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FUNCTION Ligand-activated transcription factor that forms obligate heterodimers with the retinoic acid receptor and acts as a key regulator of biological processes, such as adipocyte differentiation, lipid metabolism, glucose homeostasis and beta-oxidation of fatty acids (PubMed:21035761, PubMed:23525231, PubMed:7838715, PubMed:7926726, PubMed:8041794, PubMed:8262913). Activated by lipid ligands: binds peroxisome proliferators, such as hypolipidemic drugs, and fatty acids, such as prostaglandin J2 metabolites (PubMed:21994940, PubMed:27197753, PubMed:8041794, PubMed:8262913). Ligand-binding results in a conformational change in the receptor, promoting dissociation of repressors and recruitment of coactivators, and subsequent activation of target gene expression (PubMed:21994940, PubMed:27197753, PubMed:8041794, PubMed:8262913). Specifically binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase (PubMed:8041794, PubMed:8262913). Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated pro-inflammatory responses (By similarity). Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of BMAL1 in the blood vessels (PubMed:19041764).FUNCTION Nuclear receptor that acts as the key factor controlling the development of adipocytes (PubMed:10549290, PubMed:10549291, PubMed:10549292, PubMed:18719582, PubMed:21459326, PubMed:23473036, PubMed:7838715, PubMed:7926726, PubMed:8001151, PubMed:8521497, PubMed:8521498). Specifically activated by 15-deoxy-delta12,14-prostaglandin J2 ligand during early adipogenesis, driving differentiation of all types of adipocytes (white, beige and brown) (PubMed:7838715, PubMed:7926726, PubMed:8521497, PubMed:8521498). Acts together with retinoic acid receptor RXRA, forming the ARF6 complex, which acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer (PubMed:7838715). Following recruitment of TLE3, promotes differentiation of white adipocytes (PubMed:21459326, PubMed:23473036). Following recruitment of PRDM16, promotes differentiation of myoblastic precursors into brown adipose cells (BAT), which are specialized in dissipating energy in the form of heat in response to cold or excess feeding (PubMed:18719582, PubMed:24703692, PubMed:40355558). Also mediates diffentiation of white adipocytes into beige adipocytes by mediating recruitment of PRDM16 (PubMed:22405074).ACTIVITY REGULATION PDPK1 activates its transcriptional activity independently of its kinase activity.SUBUNIT Heterodimer with retinoic acid receptor, such as RXRA (PubMed:7838715, PubMed:7926726). The heterodimer with the retinoic acid receptor RXRA is called adipocyte-specific transcription factor ARF6 (PubMed:7838715, PubMed:7926726). Interacts with NCOA6 coactivator, leading to a strong increase in transcription of target genes (PubMed:10788465). Interacts with coactivator PPARBP, leading to a mild increase in transcription of target genes (PubMed:9325263). Interacts with NCOA7 in a ligand-inducible manner (By similarity). Interacts with NCOA1 and NCOA2 LXXLL motifs (By similarity). Interacts with ASXL1, ASXL2, DNTTIP2, FAM120B, MAP2K1/MEK1, NR0B2, PDPK1, PRMT2 and TGFB1I1 (PubMed:15687259, PubMed:17595322). Interacts (when activated by agonist) with PPP5C (PubMed:21994940). Interacts with HELZ2 and THRAP3; the interaction stimulates the transcriptional activity of PPARG (PubMed:23525231). Interacts with PER2, the interaction is ligand dependent and blocks PPARG recruitment to target promoters (PubMed:21035761). Interacts with NOCT (PubMed:20498072). Interacts with FOXO1 (acetylated form) (PubMed:19037106). Interacts with ACTN4 (By similarity). Interacts (when in the liganded conformation) with GPS2 (PubMed:25519902). Interacts with CRY1 and CRY2 in a ligand-dependent manner (PubMed:28683290). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863). In macrophages, interacts with PAQR3 and STUB1; these interactions promote PPARG poylubiquitination and STUB1-mediated degradation (PubMed:35710596). Interacts with YTDC1 (via its intrinsically disordered region); the interaction prevents the ubiquitin-mediated proteasomal degradation of PPARG (PubMed:40355558).SUBUNIT Interacts with CEBPA; promoting activation of the adipogenic program (PubMed:8001151). Interacts with PRDM16; promoting activation of brown and beige adipocytes (PubMed:18719582).INTERACTION Redistributed from the nucleus to the cytosol through a MAP2K1/MEK1-dependent manner (By similarity). NOCT enhances its nuclear translocation (PubMed:20498072).SUBCELLULAR LOCATION Highest expression in white and brown adipose tissue. Also found in liver, skeletal muscle, heart, adrenal gland, spleen, kidney and intestine.TISSUE SPECIFICITY Almost exclusively expressed in adipose tissue.DEVELOPMENTAL STAGE It appears first at 13.5 dpc and increases until birth.INDUCTION Expressed in a circadian manner in the aorta.DOMAIN The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.PTM O-GlcNAcylation at Thr-84 reduces transcriptional activity in adipocytes.PTM Phosphorylated in basal conditions and dephosphorylated when treated with the ligand. May be dephosphorylated by PPP5C. The phosphorylated Ser-112 form is recognized by PER2 and repressed, dephosphorylation at Ser-112 induces adipogenic activity. Ser-112 phosphorylation levels are reduced by 65% in brown adipose tissue compared to white adipose tissue.PTM Ubiquitinated by E3 ubiquitin-protein ligase complex containing FBXO9; leading to proteasomal degradation (PubMed:27197753). Ubiquitinated at Lys-252 by TRIM55 leading to proteasomal degradation (By similarity). Ubiquitinated by E3 ubiquitin-protein ligase STUB1/CHIP; leading to proteasomal degradation (PubMed:35710596). Ubiquitinated by E3 ubiquitin-protein ligase ARIH2; leading to proteasomal degradation (PubMed:40355558).DISRUPTION PHENOTYPE Embryonic lethality around 10 dpc (day post coitum) due to placental dysfunction (PubMed:10549291). Placental dysfunction is characterized by impaired terminal differentiation of the trophoblast and placental vascularization, leading to severe myocardial thinning and death (PubMed:10549290, PubMed:10549291). Mice are deficient for all forms of fat, characterized by a complete loss of adipocytes (PubMed:10549290, PubMed:10549291). Mice develop abnormalities in circadian variations in blood pressure and heart rate, in parallel with a reduction of diurnal variations in the sympathetic nerve activity, and impaired rhythmicity of BMAL1 in the blood vessels (PubMed:19041764).SIMILARITY Belongs to the nuclear hormone receptor family. NR1 subfamily.
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