 (Ensembl)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexComplexR-HSA-381367 (Reactome)
PPARG:RXRA HeterodimerComplexR-HSA-381281 (Reactome)
PPARG:RXRA:Corepressor ComplexComplexR-HSA-381226 (Reactome)
PPARGC1A ProteinQ9UBK2 (Uniprot-TrEMBL)
PPARGC1AProteinQ9UBK2 (Uniprot-TrEMBL)
PPARGProteinP37231 (Uniprot-TrEMBL)
Palm MetaboliteCHEBI:15756 (ChEBI)
Peroxisome Proliferator Receptor Element (PPRE) R-ALL-422139 (Reactome) Peroxisome proliferator receptor elements bind heterodimers containing a peroxisome proliferator receptor and a retinoic acid receptor. The consensus sequence is TGAMCTTTGNCCTAGWTYYG.
RELA ProteinQ04206 (Uniprot-TrEMBL)
RGZ MetaboliteCHEBI:50122 (ChEBI)
RXRA ProteinP19793 (Uniprot-TrEMBL)
RXRAProteinP19793 (Uniprot-TrEMBL)
SLC2A4 ProteinP14672 (Uniprot-TrEMBL)
SLC2A4 gene (GLUT4 gene)GeneProductENSG00000181856 (Ensembl)
SMARCD3 ProteinQ6STE5 (Uniprot-TrEMBL)
SREBF1-1(1-490) ProteinP36956-1 (Uniprot-TrEMBL)
SREBF1A,2ComplexR-HSA-1655734 (Reactome)
SREBF2(1-484) ProteinQ12772 (Uniprot-TrEMBL)
TBL1X ProteinO60907 (Uniprot-TrEMBL)
TBL1XR1 ProteinQ9BZK7 (Uniprot-TrEMBL)
TGFB1ProteinP01137 (Uniprot-TrEMBL)
TGS1 ProteinQ96RS0 (Uniprot-TrEMBL)
THRAP3 ProteinQ9Y2W1 (Uniprot-TrEMBL)
THRAP3ProteinQ9Y2W1 (Uniprot-TrEMBL)
TNF(77-233)ProteinP01375 (Uniprot-TrEMBL)
WNT1 ProteinP04628 (Uniprot-TrEMBL)
WNT1,WNT10BComplexR-HSA-976184 (Reactome)
WNT10B ProteinO00744 (Uniprot-TrEMBL)
ZNF467ProteinQ7Z7K2 (Uniprot-TrEMBL)
ZNF638ProteinQ14966 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
4xPalmC-CD36ArrowR-HSA-560517 (Reactome)
ADIPOQ geneR-HSA-1183058 (Reactome)
ADIPOQArrowR-HSA-1183058 (Reactome)
ADIRFArrowR-HSA-381283 (Reactome)
ANGPTL geneR-HSA-560473 (Reactome)
ANGPTL4ArrowR-HSA-560473 (Reactome)
ArrowR-HSA-1183058 (Reactome)
ArrowR-HSA-560491 (Reactome)
CCND3ArrowR-HSA-560510 (Reactome)
CD36 geneR-HSA-560517 (Reactome)
CDK4ArrowR-HSA-560510 (Reactome)
CEBPA geneR-HSA-560491 (Reactome)
CEBPAArrowR-HSA-1183003 (Reactome)
CEBPAArrowR-HSA-1183032 (Reactome)
CEBPAArrowR-HSA-1183058 (Reactome)
CEBPAArrowR-HSA-381283 (Reactome)
CEBPAArrowR-HSA-560491 (Reactome)
CEBPB geneR-HSA-381337 (Reactome)
CEBPBArrowR-HSA-1183058 (Reactome)
CEBPBArrowR-HSA-381283 (Reactome)
CEBPBArrowR-HSA-381337 (Reactome)
CEBPBArrowR-HSA-381377 (Reactome)
CEBPBArrowR-HSA-977271 (Reactome)
CEBPD geneR-HSA-977392 (Reactome)
CEBPDArrowR-HSA-381283 (Reactome)
CEBPDArrowR-HSA-381377 (Reactome)
CEBPDArrowR-HSA-977271 (Reactome)
CEBPDArrowR-HSA-977392 (Reactome)
CREBBPR-HSA-381309 (Reactome)
EBF1 geneR-HSA-977271 (Reactome)
EBF1ArrowR-HSA-381283 (Reactome)
EBF1ArrowR-HSA-977271 (Reactome)
EGR2ArrowR-HSA-381337 (Reactome)
EP300R-HSA-381309 (Reactome)
FABP4 geneR-HSA-560510 (Reactome)
FABP4:Ligands of PPARGR-HSA-381309 (Reactome)
FABP4ArrowR-HSA-381309 (Reactome)
FABP4ArrowR-HSA-560510 (Reactome)
FAM120BR-HSA-381309 (Reactome)
GLUT4 / SLC2A4 tetramerArrowR-HSA-1183032 (Reactome)
HDAC3ArrowR-HSA-381309 (Reactome)
HDAC3R-HSA-381290 (Reactome)
HELZ2R-HSA-381309 (Reactome)
KLF4ArrowR-HSA-381337 (Reactome)
KLF5 geneR-HSA-381377 (Reactome)
KLF5ArrowR-HSA-381283 (Reactome)
KLF5ArrowR-HSA-381377 (Reactome)
LEP geneR-HSA-1183003 (Reactome)
LEPArrowR-HSA-1183003 (Reactome)
LPL geneR-HSA-560498 (Reactome)
LPLArrowR-HSA-560498 (Reactome)
Mediator Complex (consensus)R-HSA-381309 (Reactome)
NCOA1R-HSA-381309 (Reactome)
NCOA2R-HSA-381309 (Reactome)
NCOA3R-HSA-381309 (Reactome)
NCOR1ArrowR-HSA-381309 (Reactome)
NCOR1R-HSA-381290 (Reactome)
NCOR2ArrowR-HSA-381309 (Reactome)
NCOR2R-HSA-381290 (Reactome)
PCK1 geneR-HSA-560472 (Reactome)
PCK1ArrowR-HSA-560472 (Reactome)
PLIN1 geneR-HSA-560493 (Reactome)
PLIN1ArrowR-HSA-560493 (Reactome)
PPARA:RXRA Coactivator complexArrowR-HSA-560473 (Reactome)
PPARA:RXRA Coactivator complexArrowR-HSA-560517 (Reactome)
PPARG geneR-HSA-381283 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexArrowR-HSA-381309 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexArrowR-HSA-560472 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexArrowR-HSA-560473 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexArrowR-HSA-560491 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexArrowR-HSA-560493 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexArrowR-HSA-560498 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexArrowR-HSA-560510 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexArrowR-HSA-560517 (Reactome)
PPARG:Fatty Acid:RXRA:Mediator:Coactivator ComplexTBarR-HSA-1183003 (Reactome)
PPARG:RXRA HeterodimerArrowR-HSA-381262 (Reactome)
PPARG:RXRA HeterodimerR-HSA-381290 (Reactome)
PPARG:RXRA:Corepressor ComplexArrowR-HSA-381290 (Reactome)
PPARG:RXRA:Corepressor ComplexR-HSA-381309 (Reactome)
PPARG:RXRA:Corepressor ComplexTBarR-HSA-1183032 (Reactome)
PPARGArrowR-HSA-381283 (Reactome)
PPARGC1AR-HSA-381309 (Reactome)
PPARGR-HSA-381262 (Reactome)
R-HSA-1183003 (Reactome) The Ob gene encoding leptin is transcribed to yield mRNA and translated to yield protein. Expression of leptin is positively regulated by C/EBPalpha (CEBPA, Miller et al. 1996, Melzner et al. 2002) and negatively regulated by PPARG in adipocytes (De Vos et al. 1996).
R-HSA-1183032 (Reactome) The GLUT4 (SLC2A4) gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
R-HSA-1183058 (Reactome) The Adiponectin gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Adiponectin is upregulated during adipogenesis by C/EBPalpha (CEBPA), PPARG, and CEBPB (Segawa et al. 2009, Qiao et al. 2005, Iwaki et al. 2003, Kita et al. 2005).
R-HSA-381262 (Reactome) 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.
R-HSA-381283 (Reactome) The transcription factors CEBPB, CEBPD, and KLF5 simultaneously bind the PPARG promoter and synergistically activate transcription of the PPARG gene. These three factors activate transcription after initial stimulation of adipocyte differentiation but then are replaced by CEBPA within 10 days. CEBPA and other factors may be responsible for long term maintenance of PPARG expression and the differentiated state.
Pre-adipose tissue contains both the widely expressed PPARG isoform 1 mRNA and the more tissue-specific PPARG isoform 2. The PPARG isoform 2 mRNA is translated to yield PPARG isoform 2 protein, which has 505 amino acid residues (57 KDa) and is the longest of the 4 observed variants. Isoform 2 is specific to preadipose and adipose tissue (Mukherjee et al. 1997). Confusingly, the longest variant is called isoform 1 in some publications.
In mouse, by 10 days after induction of adipocyte differentiation Cebpa, but neither Cebpb nor Cebpd, is detectable at the Pparg promoter. While adipocyte differentiation can proceed without Cebpa, adipocytes differentiated from Cebpa-knockout cells are insulin insensitive due to a defect in Glut4 (Slc2a4) vesicle trafficking.
The adipogenesis regulatory factor (ADIRF, aka AFRO, APM2, C10orf116) promotes adipogenic differentiation and stimulates transcription initiation of master adipogenesis factors like PPARG and CEBPA (Ni et al. 2013).
R-HSA-381290 (Reactome) The PPARG:RXRA heterodimer binds specific the PPRE element, two 6-bp DR-1 motifs separated by 1 nucleotide, in the promoters of target genes such as aP2/FABP4 even in the absence of fatty acid ligands that activate PPARG. When activating ligands of PPARG are absent PPARG:RXRA recruits corepressors such as NCoR2(SMRT), NCoR, and HDAC3 to maintain the target gene in an inactive state.
R-HSA-381309 (Reactome) PPARG can be activated in cell cultures by adding ligands such as polyunsaturated fatty acids and certain prostanoids (prostaglandins). Endogenous fatty acids are relatively poor activators. Which ligands are most responsible for PPARG activation in the body has not yet been established. Generally, oxidized fatty acids such as 9(S')-hydroxyoctadeca-10,12-dienoic acid (9(S')-HODE) and 13(S')-HODE are more effective activators than are endogenous fatty acids. The thiazolidinedione (TZD) class of antidiabetic drugs are agonist ligands for PPARG (Lambe and Tugwood 1996).
FABP4 delivers ligands to PPARG directly. Binding of activator ligands to PPARG causes loss of corepressors such as SMRT/NCoR2, NCoR1, and HDAC3 and gain of interactions with the basal transcription machinery (Yoo et al. 2006). The TRAP220/MED1/DRIP205 subunit of the TRAP/Mediator (DRIP) complex binds directly to the LXXLL motif of PPARG and TRAP/Mediator is necessary for full transcriptional activation of target genes (Ge et al. 2008). PPARG also interacts with the MED14 subunit of the Mediator complex (Grontved et al. 2010).
Other coactivators, including NCOA1/SRC-1, NCOA2/TIF2/GRIP1, CBP, HAT/p300, and PRIP, interact with PPARG in a ligand-dependent way and enhance transcription (Gellman et al. 1999, Wallberg et al. 2003, Yang et al. 2000, Ge et al. 2002, Puigserver et al. 1999, Bugge et al. 2009, Steger et al. 2010).
The target genes of PPARG encode proteins involved in adipocyte differentiation (PGAR/ANGPTL4, PLIN, and aP2/FABP4), carbohydrate metabolism (PEPCK-C), and fatty acid transport (FAT/CD36, LPL).
R-HSA-381337 (Reactome) Expression of the CEBPB and CEBPD transcription factors is induced by at least three factors:
1) Mitogens such as those present in fetal serum act via the Krox20 transcription factor to activate expression of CEBPB.
2) Glucocorticoids activate expression of CEBPD.
3) Hormones or drugs that increase intracellular cAMP act via pCREB to activate expression of CEBPB.
The detailed mechanisms of activation are not yet known.
R-HSA-381377 (Reactome) Increased expression of KLF5 occurs after activation of the transcription factors CEBPB and CEBPD during differentiation and activation of KLF5 depends on CEBPB and CEBPD. Both CEBPB and CEBPD bind the promoter of the KLF5 gene upstream of the site of transcription initiation and activate transcription of KLF5.
R-HSA-560472 (Reactome) The PEPCK-C gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
R-HSA-560473 (Reactome) The ANGPTL4 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
R-HSA-560491 (Reactome) The CEBPA gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
R-HSA-560493 (Reactome) The Perilipin (PLIN) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Perilipin is upregulated during adipogenesis.
R-HSA-560498 (Reactome) The LPL gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
R-HSA-560510 (Reactome) The FABP4 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of FABP4 is activated during adipogenesis.
R-HSA-560517 (Reactome) The Platelet glycoprotein IV gene (CD36, PAS IV, GPIV) is transcribed to yield mRNA and the mRNA is translated to yield proteind.
R-HSA-977271 (Reactome) The gene encoding transcription factor EBF1 is transcribed to yield mRNA and the mRNA is translated to yield protein in pre-adipocytes and adipocytes. Transcription of EBF1 is enhanced by CEBPB and CEBPD, which bind the EBF1 promoter.
R-HSA-977392 (Reactome) Expression of the CEBPB and CEBPD transcription factors is induced by at least three factors:
1) Mitogens such as those present in fetal serum act via the Krox20 transcription factor to activate expression of CEBPB.
2) Glucocorticoids activate expression of CEBPD.
3) Hormones or drugs that increase intracellular cAMP act via pCREB to activate expression of CEBPB.
The detailed mechanisms of activation are not yet known.
RXRAR-HSA-381262 (Reactome)
SLC2A4 gene (GLUT4 gene)R-HSA-1183032 (Reactome)
SREBF1A,2ArrowR-HSA-381283 (Reactome)
TBarR-HSA-381283 (Reactome)
TGFB1TBarR-HSA-381283 (Reactome)
TGFB1TBarR-HSA-560491 (Reactome)
THRAP3R-HSA-381309 (Reactome)
TNF(77-233)TBarR-HSA-560491 (Reactome)
WNT1,WNT10BTBarR-HSA-560491 (Reactome)
ZNF467ArrowR-HSA-381283 (Reactome)
ZNF638ArrowR-HSA-381283 (Reactome)
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