Affinage

PPARG

Peroxisome proliferator-activated receptor gamma · UniProt P37231

Round 2 corrected
Length
505 aa
Mass
57.6 kDa
Annotated
2026-04-28
130 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPARγ is a ligand-activated nuclear receptor that serves as the master transcriptional regulator of adipogenesis and a critical mediator of insulin sensitivity, lipid metabolism, and anti-inflammatory gene programs. Expressed as two isoforms (γ1 and γ2) from alternate promoters, PPARγ heterodimerizes with RXRα and binds PPAR-responsive elements; its large ligand-binding pocket accommodates endogenous fatty acid ligands (15d-PGJ2, 9-HODE, 13-HODE) and synthetic thiazolidinediones, with an additional alternate allosteric binding site that produces distinct coregulator recruitment profiles (PMID:9113987, PMID:9568715, PMID:24705063). Ligand-dependent SUMOylation of the PPARγ LBD mediates transrepression of NF-κB target genes by stabilizing NCoR–HDAC3 corepressor complexes on inflammatory promoters, while obesity-driven phosphorylation of Ser273 by ERK (and Cdk5) dysregulates diabetogenic gene programs—an effect blocked by anti-diabetic PPARγ ligands through an allosteric mechanism and read out by the phospho-specific cofactor Thrap3 (PMID:16127449, PMID:20651683, PMID:25409143, PMID:25316675, PMID:32239932). Dominant-negative loss-of-function mutations in the PPARγ ligand-binding domain cause severe insulin resistance, early-onset type 2 diabetes, and familial partial lipodystrophy type 3 in humans (PMID:10622252, PMID:29622583).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1994 High

    Establishing PPARγ2 as the master regulator of adipogenesis resolved how a single transcription factor could reprogram fibroblast identity toward the fat cell lineage, with C/EBPα acting cooperatively rather than in parallel.

    Evidence Retroviral expression of PPARγ2 in fibroblasts with dose-dependent adipocyte differentiation and C/EBPα cooperation assays

    PMID:8001151

    Open questions at the time
    • Endogenous ligand identity unknown at this stage
    • Mechanism of C/EBPα cooperation not molecularly defined
    • Whether PPARγ is required (not just sufficient) for adipogenesis not yet tested
  2. 1997 High

    Identification of endogenous fatty acid and eicosanoid ligands (including 15d-PGJ2) that directly bind PPARγ established it as a physiological lipid sensor, answering the question of what activates the receptor in vivo.

    Evidence Radioligand competition binding assays with multiple fatty acids and eicosanoids in COS cells; gene structure determination confirming two isoforms

    PMID:9113987 PMID:9228052

    Open questions at the time
    • Whether these ligands reach sufficient intracellular concentrations in specific tissues
    • Relative contributions of individual ligands in vivo unresolved
  3. 1998 High

    Crystal structures of the PPARγ LBD alone and in complex with rosiglitazone and SRC-1 defined the charge-clamp mechanism of coactivator recruitment and revealed the unusually large ligand-binding pocket, providing the atomic framework for understanding ligand selectivity and coregulator assembly.

    Evidence X-ray crystallography at 2.2 Å (apo) and 2.3 Å (ternary complex with rosiglitazone and SRC-1 peptide)

    PMID:9744270

    Open questions at the time
    • Full-length receptor structure with DNA and heterodimer partner not available
    • Dynamics of coactivator exchange not captured by static structure
  4. 1998 High

    Discovery that oxidized LDL components 9-HODE and 13-HODE activate PPARγ to induce CD36 in macrophages established a feed-forward loop linking PPARγ to foam cell formation and atherosclerosis, extending PPARγ biology beyond adipogenesis.

    Evidence Transcriptional reporter and ligand-binding competition assays in myelomonocytic cell lines; CD36 induction by PPARγ:RXRα activation

    PMID:9568715 PMID:9568716

    Open questions at the time
    • In vivo net effect (pro- vs. anti-atherogenic) of macrophage PPARγ unresolved
    • Whether PPARγ activation promotes or resolves foam cell phenotype debated
  5. 1999 High

    Human dominant-negative PPARγ LBD mutations causing severe insulin resistance and early-onset diabetes provided direct genetic proof that PPARγ is essential for systemic insulin sensitivity, not merely a pharmacological target of thiazolidinediones.

    Evidence Mutation identification in insulin-resistant families, in vitro dominant-negative transcriptional assays, structural modeling of helix 12 destabilization

    PMID:10622252

    Open questions at the time
    • Tissue-specific contributions to systemic insulin resistance not dissected
    • Whether haploinsufficiency alone is pathogenic or requires dominant-negative effect
  6. 2002 High

    Genetic epistasis experiments using PPARγ-null fibroblasts demonstrated that C/EBPα cannot promote adipogenesis without PPARγ, resolving the hierarchy: PPARγ is the necessary proximal effector of a single adipogenic pathway, not a parallel player.

    Evidence Adipogenesis assays in PPARγ-null immortalized fibroblasts with ectopic C/EBPα expression

    PMID:11782441

    Open questions at the time
    • Downstream gene network through which PPARγ executes the adipogenic program not yet mapped genome-wide
  7. 2003 High

    Muscle-specific PPARγ deletion causing progressive insulin resistance and impaired glucose disposal demonstrated a cell-autonomous insulin-sensitizing role outside adipose tissue, answering whether PPARγ acts solely through fat.

    Evidence Cre-loxP conditional knockout in muscle, hyperinsulinemic-euglycemic clamp, glucose tolerance testing

    PMID:14625542

    Open questions at the time
    • Muscle PPARγ target genes mediating insulin sensitivity not identified
    • Relative contribution of muscle vs. adipose PPARγ to whole-body glucose homeostasis unclear
  8. 2005 High

    The discovery that ligand-dependent SUMOylation of the PPARγ LBD mediates transrepression of NF-κB inflammatory genes by stabilizing NCoR–HDAC3 complexes on promoters provided a mechanistic explanation for anti-inflammatory effects that are separable from classical agonism.

    Evidence SUMOylation assays, ChIP, co-immunoprecipitation, reporter assays, and mutagenesis in mouse macrophages

    PMID:16127449

    Open questions at the time
    • Identity of the SUMO E3 ligase acting on PPARγ in macrophages
    • Whether transrepression operates genome-wide or at select promoters
  9. 2007 High

    PPARγ activation was shown to prime human monocytes toward an anti-inflammatory M2 macrophage phenotype, linking nuclear receptor signaling to macrophage polarization and providing a functional context for transrepression.

    Evidence Primary human monocyte differentiation assays, flow cytometry, immunohistochemistry in human atherosclerotic lesions

    PMID:17681149

    Open questions at the time
    • Whether PPARγ is sufficient for M2 commitment or requires co-signals
    • In vivo confirmation of monocyte-to-M2 reprogramming via PPARγ in human disease settings
  10. 2010 High

    Identification of Cdk5-mediated phosphorylation of PPARγ at Ser273 as a modification that dysregulates diabetogenic genes without affecting adipogenesis fundamentally reframed the anti-diabetic mechanism of PPARγ ligands: they work by blocking pS273 rather than by full agonism.

    Evidence In vitro kinase assays, site-directed mutagenesis, gene expression profiling in high-fat diet mouse models, human patient correlations

    PMID:20651683

    Open questions at the time
    • Identity of downstream effector recognizing pS273 unknown at this point
    • Whether blocking pS273 fully accounts for insulin-sensitizing activity
  11. 2014 High

    Three advances refined the Ser273 phosphorylation axis: ERK was identified as the dominant kinase for pS273 (with Cdk5 paradoxically restraining ERK through MEK); Thrap3 was identified as the phospho-specific cofactor that reads pS273 to control diabetogenic transcription; and an alternate ligand-binding site distinct from the canonical pocket was characterized structurally.

    Evidence In vitro kinase assays, adipose-specific Cdk5 KO, proteomics, Co-IP/MS for Thrap3, ASO knockdown in mice, HDX-MS and coregulator assays for alternate site

    PMID:24705063 PMID:25316675 PMID:25409143

    Open questions at the time
    • Whether alternate-site ligands regulate pS273 in vivo
    • Full structural model of PPARγ–Thrap3 interface lacking
    • Relative contributions of ERK vs. Cdk5 in different tissues
  12. 2016 High

    Dissection of site-specific phosphorylation (pS112 vs. pS273) effects on bone cell differentiation and the discovery that osteocyte PPARγ directly transcribes sclerostin (Sost) to regulate bone mass expanded PPARγ's roles to skeletal biology and explained TZD-associated bone loss.

    Evidence Osteocyte-specific PPARγ conditional KO, ChIP on Sost PPRE, bone histomorphometry, inverse agonist SR10171 treatment in mice

    PMID:27422345 PMID:33722775

    Open questions at the time
    • Whether pS112 and pS273 are independently regulated in osteocytes
    • Structural basis for how inverse agonists selectively block pS273 but not pS112
  13. 2020 High

    Multi-technique structural studies (crystallography, NMR, HDX-MS, MD simulations) defined the allosteric mechanism by which PPARγ ligands inhibit Cdk5/ERK-mediated pS273 through conformational changes distant from the phosphorylation site, providing the structural rationale for non-agonist insulin sensitizers.

    Evidence X-ray crystallography, NMR, HDX-MS, MD simulations, and site-directed mutagenesis of PPARγ

    PMID:32239932

    Open questions at the time
    • Whether allosteric inhibition operates identically for all non-agonist ligand scaffolds
    • In vivo structural validation lacking
  14. 2022 High

    Identification of C/EBPβ and CSF2 signaling as the isoform-specific transcriptional activators of Pparg2 in alveolar macrophages provided the first upstream regulatory circuit for tissue-specific PPARγ isoform expression.

    Evidence ATAC-seq, transcriptome analysis, conditional C/EBPβ knockout, ChIP in CSF2-primed macrophage populations

    PMID:36112694

    Open questions at the time
    • Whether this mechanism applies to Pparg2 induction in adipocytes
    • Chromatin state prerequisites for isoform-specific activation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the full genome-wide map of transrepression targets in vivo, the structural basis for PPARγ–Thrap3 interaction, whether alternate-site binding operates physiologically, and how tissue-specific cofactor availability determines divergent PPARγ outputs in adipocytes, macrophages, osteocytes, and urothelium.
  • Full-length PPARγ:RXRα:DNA cryo-EM/crystal structure still missing
  • Endogenous ligand identity and sufficiency in each tissue remains debated
  • Systematic mapping of tissue-specific coregulator complexes not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 10 GO:0003677 DNA binding 6 GO:0008289 lipid binding 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 2
Pathway
R-HSA-74160 Gene expression (Transcription) 10 R-HSA-1430728 Metabolism 5 R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 3
Partners
CACUL1KLF11LPIN1NCOA1NCOR1NCOR2RXRATHRAP3
Complex memberships
NCoR–HDAC3 corepressor complexPPARγ:RXRα heterodimer

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 PPARγ2 (PPARgamma2) is a lipid-activated transcription factor that, when expressed by retrovirus in fibroblasts, is sufficient to stimulate adipose differentiation; PPAR activators promote differentiation in a dose-dependent manner, and C/EBPα cooperates with PPARγ2 to dramatically stimulate the adipocyte program, identifying PPARγ2 as the master regulator of adipogenesis. Retroviral expression in fibroblasts, cell differentiation assays, co-expression with C/EBPα Cell High 8001151
1997 Certain mono- and polyunsaturated fatty acids bind directly to PPARα and PPARγ at physiological concentrations, and the eicosanoids 8(S)-HETE and 15-deoxy-Δ12,14-prostaglandin J2 function as subtype-selective ligands for PPARα and PPARγ, respectively, demonstrating that PPARs serve as physiological lipid sensors. Radioligand competition binding assays using GW2331 as radioligand in COS cells Proceedings of the National Academy of Sciences of the United States of America High 9113987
1997 The human PPARγ gene has nine exons spanning >100 kb of genomic DNA; alternate transcription start sites and alternate splicing generate PPARγ1 and PPARγ2 isoforms differing at their 5'-ends. PPARγ is most highly expressed in adipose tissue and large intestine. Both isoforms are activated by thiazolidinediones and prostaglandin J and bind with high affinity to a PPRE. cDNA cloning, genomic structure determination, RT-competitive PCR, promoter analysis, reporter assays The Journal of biological chemistry High 9228052
1998 X-ray crystal structure of the human PPARγ ligand-binding domain (LBD) at 2.2 Å reveals a large ligand-binding pocket. The ternary complex of PPARγ LBD with rosiglitazone and SRC-1 coactivator (88 aa) at 2.3 Å shows that conserved glutamate and lysine residues form a 'charge clamp' contacting backbone atoms of LXXLL helices of SRC-1, and that two consecutive LXXLL motifs of SRC-1 make identical contacts with both subunits of a PPARγ homodimer, defining a general mechanism for nuclear receptor–coactivator assembly. X-ray crystallography (apo-LBD at 2.2 Å; ternary complex at 2.3 Å) Nature High 9744270
1998 PPARγ is induced in human monocytes by oxidized LDL (oxLDL) and is expressed at high levels in foam cells of atherosclerotic lesions. Ligand activation of the PPARγ:RXRα heterodimer in myelomonocytic cell lines induces changes characteristic of monocytic differentiation and promotes uptake of oxLDL through transcriptional induction of the scavenger receptor CD36. Reporter assays, transient transfection, differentiation assays, Northern/Western blotting in myelomonocytic cell lines Cell High 9568716
1998 Oxidized LDL activates PPARγ-dependent transcription through scavenger receptor-mediated particle uptake; two major oxidized lipid components of oxLDL, 9-HODE and 13-HODE, are identified as endogenous activators and ligands of PPARγ, showing that PPARγ coordinates gene expression in response to oxidized lipids. PPARγ transcriptional reporter assays, ligand-binding competition assays, macrophage cell lines Cell High 9568715
1999 Two different heterozygous dominant negative mutations in the ligand-binding domain of PPARγ (destabilizing helix 12 that mediates transactivation) cause severe insulin resistance, type 2 diabetes mellitus, and hypertension at early age in humans, providing direct genetic evidence that PPARγ is required for insulin sensitivity and glucose homeostasis. Human genetics (mutation identification), in vitro transcriptional activity assays, dominant negative co-expression assays, structural modeling Nature High 10622252
2000 The common Pro12Ala polymorphism in PPARγ is confirmed to be associated with a 1.25-fold increase in type 2 diabetes risk for the proline allele, implicating inherited variation in PPARγ in the pathogenesis of type 2 diabetes and suggesting a functional role for this variant. Family-based genetic association study with >3000 individuals, multiple replication samples Nature genetics High 10973253
2000 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) inhibits NF-κB-dependent transcription through PPARγ-independent mechanisms involving direct covalent modification of critical cysteine residues in IκB kinase and the DNA-binding domains of NF-κB subunits, in addition to PPARγ-dependent anti-inflammatory effects. NF-κB reporter assays, in vitro kinase assays, cysteine modification studies, gene expression assays Proceedings of the National Academy of Sciences of the United States of America High 10781090
2002 C/EBPα has no ability to promote adipogenesis in the absence of PPARγ (using PPARγ-null immortalized fibroblasts), demonstrating that C/EBPα and PPARγ participate in a single pathway of fat cell development with PPARγ as the proximal effector, not two parallel pathways. Genetic epistasis using PPARγ-null immortalized fibroblasts, adipogenesis assays Genes & development High 11782441
2003 Muscle-specific deletion of Pparg in mice causes glucose intolerance and progressive insulin resistance by 4 months of age, with ~80% reduction in in vivo insulin-stimulated glucose disposal rate, demonstrating a crucial cell-autonomous role for muscle PPARγ in maintaining skeletal muscle insulin action. Cre-loxP conditional knockout, hyperinsulinemic-euglycemic clamp, glucose tolerance testing Nature medicine High 14625542
2005 Ligand-dependent SUMOylation of the PPARγ ligand-binding domain targets PPARγ to NCoR-HDAC3 complexes on inflammatory gene promoters, preventing ubiquitylation/19S proteasome-mediated removal of corepressor complexes required for gene activation, thereby maintaining NF-κB target genes in a repressed state. This identifies a molecular mechanism for transrepression distinct from classical transcriptional activation. SUMOylation assays, ChIP, co-immunoprecipitation, reporter assays in mouse macrophages, mutagenesis Nature High 16127449
2007 MEK1/2 physically interacts with nuclear PPARγ and, upon mitogenic stimulation, exports PPARγ from the nucleus via MEK's N-terminal nuclear export signal, providing a mechanism by which mitogenic ERK/MAPK cascade controls PPARγ nucleo-cytoplasmic compartmentalization and suppresses its transcriptional activity. Co-immunoprecipitation, nuclear export assays, subcellular fractionation, dominant-negative MEK constructs Cell cycle (Georgetown, Tex.) Medium 17611413
2007 PPARγ activation primes primary human monocytes (but not resting or M1 macrophages) into an alternative M2 differentiation programme with anti-inflammatory properties, with M2 marker and PPARγ expression positively correlating in human atherosclerotic lesions. Primary human monocyte differentiation assays, flow cytometry, immunohistochemistry in human lesions, gene expression analysis Cell metabolism High 17681149
2008 TNF-α inhibits PPARγ activity through serine kinase activation (IKK, ERK, JNK, p38), with IKK acting as the dominant kinase, through at least two mechanisms: suppression of PPARγ expression and activation of PPARγ corepressor. Reporter assays, kinase inhibitor studies, Western blotting, gene expression analysis Biochemical and biophysical research communications Medium 18655773
2008 PPARγ agonists (thiazolidinediones) transcriptionally induce klotho expression through a non-canonical PPAR-responsive element in the 5'-flanking region of the human klotho gene, as confirmed by chromatin immunoprecipitation, gel shift assays, and promoter-reporter assays. ChIP, EMSA, promoter-reporter assays, siRNA knockdown, adenoviral overexpression in mouse kidneys Kidney international High 18547997
2010 Obesity-induced activation of Cdk5 in adipose tissues results in phosphorylation of PPARγ at serine 273, which does not alter its adipogenic capacity but dysregulates a large number of genes altered in obesity (including reducing adiponectin expression). Anti-diabetic PPARγ ligands (rosiglitazone, MRL24) block this Cdk5-mediated phosphorylation independently of classical receptor transcriptional agonism, and inhibition of S273 phosphorylation is tightly associated with anti-diabetic effects in obese patients. In vitro kinase assays, site-directed mutagenesis, gene expression profiling, mouse high-fat diet models, human patient correlations Nature High 20651683
2005 Cdk4 promotes adipogenesis through activation of PPARγ; disruption of cdk4 impairs adipocyte differentiation and function while activating mutations increase adipogenic potential in primary mouse embryonic fibroblasts, identifying cdk4 as a regulator of both adipocyte differentiation and PPARγ activity. Cdk4 knockout and activating mutation in primary MEFs, adipogenesis assays, PPARγ activity measurements Cell metabolism High 16213226
2014 ERK directly phosphorylates PPARγ at serine 273 in a robust manner; Cdk5 suppresses ERK-mediated S273 phosphorylation through direct action on a novel site in MEK. Adipose-specific Cdk5 knockout paradoxically increases PPARγ S273 phosphorylation and worsens insulin resistance via ERK activation. Pharmacological inhibition of MEK/ERK markedly improves insulin resistance in obese mice. In vitro kinase assays, adipose-specific Cdk5 knockout mice, unbiased proteomics, MEK/ERK pharmacological inhibition, ob/ob mouse model Nature High 25409143
2014 Thrap3 (thyroid hormone receptor-associated protein 3) directly interacts with PPARγ specifically when it is phosphorylated at Ser273, and this interaction controls diabetogenic gene programming. Thrap3 knockdown restores genes dysregulated by Cdk5-mediated PPARγ phosphorylation; antisense oligonucleotide-mediated reduction of Thrap3 in fat tissue improves hyperglycemia and insulin resistance in high-fat-fed mice. Co-immunoprecipitation, mass spectrometry, gene expression profiling, ASO knockdown in mice, adipocyte cell models Genes & development High 25316675
2014 Synthetic PPARγ ligands bind to an alternate site distinct from the canonical ligand-binding pocket, leading to unique receptor conformational changes that impact coregulator binding, transactivation, and target gene expression. Alternate site binding is not blocked by covalently bound synthetic antagonists or by endogenous ligands, indicating non-overlapping binding with the canonical pocket. Structure-function studies, hydrogen-deuterium exchange mass spectrometry, coregulator binding assays, reporter gene assays Nature communications High 24705063
2015 The structural mechanism by which PPARγ antagonist SR1664 blocks obesity-induced phosphorylation of Ser273 (active antagonism) was identified, enabling development of inverse agonist SR2595. SR2595 treatment of bone marrow-derived mesenchymal stem cells promotes osteogenic differentiation, defining structural determinants of ligand-mediated PPARγ repression. X-ray crystallography, cell-based differentiation assays, ligand-binding studies Nature communications High 26068133
2016 PPARγ post-translational modifications at S112 and S273 determine both pro-adipocytic/insulin-sensitizing activities and osteoblastic (pS112) and osteoclastic (pS273) activities, respectively. SR10171 (inverse agonist blocking pS273 but not pS112) treatment in mice increases trabecular and cortical bone while normalizing metabolic parameters and modulating osteocyte/osteoblast/osteoclast activities. Site-directed mutagenesis, mouse models (hyperglycemic and normoglycemic), bone histomorphometry, metabolic phenotyping EBioMedicine High 27422345
2016 PPARγ plays an essential role in angiogenesis; loss of PPARγ in endothelial cells (Tie2CrePPARγflox/flox mice) impairs angiogenic capacity and migration of pulmonary microvascular endothelial cells. E2F1 was identified as a novel PPARγ target in regulation of PMVEC migration, and disruption of the PPARγ-E2F1 axis dysregulates a Wnt pathway involving GSKIP. Conditional endothelial knockout, bone marrow transplantation, RNA sequencing, in vitro migration/angiogenesis assays Journal of cell science Medium 26743080
2008 HDAC1/HDAC3 are recruited to the PPARG2 promoter through sumoylated CEBPD (sumoylated at K120) to repress PPARG2 transcription; non-sumoylated CEBPD acts as an activator that reverses this repression and promotes hepatic lipogenesis. 5'-serial deletion reporter analysis, in vivo ChIP, SUMO1 sumoylation assays, HDAC co-IP Biochimica et biophysica acta Medium 18619497
2013 Lipin1 activates PPARγ by releasing co-repressors NCoR1 and SMRT from PPARγ in the absence of ligand. A novel lipin1 TAD (residues 217-399) is required for PPARγ (but not PPARα) activation, and the VXXLL motif at residue 885 is critical for physical interaction with and activation of PPARγ. Enhanced PPARγ activity by lipin1 promotes adipocyte differentiation. Co-immunoprecipitation, reporter assays, deletion/mutagenesis mapping, adipocyte differentiation assays The Biochemical journal Medium 23627357
2017 CACUL1 directly binds PPARγ through the CoRNR box 2 and represses PPARγ transcriptional activity and adipogenic potential. CACUL1 acts through mutual opposition between SIRT1 and LSD1: upon CACUL1 depletion, less SIRT1 and more LSD1 are recruited to PPARγ-responsive gene promoters, leading to increased H3K9 acetylation, decreased H3K9 methylation, and PPARγ activation during adipogenesis. Co-immunoprecipitation, ChIP, histone modification analysis, RNA sequencing, adipocyte differentiation assays in 3T3-L1 and human adipose stem cells Cell death & disease Medium 29233982
2009 PPARγ activation by rosiglitazone in macrophages represses transcription of the fractalkine receptor (FR) gene and prevents plasma membrane translocation of FR protein; in endothelial cells, PPARγ activation impedes nuclear export of fractalkine, collectively suppressing fractalkine signaling as a novel anti-inflammatory mechanism. Reporter assays, subcellular fractionation, confocal immunofluorescence, Western blotting Journal of molecular endocrinology Medium 19850645
2012 PPARγ transcription factor binds to hexokinase 2 and pyruvate kinase M promoters to activate their transcription in PTEN-null fatty liver, contributing to aerobic glycolysis. PPARγ expression, liver steatosis, and the shift to aerobic glycolysis are under control of Akt2 kinase. ChIP, reporter assays, genetic mouse model (PTEN-null liver), Akt2 knockout Nature communications High 22334075
2013 KLF11 is identified as a novel PPARγ co-regulator (via genome-wide co-activation screen) that physically interacts with PPARγ and is also a direct PPARγ transcriptional target. KLF11 enhances PPARγ-mediated transcriptional suppression of pro-apoptotic microRNA-15a, providing cerebrovascular endothelial protection after ischemia. Genome-wide co-activation screen, co-immunoprecipitation, KLF11 knockout mouse MCAO model, ChIP Brain : a journal of neurology Medium 23408111
2016 PPARγ is expressed in osteocytes and is essential for sclerostin production; osteocyte-specific PPARγ deletion (Dmp1CrePparγfl/fl) increases bone mass and reduces marrow adiposity with upregulation of WNT signaling. PPARγ directly binds PPREs in the 8 kb upstream region of the Sost gene to regulate sclerostin transcription, with PPARγ activation by rosiglitazone increasing sclerostin levels (Pearson's r=0.991, p=0.001). Conditional osteocyte-specific KO, ChIP-PPRE binding, gene expression correlation, rosiglitazone treatment Bone High 33722775
2020 Photoswitchable PPARγ agonists (AzoGW1929 and AzoRosi, based on known PPARγ ligands) bind and activate PPARγ preferentially in their light-activated cis-configuration, providing optochemical tools that confirm direct ligand-binding as required for PPARγ activation. Cell-based transcriptional reporter assays, protein binding assays, photoswitching experiments Journal of medicinal chemistry Medium 32886507
2020 CDK5-mediated phosphorylation of PPARγ at S245 (equivalent to human S273) is inhibited by specific PPARγ ligands through conformational changes in PPARγ distant from the phosphorylation site, providing an allosteric inhibition mechanism; X-ray crystallography, NMR, HDX-MS, MD simulations, and mutagenesis defined the structural basis. X-ray crystallography, NMR, HDX-MS, MD simulations, protein-protein docking, site-directed mutagenesis Journal of medicinal chemistry High 32239932
2021 PPARγ signaling in bladder urothelium controls cell fate: activated PPARγ in basal progenitors induces superficial cell formation and cell cycle exit (preventing tumor formation), whereas in injury-activated progenitors it promotes luminal tumor formation. These luminal tumors are immune-deserted, linked to downregulation of NF-κB, a PPARγ target. Transgenic mouse model (VP16;Pparg activated form), conditional expression in basal progenitors with/without injury, tumor analysis, immune profiling Nature communications Medium 34697317
2022 C/EBPβ (LAP* and LAP isoforms) together with CSF2 signaling specifically induces expression of Pparg isoform 2 (but not isoform 1) in alveolar macrophages, providing a molecular mechanism for isoform-specific regulation of PPARγ in tissue macrophages. C/EBPβ deficiency causes severe defects in AM proliferation, phagocytosis, and lipid metabolism, causing pulmonary alveolar proteinosis. Transcriptome and chromatin accessibility analysis (ATAC-seq), conditional knockout, chromatin immunoprecipitation, comparison across CSF2-primed macrophage populations Science immunology High 36112694
2008 PPARγ protein expression is upregulated in the infarcted area of the heart (localized to cardiac myocytes and fibroblasts) following myocardial infarction in rats, paralleling increased CTGF expression, suggesting a role for PPARγ in post-infarction remodeling. Immunofluorescence, Western blotting, gene expression analysis in rat MI model European journal of heart failure Low 18162196
2012 PPARγ activates FXR gene transcription by directly binding to a PPAR-responsive element (PPRE) in the FXR promoter during adipogenesis; FXR in turn induces stearoyl-CoA desaturase (SCD) expression by binding an FXRE in the SCD promoter, establishing a PPARγ→FXR→SCD axis promoting lipogenesis. ChIP assay, PPRE identification, promoter-reporter assays, pharmacological agonist/antagonist studies in 3T3-L1 cells Biochemical and biophysical research communications Medium 32446390
2016 PPARγ stimulates lipid synthesis in mouse meibocytes and is associated with SUMO1 sumoylation and cytoplasmic accumulation of the 72 kDa PPARγ isoform upon rosiglitazone treatment, with loss of cytoplasmic PPARγ in aging mice linked to meibomian gland atrophy. Subcellular fractionation, Western blotting, PPARγ immunolocalization, lipid staining (LipidTox), CARS/Raman microspectroscopy in cultured meibocytes The ocular surface Medium 27531629
2018 Loss-of-function PPARG mutations (R308P and A261E) cause familial partial lipodystrophy type 3 (FPLD3) with negligible constitutive or PGJ2-induced transcriptional activity; structural modeling shows these mutations selectively impair helix 12 stabilization. Synthetic agonists (pioglitazone, rosiglitazone) selectively rescue transcriptional function of these specific mutants and produce dramatic clinical improvement, demonstrating pharmacogenetic response. In vitro transcriptional activity assays, structural modeling, patient clinical assessment, synthetic ligand rescue experiments Diabetes Medium 29622583

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 3116 8001151
2007 Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science (New York, N.Y.) 2225 17463246
2007 A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science (New York, N.Y.) 2110 17463248
2011 Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nature reviews. Immunology 1806 22025054
1997 Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proceedings of the National Academy of Sciences of the United States of America 1782 9113987
2008 Fat and beyond: the diverse biology of PPARgamma. Annual review of biochemistry 1702 18518822
2007 Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science (New York, N.Y.) 1702 17463249
2003 Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocrine reviews 1695 12588810
1998 Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 1640 9744270
1998 PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 1572 9568716
1998 Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 1571 9568715
1998 PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 1481 9568680
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2008 Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nature genetics 1435 18372903
2010 Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nature genetics 1401 20581827
2000 The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nature genetics 1371 10973253
2005 The many faces of PPARgamma. Cell 1207 16360030
2009 A census of human transcription factors: function, expression and evolution. Nature reviews. Genetics 1191 19274049
2002 C/EBPalpha induces adipogenesis through PPARgamma: a unified pathway. Genes & development 1177 11782441
2007 PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell metabolism 1153 17681149
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2005 A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 1048 16127449
1999 Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 1045 10622252
1997 The organization, promoter analysis, and expression of the human PPARgamma gene. The Journal of biological chemistry 1031 9228052
2008 AMPK and PPARdelta agonists are exercise mimetics. Cell 977 18674809
2003 Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 901 12955147
2000 15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway. Proceedings of the National Academy of Sciences of the United States of America 876 10781090
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2016 Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology 848 26874076
2014 Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nature genetics 834 24509480
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2010 Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature 742 20651683
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nature genetics 661 22581228
1999 PPARgamma, the ultimate thrifty gene. Diabetologia 512 10447513
2014 Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review. Biochemical pharmacology 439 25083916
2009 Wnt and PPARgamma signaling in osteoblastogenesis and adipogenesis. Nature reviews. Rheumatology 423 19581903
2003 Muscle-specific Pparg deletion causes insulin resistance. Nature medicine 413 14625542
2003 Activation of PPARalpha and PPARgamma by environmental phthalate monoesters. Toxicological sciences : an official journal of the Society of Toxicology 397 12805656
2002 PPAR(gamma) and glucose homeostasis. Annual review of nutrition 361 12055342
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