Other entities represented in this entry:
HGNC Approved Gene Symbol: PPARG
SNOMEDCT: 1197745002, 238136002, 83911000119104; ICD9CM: 278.01;
Cytogenetic location: 3p25.2 Genomic coordinates (GRCh38): 3:12,287,368-12,434,344 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p25.2 | [Obesity, resistance to] | 3 | ||
| {Diabetes, type 2} | 125853 | Autosomal dominant | 3 | |
| Carotid intimal medial thickness 1 | 609338 | 3 | ||
| Insulin resistance, severe, digenic | 604367 | Autosomal dominant | 3 | |
| Lipodystrophy, familial partial, type 3 | 604367 | Autosomal dominant | 3 | |
| Obesity, severe | 601665 | Autosomal dominant; Autosomal recessive; Multifactorial | 3 |
Peroxisome proliferator-activated receptors (PPARs), such as PPARG, are so named because they bind chemicals that induce proliferation of peroxisomes, organelles that contribute to the oxidation of fatty acids. As members of the nuclear receptor superfamily, PPARs act by controlling networks of target genes. PPARs can be activated by both dietary fatty acids and their metabolic derivatives in the body, and thus serve as lipid sensors that, when activated, can markedly redirect metabolism. PPARA (170998) and PPARG are predominantly expressed in liver and adipose tissue, respectively. PPARD (600409) is abundantly expressed throughout the body, but at only low levels in liver. Consistent with their expression profiles, the PPARs each have unique functions in the regulation of energy metabolism. PPARG is involved in adipocyte differentiation (summary by Evans et al., 2004).
Tontonoz et al. (1994) found 2 isoforms of PPAR-gamma in mouse, gamma-1 and gamma-2, resulting from the use of different initiator methionines.
Elbrecht et al. (1996) cloned cDNAs of PPAR-gamma-1 and PPAR-gamma-2 from human fat cell cDNA by PCR using primers based on the mouse sequence and on a previously published human cDNA sequence (Greene et al., 1995). They found that the human PPAR-gamma-1 and PPAR-gamma-2 genes have identical sequences except that PPAR-gamma-2 contains an additional 84 nucleotides at its 5-prime end. The sequences obtained by Elbrecht et al. (1996) differed at 3 sites from the previously published human PPAR-gamma-1 sequence of Greene et al. (1995). By Northern blot analysis, Elbrecht et al. (1996) found that human PPAR-gamma is expressed at high levels in adipocytes and at a much lower level in bone marrow, spleen, testis, brain, skeletal muscle, and liver.
Fajas et al. (1997) used competitive RT-PCR to distinguish relative PPARG1 and PPARG2 mRNA levels in tissues. They determined that PPARG2 is much less abundant than PPARG1. The highest levels of PPARG are found in adipose tissue and large intestine, with intermediate levels in kidney, liver, and small intestine, and barely detectable levels in muscle. Western blot analysis showed that PPARG is expressed as a 60-kD protein. EMSA analysis indicated that PPARG2 binds to and transactivates through a peroxisome proliferator response element. Through alternative transcription start sites and alternate splicing, the PPARG mRNAs differ at their 5-prime ends.
By RT-PCR, Temelkova-Kurktschiev et al. (2004) detected expression of PPARG2 in human atherosclerotic lesions as well as in cultured primary macrophages and foam cells.
Using mouse Pparg as probe to screen a heart cDNA library, Mukherjee et al. (1997) cloned PPARG2. The deduced 505-amino acid protein shares 97% identity with mouse Pparg2. The DNA-binding domain of PPARG2 shows 83% conservation with those of PPARA and PPARB. Northern blot analysis and RNase protection assays indicated that PPARG1 is expressed in skeletal muscle and both PPARG1 and PPARG2 are expressed in fat. The ratio of PPARG1 to PPARG2 in fat varied in different individuals. SDS-PAGE of in vitro transcription/translation reactions detected 2 PPARG proteins. The larger protein, PPARG2, has an apparent molecular mass of about 57 kD and results from translation initiation from the first methionine. The smaller protein, PPARG1, has an apparent molecular mass of about 53 kD and results from translation initiation from the methionine at position 31.
Martin et al. (1998) reported that there are 3 PPARG isoforms which differ at their 5-prime ends, each under the control of its own promoter. PPARG1 and PPARG3, however, give rise to the same protein, encoded by exons 1 through 6, because neither the A1 nor the A2 exon are translated.
Fajas et al. (1998) identified the third PPARG isoform, PPARG3, which is transcribed from a novel promoter localized 5-prime of exon A2. The promoter region contains a TATA-like element, a CAAT-like sequence, and a potential E box. PPARG3 mRNA expression was restricted to adipose tissue and to large intestine.
Aprile et al. (2018) identified human and mouse PPARG splice variants lacking exon 5 that they termed PPARG-delta-5 variants. Skipping of exon 5 increased with activation of PPARG and involved SRSF1 (600812)-mediated splicing. PPARG-delta-5 encodes a 250-amino acid isoform lacking the ligand-binding domain of full-length PPARG. Epitope-tagged PPARG-delta-5 localized to nuclei of transfected HEK293 cells.
Fajas et al. (1997) determined that the PPARG gene contains 9 exons and spans more than 100 kb. PPARG1 is encoded by 8 exons and PPARG2 by 7 exons. PPARG1 uses exons A1 and A2, whereas PPARG2 uses exon B; both use exons 1 through 6.
By somatic cell hybridization and linkage analysis, Greene et al. (1995) mapped the PPARG gene to chromosome 3p25.
By FISH analysis, Beamer et al. (1997) mapped the PPARG gene to chromosome 3p25.
FMOC-L-leucine (F-L-leu) is a chemically distinct PPARG ligand. Rocchi et al. (2001) found that 2 molecules of F-L-leu bind to the ligand-binding domain of a single PPARG molecule, making its mode of receptor interaction distinct from that of other nuclear receptor ligands. F-L-leu induces a particular allosteric configuration of PPARG resulting in differential cofactor recruitment and translating in distinct pharmacologic properties. F-L-leu activates PPARG with a lower potency than rosiglitazone, but with a similar maximal efficacy. The particular PPARG configuration induced by F-L-leu leads to a modified pattern of target gene activation. F-L-leu improves insulin sensitivity in normal, diet-induced glucose-intolerant, and diabetic db/db mice, yet it has a lower adipogenic activity. These biologic effects suggest that F-L-leu is a selective PPARG modulator that activates some (insulin sensitization) but not all (adipogenesis) PPARG-signaling pathways.
Crystal Structure
The nuclear receptor PPARG/RXRA (180245) heterodimer regulates glucose and lipid homeostasis and is the target for the antidiabetic drugs GI262570 and the thiazolidinediones (TZDs). Gampe et al. (2000) reported the crystal structures of the PPARG and RXRA ligand-binding domains complexed with the RXRA ligand 9-cis-retinoic acid, the PPARG agonist GI262570, and coactivator peptides. The structures provided a molecular understanding of the ability of RXRs to heterodimerize with many nuclear receptors and of the permissive activation of the PPARG/RXRA heterodimer by 9-cis-retinoic acid.
Chandra et al. (2008) presented structures of intact PPAR-gamma and RXR-alpha as a heterodimer bound to DNA, ligands, and coactivator peptides. PPAR-gamma and RXR-alpha form a nonsymmetric complex, allowing the ligand-binding domain of PPAR-gamma to contact multiple domains in both proteins. Three interfaces link PPAR-gamma and RXR-alpha, including some that are DNA-dependent. The PPAR-gamma ligand-binding domain cooperates with both DNA-binding domains to enhance response-element binding. The A/B segments are highly dynamic, lacking folded substructures despite their gene-activation properties.
Mukherjee et al. (1997) found that recombinant PPARG1 or PPARG2 alone did not form a complex with oligonucleotides containing peroxisome proliferator response elements (PREs), but PPARG1 and PPARG2 bound to PPREs as heterodimers with RXR. PPARG1 and PPARG2 also formed complexes with RXRB (180246) and RXRG (180247). PPARG2/RXR heterodimers were activated by both RXR agonists and antagonists. The addition of PPARG ligands with retinoids resulted in greater than additive activation. PPARG2 and PPARG1 were similarly activated by PPARG activators.
Deeb et al. (1998) noted that PPARG1 and PPARG2 have ligand-dependent and -independent activation domains. PPARG2 has an additional 28 amino acids at the amino terminus that render its ligand-independent activation domain 5- to 10-fold more effective than that of PPARG1. Insulin stimulates the ligand-independent activation of PPARG1 and PPARG2; however, obesity and nutritional factors influence only the expression of PPARG2 in human adipocytes.
Aljada et al. (2001) examined the possibility that troglitazone may modulate the expression of PPARA and PPARG. Seven obese hyperinsulinemic subjects were administered 400 mg troglitazone daily for 4 weeks. Fasting blood samples were obtained before and during troglitazone therapy at 1, 2, and 4 weeks. Fasting insulin concentrations fell at week 1 and persisted at lower levels until 4 weeks. PPARG expression fell significantly at week 1 and fell further at weeks 2 and 4. In contrast, PPARA expression increased significantly at week 2 and further at week 4. Two products of linoleic acid peroxidation and agonists of PPARG, 9- and 13-hydroxyoctadecanoic acid, decreased during troglitazone therapy. The authors concluded that troglitazone, an agonist for both PPARA and PPARG, has significant but dramatically opposite effects on PPARA and PPARG. They also concluded that these effects may be relevant to its insulin-sensitizing and antiinflammatory effects.
Nakamichi et al. (2003) found that overexpression of Pparg in a mouse insulinoma cell line inhibited glucose-stimulated proinsulin biosynthesis and insulin release.
Pascual et al. (2005) reported the identification of a molecular pathway by which PPAR-gamma represses the transcriptional activation of inflammatory response genes in mouse macrophages. The initial step of this pathway involves ligand-dependent sumoylation of the PPAR-gamma ligand-binding domain, which targets PPAR-gamma to nuclear receptor corepressor (NCoR; see 600849)-histone deacetylase-3 (HDAC3; 605166) complexes on inflammatory gene promoters. This in turn prevents recruitment of the ubiquitylation/19S proteasome machinery that normally mediates the signal-dependent removal of corepressor complexes required for gene activation. As a result, NCoR complexes are not cleared from the promoter and target genes are maintained in a repressed state. Pascual et al. (2005) concluded that this mechanism provides an explanation for how an agonist-bound nuclear receptor can be converted from an activator of transcription to a promoter-specific repressor of NF-kappa-B (164011) target genes that regulate immunity and homeostasis.
Regulation of Adipose Tissue
Tontonoz et al. (1994) identified a novel adipocyte-specific transcription factor, which they termed ARF6, and showed that it is a heterodimeric complex of RXRA and PPARG. (This ARF6 is not to be confused with ADP-ribosylation factor-6 (600464), which is also symbolized ARF6.) Tontonoz et al. (1995) demonstrated that PPAR-gamma-2 regulates adipocyte expression of the phosphoenolpyruvate carboxykinase gene (PCK1, 261680; PCK2, 261650).
Lowell (1999) reviewed the role of PPARG in adipogenesis.
Tong et al. (2000) showed that murine Gata2 (137295) and Gata3 (131320) are specifically expressed in white adipocyte precursors and that their downregulation sets the stage for terminal differentiation. Constitutive Gata2 and Gata3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage. This effect was mediated, at least in part, through the direct suppression of PPARG.
By semiquantitative RT-PCR analysis of freeze-dried muscle samples from 14 male subjects, Lapsys et al. (2000) examined the potential regulation of genes by PPARG in human skeletal muscle. The expression of 3 genes important in lipid metabolism, lipoprotein lipase (LPL; see 238600), muscle carnitine palmitoyltransferase-1 (601987), and fatty acid-binding protein (e.g., 134650), correlated significantly with PPARG expression in the same samples. The authors concluded that these findings support the hypothesis that PPARG activators such as the antidiabetic thiazolidinediones may regulate fatty acid metabolism in skeletal muscle as well as in adipose tissue.
Sewter et al. (2002) examined the relationship between BMI and PPARG isoform expression in freshly isolated human adipocytes. In a group of 17 subjects there was a strong and highly significant inverse correlation (r = -0.68; P less than 0.005) between PPARG1 mRNA expression in adipocytes and BMI, whereas no significant relationship was apparent for PPARG2. Vidal-Puig et al. (1997) had demonstrated that PPARG1 mRNA levels were decreased in adipocytes from morbidly obese subjects. In contrast, there was a significant increase in the expression of PPARG2 mRNA levels between the morbidly obese and lean groups. Sewter et al. (2002) concluded that the strong inverse relationship between BMI and PPARG1 expression in human adipocytes may represent part of an autoregulatory mechanism restraining the expansion of individual adipocytes in states of positive energy balance.
Rosen et al. (2002) created an immortalized mouse fibroblast cell line lacking Pparg. They found that both Cebpa (116897) and Pparg were involved in fat cell development; however, Cebpa required Pparg to promote adipogenesis. Rosen et al. (2002) concluded that Pparg is downstream of Cebpa in the adipogenesis pathway.
Using engineered zinc finger repressor proteins expressed in an adipogenic mouse cell line, Ren et al. (2002) found evidence that Pparg2, and not Pparg1, is required for adipogenesis.
Ge et al. (2002) demonstrated that Trap220 -/- fibroblasts are refractory to PPAR-gamma-2-stimulated adipogenesis, but not to MyoD-stimulated myogenesis, and do not express adipogenesis markers or PPAR-gamma-2 target genes. These defects could be restored by expression of exogenous TRAP220. Further indicative of a direct role for TRAP220 in PPARG2 function via the TRAP complex, TRAP functioned directly as a transcriptional coactivator for PPARG2 in a purified in vitro system and interacted with PPARG2 in a ligand- and TRAP220-dependent manner. Ge et al. (2002) concluded that TRAP220 acts, via the TRAP complex, as a PPARG2-selective coactivator and, accordingly, that it is specific for 1 fibroblast differentiation pathway (adipogenesis) relative to another (myogenesis).
Using electrophoretic mobility shift assays and immunoprecipitation experiments, Fajas et al. (2002) demonstrated that members of the E2F transcription factor family (see E2F1, 189971) bind in vitro and in vivo to the PPARG1 promoter. Specifically, they found that E2F1 and E2F3 (600427) induce PPARG transcription during the early stages of adipogenesis, whereas E2F4 (600659) represses PPARG expression during terminal adipocyte differentiation.
Adipocyte differentiation is inhibited by hypoxia. Yun et al. (2002) found that hypoxia inhibited Pparg2 transcription in mouse fibroblasts, and overexpression of Pparg2 or Cebpb (189965) stimulated adipogenesis under hypoxic conditions. Furthermore, Hif1a (603348)-deficient fibroblasts were refractory to hypoxia-mediated inhibition of adipogenesis. Yun et al. (2002) found that the Hif1a-regulated gene Dec1 (BHLHB2; 604256) repressed Pparg2 promoter activation and functioned as an effector of hypoxia-mediated inhibition of adipogenesis.
Fajas et al. (2002) found that Pparg promoted adipocyte differentiation more efficiently in Rb (614041)-deficient mouse embryonic fibroblasts than in Rb-expressing controls. Pparg and Rb coimmunoprecipitated, and the Pparg-Rb complex also contained histone deacetylase-3 (HDAC3; 605166). Rb recruited Hdac3 to the Pparg-Rb complex, and recruitment attenuated Pparg-mediated gene expression and adipocyte differentiation. Dissociation of the Pparg-Rb-Hdac3 complex by Rb phosphorylation or inhibition of Hdac activity stimulated adipocyte differentiation.
PRIP (NCOA6; 605299) and PBP (PPARBP; 604311) are PPARG coactivators, suggesting they have roles in PPARG-induced adipogenesis. Qi et al. (2003) found that, like Pbp-null fibroblasts, Prip-null mouse embryonic fibroblasts failed to exhibit Pparg-stimulated adipogenesis. Furthermore, they did not express fatty acid-binding protein-4 (FABP4; 600434), a Pparg-responsive gene and adipogenic marker. Chromatin immunoprecipitation assays revealed the presence of endogenous Pparg on the Fabp4 promoter in Prip-null cells, but recruitment of Pimt (606461) to the promoter in response to exogenous Pparg was less robust compared with wildtype cells. Binding of Pimt to Cbp (CREBBP; 600140)/p300 (EP300; 602700) was weaker in Prip-null cells compared with wildtype cells. Qi et al. (2003) concluded that both PRIP and PBP are essential downstream activators of PPARG-mediated adipogenesis.
Using fibroblasts from cyclin D1 (CCND1; 168461)-null mouse embryos and various cell systems, Wang et al. (2003) determined that cyclin D1 inhibited ligand-induced Pparg function through an Rb- and Cdk (see 116940)-independent mechanism. The inhibition required a region of cyclin D1 predicted to form a helix-loop-helix. Adipocyte differentiation by Pparg-specific ligands was enhanced in cyclin D1-null fibroblasts and could be reversed by retroviral expression of cyclin D1. Cyclin D1-null mice showed hepatic steatosis consistent with increased Pparg activity. Reduced cyclin D1 abundance in transgenic mice showed increased Pparg expression in vivo.
Yu et al. (2003) found that overexpression of Pparg in Ppara -/- mice induced hepatic steatosis. Northern blot analysis and gene expression profiling showed that adipocyte-specific genes and lipogenesis-related genes were highly induced in livers from these mice. In contrast, hepatic steatosis induced in Ppara -/- mice either by feeding a choline-deficient diet or by fasting failed to induce expression of these Pparg-regulated adipogenesis-related genes. Yu et al. (2003) concluded that a high level of Pparg in mouse liver is sufficient for adipogenic transformation of hepatocytes.
Picard et al. (2004) demonstrated that SIRT1 (604479) activates a critical component of calorie restriction in mammals, i.e., fat mobilization in white adipocytes. Upon food withdrawal, Sirt1 protein bound to and repressed genes controlled by the fat regulator PPAR-gamma, including genes mediating fat storage. Sirt1 repressed PPAR-gamma by docking with its cofactors Ncor (600849) and Smrt (600848). Mobilization of fatty acids from white adipocytes upon fasting was compromised in Sirt1 heterozygous mice. Repression of PPAR-gamma by Sirt1 was also evident in 3T3-L1 adipocytes, where overexpression of Sirt1 attenuated adipogenesis, and RNA interference of Sirt1 enhanced it. In differentiated fat cells, upregulation of Sirt1 triggered lipolysis and loss of fat. As a reduction in fat is sufficient to extend murine life span, Picard et al. (2004) concluded that their results provided a possible molecular pathway connecting calorie restriction to life extension in mammals.
Using quantitative PCR in murine and human adipocytes, Patsouris et al. (2004) demonstrated that the expression of cytosolic glycerol-3-phosphate dehydrogenase (138430) was enhanced by PPAR-gamma and PPAR-delta agonists, whereas expression was decreased in Pparg heterozygous and Ppard-null mice. Transactivation, gel shift, and chromatin immunoprecipitation experiments showed that cytosolic glycerol-3-phosphate dehydrogenase is a direct PPAR target gene. Patsouris et al. (2004) concluded that these data indicated that PPAR-gamma regulates glycerol metabolism in adipose tissue.
Uno et al. (2006) identified a neuronal pathway that participates in the crosstalk between the liver and adipose tissue. By studying a mouse model, Uno et al. (2006) showed that adenovirus-mediated expression of PPARG2 in the liver induces acute hepatic steatosis while markedly decreasing peripheral adiposity. These changes were accompanied by increased energy expenditure and improved systemic insulin sensitivity. Hepatic vagotomy and selective afferent blockage of the hepatic vagus revealed that the effects on peripheral tissues involve the afferent vagal nerve. Furthermore, the antidiabetic thiazolidinedione, a PPARG agonist, enhanced this pathway. Uno et al. (2006) hypothesized that this neuronal pathway from the liver may function to protect against metabolic perturbation induced by excessive energy storage.
Tang et al. (2008) generated PPARG tet transactivator (tTA) knockin mice, placing the tTA under the control of the PPARG locus. With additional genetic manipulations, they created a PPARG reporter strain in which the endogenous PPARG promoter/enhancer induced expression of tTA, leading to Cre expression and an indelible lacZ marking of PPARG-expressing cells and all descendants. Using these genetically marked mice, Tang et al. (2008) were able to isolate proliferating and renewing adipogenic progenitors. Tang et al. (2008) found that most adipocytes descend from a pool of these proliferating progenitors that are already committed, either prenatally or early in postnatal life. These progenitors reside in the mural cell compartment of the adipose vasculature, but not in the vasculature of other tissues. Tang et al. (2008) concluded that thus, the adipose vasculature appears to function as a progenitor niche and may provide signals for adipocyte development.
Gupta et al. (2010) identified the zinc finger protein Zfp423 (604557) as a factor enriched in preadipose versus nonpreadipose fibroblasts. Ectopic expression of Zfp423 in nonadipogenic NIH 3T3 fibroblasts robustly activated expression of Pparg in undifferentiated cells and permitted cells to undergo adipocyte differentiation under permissive conditions. Short hairpin RNA-mediated reduction of Zfp423 expression in 3T3-L1 cells blunted preadipocyte Pparg expression and diminished the ability of those cells to differentiate. Furthermore, both brown and white adipocyte differentiation was markedly impaired in Zfp423-deficient mouse embryos. Zfp423 regulates Pparg expression, in part, through amplification of the BMP signaling pathway, an effect dependent on the SMAD-binding capacity of Zfp423. Gupta et al. (2010) concluded that their study identifies Zfp423 as a transcriptional regulator of preadipocyte determination.
Lefebvre et al. (2010) found that Pparg target genes were more sensitive to activation by agonist in visceral white adipose tissue (WAT) from obese mice than from lean mice. In visceral WAT of obese humans and mice, UCHL1 (191342) expression was upregulated for degradation of RXRA through the ubiquitin proteasome system, resulting in increased PPARG-mediated transcription. RXRA acted a repressor of PPARG-mediated transcription in response to agonist, whereas RXRB potentiated PPARG-mediated transcription. The RXRA/RXRB ratio determined PPARG responsiveness to agonist in mouse adipocytes and other cell types. PPARG interacted with RXRA or RXRB and formed a heterodimer that bound to the promoters of PPARG-regulated genes in adipocytes. PPARG-containing heterodimers also recruited SMRT as a corepressor, forming a ternary complex through interaction between PPARG and SMRT. When the ternary complex contained RXRB instead of RXRA, it was able to dismiss SMRT from PPARG upon agonist binding, resulting in a higher RXRA/RXRB ratio, which in turn increased the PPARG responsiveness to agonist stimulation.
Cipolletta et al. (2012) identified PPAR-gamma as a crucial molecular orchestrator of visceral adipose tissue T-regulatory cell accumulation, phenotype, and function. Unexpectedly, PPAR-gamma expression by visceral adipose tissue T-regulatory cells was necessary for complete restoration of insulin sensitivity in obese mice by the thiazolidinedione drug pioglitazone. Cipolletta et al. (2012) concluded that their findings suggested a previously unknown cellular mechanism for this important class of thiazolidinedione drugs, and provided proof of principle that discrete populations of T-regulatory cells with unique functions can be precisely targeted to therapeutic ends.
Aprile et al. (2018) showed that PPARG-delta-5 acted as a dominant-negative isoform and modified the PPARG-dependent transcriptional network. Human PPARG-delta-5 was expressed in insulin-responsive tissues. In vitro and ex vivo differentiation analyses revealed that human PPARG-delta-5 was expressed during differentiation of mesenchymal stem cells into mature adipocytes and impaired their differentiation ability. PPARG-delta-5 was also highly expressed in subcutaneous adipose tissue of overweight or obese patients, and its expression positively correlated with their BMI.
Role in Lipid Oxidation
The formation of foam cells from macrophages in the arterial wall is characterized by dramatic changes in lipid metabolism, including increased expression of scavenger receptors and the uptake of oxidized low density lipoprotein (oxLDL). Tontonoz et al. (1998) demonstrated that the nuclear receptor PPAR-gamma is induced in human monocytes following exposure to oxLDL and is expressed at high levels in the foam cells of atherosclerotic lesions. Ligand activation of the PPAR-gamma:RXR-alpha heterodimer in myelomonocytic cell lines induced changes characteristic of monocytic differentiation and promoted uptake of oxLDL through transcriptional induction of the scavenger receptor CD36. These results revealed a novel signaling pathway controlling differentiation and lipid metabolism in monocytic cells. Tontonoz et al. (1998) suggested that endogenous PPAR-gamma ligands may be important regulators of gene expression during atherogenesis.
Nagy et al. (1998) demonstrated that oxLDL activates PPAR-gamma-dependent transcription through a signaling pathway involving scavenger receptor-mediated particle uptake. Moreover, they identified 2 of the major oxidized linoleic acid metabolite components of oxLDL, 9-HODE and 13-HODE, as endogenous activators and ligands of PPAR-gamma. The authors found that the biologic effects of oxLDL are coordinated by 2 sets of receptors, one on the cell surface, which binds and internalizes the particle, and one in the nucleus, which is transcriptionally activated by its component lipids. Nagy et al. (1998) suggested that PPAR-gamma may be a key regulator of foam cell gene expression.
Chawla et al. (2001) provided evidence that in addition to lipid uptake, PPARG regulates a pathway of cholesterol efflux. PPARG induces ABCA1 (600046) expression and cholesterol removal from macrophages through a transcriptional cascade mediated by the nuclear receptor LXRA (NR1H3; 602423). Ligand activation of PPARG leads to primary induction of LXRA and to coupled induction of ABCA1. Transplantation of PPAR-null bone marrow into Ldlr -/- mice resulted in a significant increase in atherosclerosis, consistent with the hypothesis that regulation of LXRA and ABCA1 expression is protective in vivo. Chawla et al. (2001) proposed that PPARG coordinates a complex physiologic response to oxLDL that involves particle uptake, processing, and cholesterol removal through ABCA1.
By RNase protection analysis, Ricote et al. (1998) showed that in phorbol ester-stimulated macrophage cell lines, a probe to PPARG1 protected a 218-nucleotide fragment of PPARG1, but only a 174-nucleotide fragment of PPARG3. A PPARG2 probe protected a common 104-nucleotide fragment of both PPARG1 and PPARG3. PPARG2 itself was not expressed in the stimulated macrophages. PPARG1 and PPARG2 promoters are primarily used in adipose tissue. The authors speculated that other inducing factors, such as cytokines MCSF (120420) or GMCSF (138960), or oxidized LDL (see OLR1, 602601), might differentially regulate expression of the 3 isoforms.
Using the Cre/loxP system, Akiyama et al. (2002) generated conditional Pparg-deficient mice lacking exon 2 of the gene, which encodes the DNA-binding region of the protein. The majority of elicited peritoneal macrophages maintained an intact Pparg gene. Induction of Cre recombinase resulted in loss of exon 2 and marked reductions in basal and troglitazone-stimulated expression of the Ldl, Cd36 (173510), Lxra, and Abcg1 (603076) genes. In addition, there were reductions in the basal levels of apolipoprotein E (APOE; 107741) mRNA in macrophages and apoE protein and high-density lipoprotein (HDL) in plasma. Basal cholesterol efflux from cholesterol-laden macrophages to HDL was significantly reduced. Troglitazone, but not other TZD compounds, inhibited Abca1 expression and cholesterol efflux in both control and Pparg-deficient macrophages. Akiyama et al. (2002) concluded that PPARG plays an important role in the regulation of cholesterol homeostasis by controlling the expression of a network of genes that mediate cholesterol efflux from cells and its transport in plasma.
Role in Type 2 Diabetes Mellitus
The thiazolidinediones (TZDs) are synthetic compounds that can normalize elevated plasma glucose levels in obese, diabetic rodents and may be efficacious therapeutic agents for the treatment of noninsulin-dependent diabetes mellitus (NIDDM; 125853). Lehmann et al. (1995) identified the TZDs as high-affinity ligands for mouse PPAR-gamma receptors. Elbrecht et al. (1996) confirmed that human PPAR-gamma-1 and PPAR-gamma-2 have similar activity and determined that 3 different TZD compounds are agonists of PPAR-gamma-1 and PPAR-gamma-2. Elbrecht et al. (1996) speculated that the antidiabetic activity of the TZDs in humans is mediated through the activation of PPAR-gamma-1 and PPAR-gamma-2.
The use of TZDs to treat type-2 diabetes mellitus is complicated by systemic fluid retention. Guan et al. (2005) found that treatment of mice with amiloride, a collecting duct-specific diuretic, reversed the enhanced renal Na+ absorption, edema, and water weight gain caused by TZDs. Deletion of Pparg in mouse collecting duct blocked TZD-induced weight gain, decreased renal Na+ avidity, and increased plasma aldosterone. Treatment of cultured mouse collecting ducts with TZDs increased amiloride-sensitive Na+ absorption and Scnn1g (600761) mRNA expression through a Pparg-dependent pathway. Guan et al. (2005) concluded that SCNN1G is a PPARG target gene in the collecting duct and that activation of this pathway mediates fluid retention associated with TZDs.
Choi et al. (2010) showed that obesity induced in mice by high fat feeding activates the protein kinase CDK5 (123831) in adipose tissues. This results in phosphorylation of the nuclear receptor PPARG, a dominant regulator of adipogenesis and fat cell gene expression, at ser273. This modification of PPARG does not alter its adipogenic capacity, but leads to dysregulation of a large number of genes whose expression is altered in obesity, including a reduction in the expression of the insulin-sensitizing adipokine adiponectin (605441). The phosphorylation of PPARG by CDK5 is blocked by antidiabetic PPARG ligands such as rosiglitazone and MRL24. This inhibition works both in vitro and vivo, and is completely independent of classic receptor transcriptional agonism. Similarly, inhibition of PPARG phosphorylation in obese patients by rosiglitazone was very tightly associated with the antidiabetic effects of this drug. Choi et al. (2010) concluded that these results suggested that CDK5-mediated phosphorylation of PPARG may be involved in the pathogenesis of insulin resistance and presented an opportunity for development of an improved generation of antidiabetic drugs through PPARG.
Choi et al. (2011) described novel synthetic compounds that have a unique mode of binding to PPAR-gamma, completely lack classic transcriptional agonism, and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity without causing the fluid retention and weight gain that are serious side effects of many of the PPAR-gamma drugs. Also, unlike TZDs, SR1664 does not interfere with bone formation in culture. Choi et al. (2011) concluded that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPAR-gamma.
Dutchak et al. (2012) reported that FGF21 (609436) is an inducible, fed-state autocrine factor in adipose tissue that functions in a feed-forward loop to regulate the activity of PPAR-gamma. FGF21 knockout (KO) mice displayed defects in PPAR-gamma signaling including decreased body fat and attenuation of PPAR-gamma-dependent gene expression. Moreover, FGF21-KO mice were refractory to both the beneficial insulin-sensitizing effects and the detrimental weight gain and edema side effects of the PPAR-gamma agonist rosiglitazone. This loss of function in FGF21-KO mice was coincident with a marked increase in the sumoylation of PPAR-gamma, which reduces its transcriptional activity. Adding back FGF21 prevented sumoylation and restored PPAR-gamma activity. Dutchak et al. (2012) concluded that FGF21 is a key mediator of the physiologic and pharmacologic actions of PPAR-gamma.
Jonker et al. (2012) identified FGF1 (131220) as a critical transducer in the process of metabolic homeostasis through feast or famine in mice. Jonker et al. (2012) linked the regulation of FGF1 to the nuclear receptor PPAR-gamma. FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiologic processes, including development, wound healing, and cardiovascular changes. Surprisingly, FGF1 knockout mice displayed no significant phenotype under standard laboratory conditions. Jonker et al. (2012) showed that FGF1 was highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 developed an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution, and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue failed to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, Jonker et al. (2012) showed that adipose induction of FGF1 in the fed state is regulated by PPAR-gamma acting through an evolutionarily conserved promoter-proximal PPAR response element (PPRE) within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse established the PPAR-gamma-FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization.
Role in Cancer
Mueller et al. (1998) showed that PPAR-gamma is expressed at significant levels in human primary and metastatic breast adenocarcinomas. Ligand activation of this receptor in cultured breast cancer cells caused extensive lipid accumulation, changes in breast epithelial gene expression associated with a more differentiated, less malignant state, and a reduction in growth rate and clonogenic capacity of the cells. Inhibition of MAP kinase, a powerful negative regulator of PPAR-gamma, improves the TZD ligand sensitivity of nonresponsive cells. These data suggested that the PPAR-gamma transcriptional pathway can induce terminal differentiation of malignant breast epithelial cells.
Mueller et al. (2000) showed that PPAR-gamma is expressed in human prostate adenocarcinomas and cell lines derived from these tumors. Activation of this receptor with specific ligands exerts an inhibitory effect on the growth of prostate cancer (PC; 176807) cell lines. They showed that prostate cancer tumors and cell lines do not have intragenic mutations in the PPARG gene, although 40% of the informative tumors have hemizygous deletions of this gene. They conducted a phase II clinical study in patients with advanced prostate cancer using troglitazone (Rezulin), a PPAR-gamma ligand used for the treatment of type 2 diabetes. Oral treatment was administered to 41 men with histologically confirmed prostate cancer and no symptomatic metastatic disease. An unexpectedly high incidence of prolonged stabilization of prostate-specific antigen (KLK3; 176820) was seen in patients treated with troglitazone. In addition, 1 patient had a dramatic decrease in serum prostate-specific antigen to nearly undetectable levels. The findings suggested that PPAR-gamma may serve as a biologic modifier in human prostate cancer and that its therapeutic potential should be studied further.
Harris and Phipps (2002) showed that prostaglandin D2 (PGD2; see 176803) induced apoptosis in T-cell leukemia and lymphoma cell lines but not in normal peripheral blood T cells. The malignant T cells, but not the normal T cells, expressed mRNA for DPR, the PGD2 receptor (PTGDR; 604687); however, DPR agonists failed to induce apoptosis. RT-PCR and immunocytochemical analysis demonstrated that the malignant T cell lines, but not normal resting T cells, expressed PPARG mRNA as well as cytoplasmic and nuclear PPARG protein. In addition, PPARG agonists, but not PPARA (170998) agonists, mimicked the action of PGD2 and its metabolite, 15-d-PGJ2, in inhibiting the proliferation and viability of the T-cell tumor lines and in inducing apoptosis in these cells. Harris and Phipps (2002) concluded that PPARG ligands, which may include PGD2, provide strong apoptotic signals to transformed but not normal T lymphocytes.
Adrenocorticotrophic hormone (ACTH)-secreting pituitary tumors are associated with high morbidity due to excess glucocorticoid production. Heaney et al. (2002) demonstrated immunoreactive expression of PPAR-gamma exclusively in normal ACTH-secreting human anterior pituitary cells. Furthermore, PPAR-gamma was abundantly expressed in all of 6 human ACTH-secreting pituitary tumors studied. PPAR-gamma activators induced G0/G1 cell cycle arrest and apoptosis and suppressed ACTH secretion in human and murine corticotroph tumor cells. Development of murine corticotroph tumors, generated by subcutaneous injection of ACTH-secreting AtT20 cells, was prevented in 4 of 5 mice treated with the TZD compound rosiglitazone, and ACTH and corticosterone secretion was suppressed in all treated mice. Based on these findings, Heaney et al. (2002) suggested that TZDs may be an effective therapy for Cushing disease (219090).
Using database and luciferase reporter analyses, Fan et al. (2020) showed that the long noncoding RNA (lncRNA) PRRT3AS1 (619106) bound to the 3-prime UTR of PPARG. Quantitative RT-PCR showed that PRRT3AS1 was highly expressed in human PC cell lines, whereas PPARG was downregulated in PC cells compared with normal prostate epithelium. Knockdown and overexpression experiments in PC3 cells demonstrated that PRRT3AS1 expression was inversely correlated with PPARG expression, phosphorylation, and transcriptional activity. Additional experiments showed that inhibition of PRRT3AS1 or overexpression of PPARG suppressed the MTOR signaling pathway (see 601231), inhibited PC cell proliferation, tumor growth, migration, and invasion, and promoted apoptosis and autophagy. The authors concluded that PRRT3AS1 negatively regulates PPARG, and that PPARG suppresses tumorigenicity via the MTOR pathway.
Role in Immunology
Natural and synthetic agonists of PPAR-gamma regulate adipocyte differentiation, glucose homeostasis, and inflammatory responses. The proinflammatory response of macrophages to stimuli such as lipopolysaccharide (LPS) or interferon-gamma (IFNG; 147570) can be blocked by ligands for PPARs. Welch et al. (2003) studied the dependence on PPAR-gamma of antiinflammatory responses of these natural and synthetic agonists. They used a combination of mRNA expression profiling and conditional disruption of the Pparg gene in mice to characterize programs of transcriptional activation and repression by PPAR-gamma agonists in elicited peritoneal macrophages. Studies established overlapping transactivation and transrepression functions of Ppar-gamma and Ppar-delta (600409) in macrophages and suggested that a major transcriptional role of PPAR-gamma is negative regulation of specific subsets of genes that are activated by T helper-1 cytokines and pathogenic molecules that signal through pattern recognition receptors. The findings supported a physiologic role of PPAR-gamma in regulating both native and acquired immune responses.
Using cDNA microarray and in vitro analyses, Kelly et al. (2004) found that the commensal bacterium Bacteroides thetaiotaomicron attenuated inflammatory responses, notably IL8 (146930) production, in intestinal cell lines exposed to pathogenic Salmonella enteritidis and a number of other inflammatory mediators. The commensal organism induced CRM1 (XPO1; 602559)-independent nuclear export, rather than import only, of the NFKB subunit RELA (164014), with an eventual predominance of RELA cytoplasmic distribution after the peak of RELA induction by IL1A (147760) and IL1B (147720). RELA nucleocytoplasmic redistribution coincided with export of PPARG, and immunoprecipitation analysis indicated that PPARG-RELA association was dependent on the PPARG C-terminal ligand-binding domain. Kelly et al. (2004) concluded that at least some commensal bacteria contribute to immune homeostasis through an antiinflammatory mechanism involving PPARG and NFKB.
Are et al. (2008) reported that, in colonic cell lines and primary colonic cells, Erythrococcus faecalis isolated from newborn babies could regulate PPARG1 activity through transient phosphorylation, resulting in elevated DNA binding and transcriptional activation of downstream target genes, including IL10 (124092). They concluded that PPARG1 is involved in myriad physiologic processes and that microflora-driven regulation of PPARG1 may be important for homeostasis in the gut.
Almeida et al. (2009) used Mycobacterium bovis BCG as a model organism to study the formation of lipid droplets in macrophages during infection. They found that BCG infection increased expression of Pparg in mouse peritoneal macrophages. Lipid body formation was reduced in macrophages lacking Tlr2 (603028) and increased following treatment with a Pparg agonist. Treatment with a Pparg antagonist reduced lipid body formation without inhibiting cytokine production and enhanced mycobactericidal activity of macrophages. Almeida et al. (2009) concluded that PPARG is involved in lipid body biogenesis, which is linked to TLR2 and to mycobacterial pathogenesis.
Byndloss et al. (2017) found that the depletion of butyrate-producing microbes by antibiotic treatment reduced epithelial signaling through the intracellular butyrate sensor PPARG. Nitrate levels increased in the colonic lumen because epithelial expression of NOS2 (163730), the gene encoding inducible nitric oxide synthase, was elevated in the absence of PPARG signaling. Microbiota-induced PPARG signaling also limits the luminal bioavailability of oxygen by driving the energy metabolism of colonic epithelial cells (colonocytes) toward beta-oxidation. Therefore, Byndloss et al. (2017) concluded that microbiota-activated PPARG signaling is a homeostatic pathway that prevents a dysbiotic expansion of potentially pathogenic Escherichia and Salmonella by reducing the bioavailability of respiratory electron acceptors to Enterobacteriaceae in the lumen of the colon.
Other Roles
Kersten et al. (2000) reviewed the roles of PPARs in health and chronic disease.
Tarrade et al. (2001) examined the expression and role of the PPARG/RXRA heterodimers in human invasive trophoblasts. They reported that in human first-trimester placenta, PPARG and RXRA are highly expressed in cytotrophoblasts at the fetomaternal interface, especially in the extravillous cytotrophoblasts involved in uterus invasion. They also found that both synthetic and natural PPARG agonists inhibit extravillous cytotrophoblast invasion in a concentration-dependent manner and synergize with pan-RXR agonists. They concluded that these data underscore an important function of PPARG/RXRA heterodimers in the modulation of trophoblast invasion.
Using primary human lung bronchial epithelial cells and several human lung epithelial cell lines, Pawliczak et al. (2002) found evidence that CPLA2 (see 600522) has a role in the control of PPARG expression.
Ameshima et al. (2003) found that PPAR-gamma is abundantly expressed in normal lung tissues, especially in endothelial cells, but that its expression is reduced or absent in the angiogenic plexiform lesions of pulmonary hypertensive lungs and in the vascular lesions of a rat model of severe pulmonary hypertension. They showed that fluid shear stress reduced PPAR-gamma expression in ECV304 cells, that ECV304 cells that stably express dominant-negative PPAR-gamma form sprouts when placed in matrigel, and that the latter cells, after tail vein injection into nude mice, form lumen-obliterating lung vascular lesions. Ameshima et al. (2003) concluded that fluid shear stress decreases the expression of PPAR-gamma in endothelial cells and that loss of PPAR-gamma expression characterizes an abnormal, proliferating, apoptosis-resistant endothelial cell phenotype.
In an investigation of the role of PPARG in bone metabolism, Akune et al. (2004) found that Pparg -/- embryonic stem cells failed to differentiate into adipocytes, but spontaneously differentiated into osteoblasts. Reintroduction of the PPARG gene restored adipogenesis to wildtype levels. Heterozygous Pparg-deficient mice exhibited high bone mass with increased osteoblastogenesis but normal osteoblast and osteoclast functioning, and this effect was not mediated by insulin (176730) or leptin (164160). The osteogenic effect of PPARG haploinsufficiency became prominent with aging but was not changed upon ovariectomy. Akune et al. (2004) concluded that PPARG regulates bone metabolism in vivo.
Bruemmer et al. (2003) presented evidence that PPARG ligands induce caspase-mediated apoptosis via GADD45 (126335) expression in human coronary artery vascular smooth muscle cells. Deletion analysis of the GADD45 promoter revealed a region between -234 and -81 bp proximal to the transcription start that contains an OCT1 (164175) element and is crucial for PPARG ligand-mediated induction of the GADD45 promoter. PPARG activation induced OCT1 protein expression and DNA binding and stimulated activity of a reporter plasmid driven by multiple OCT1 elements. Bruemmer et al. (2003) concluded that activation of PPARG can lead to apoptosis and growth arrest in vascular smooth muscle cells, at least in part, by inducing OCT1-mediated transcription of GADD45.
Wisloff et al. (2005) hypothesized that artificial selection of rats based on low and high intrinsic exercise capacity would yield models that also contrast for cardiovascular disease risk. After 11 generations, rats with low aerobic capacity scored higher on cardiovascular risk factors that constitute the metabolic syndrome. The decrease in aerobic capacity was associated with decreases in the amounts of transcription factors required for mitochondrial biogenesis and in the amounts of oxidative enzymes in skeletal muscle. Wisloff et al. (2005) found that the amount of PPARG, PPARG coactivator-1-alpha (PGC-1-alpha; 604517), ubiquinol-cytochrome c oxidoreductase core 2 subunit (UQCRC2; 191329), cytochrome c oxidase subunit I (MTCO1; 516030), uncoupling protein-2 (UCP2; 601693), and ATP synthase H(+)-transporting mitochondrial F1 complex (F1-ATP synthase; see 108729) were markedly reduced in the low capacity runner rats in comparison with the high capacity runners. The uniform decline in these proteins was consistent with the hypothesis that reduced aerobic metabolism plays a causal role in the development of the differences between the low capacity runner and high capacity runner rats. Wisloff et al. (2005) concluded that impairment of mitochondrial function may link reduced fitness to cardiovascular and metabolic disease.
Sahin et al. (2011) used transcriptomic network analyses in mice null for either Tert (187270) or Terc (602322), which exhibit telomere dysfunction, to identify common mechanisms operative in hematopoietic stem cells, heart, and liver. Their studies revealed profound repression of PPARG, PCG1-alpha and PGC1-beta (608886), and the downstream network. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction was associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC1-alpha expression or germline deletion of p53 (191170) substantially restored PGC network expression, mitochondrial respiration, cardiac function, and gluconeogenesis. Sahin et al. (2011) demonstrated that telomere dysfunction activates p53 which in turn binds and represses PGC1-alpha and PGC1-beta promoters, thereby forging a direct link between telomere and mitochondrial biology. Sahin et al. (2011) proposed that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.
Zhang et al. (2015) observed rapid proliferation of preadipocytes and expansion of the dermal fat layer after infection of the skin by Staphylococcus aureus. Impaired adipogenesis resulted in increased infection as seen in Zfp423(nur12) (604557) mice or in mice given inhibitors of Pparg (601487). This host defense function was mediated through the production of Camp from adipocytes, since cathelicidin expression was decreased by inhibition of adipogenesis and adipocytes from Camp-null mice lost the capacity to inhibit bacterial growth. Zhang et al. (2015) concluded that the production of an antimicrobial peptide by adipocytes is an important element for protection against S. aureus infection of the skin.
Chiang et al. (2010) reported that the transcript of PPARG, a transcription factor that is critical for energy homeostasis, was markedly downregulated in multiple tissues of the R6/2 mouse model of Huntington disease (HD; 143100) and in lymphocytes of HD patients. Chronic treatment of R6/2 mice with an agonist of PPARG (thiazolidinedione, TZD) rescued progressive weight loss, motor deterioration, formation of mutant huntingtin (HTT; 613004) aggregates, jeopardized global ubiquitination profiles, reduced expression of 2 neuroprotective proteins (BDNF, 113505 and BCL2, 151430) and shortened life span exhibited by these mice. By reducing HTT aggregates and, thus, ameliorating the recruitment of PPARG into HTT aggregates, chronic TZD treatment also elevated the availability of the PPARG protein and subsequently normalized the expression of 2 of its downstream genes, the glucose transporter type 4 (GLUT4; 138390) and PPARGC1A. In addition, the PPARG agonist rosiglitazone protected striatal cells from mHTT-evoked energy deficiency and toxicity. The authors concluded that the systematic downregulation of PPARG may play a critical role in the dysregulation of energy homeostasis observed in HD, and that PPARG may be a potential therapeutic target for this disease.
Type 2 Diabetes Mellitus and Obesity
In 4 of 121 obese subjects, Ristow et al. (1998) identified a missense mutation in the PPARG2 gene (601487.0001). None of 237 subjects of normal weight had the mutation. All the subjects with the mutant allele were markedly obese.
Yen et al. (1997) identified a pro12-to-ala (P12A) change in the PPARG2 gene (601487.0002), which may modify susceptibility to type 2 diabetes mellitus (125853) and obesity (601665). Lohmueller et al. (2003) performed a metaanalysis of 301 published genetic association studies covering 25 different reported associations. For 8 of the associations, pooled analysis of follow-up studies yielded statistically significant replication of the first report, with modest estimated genetic effects. One of these was the association between type 2 diabetes and the PPARG2 P12A polymorphism as first reported by Deeb et al. (1998). Resistance to diabetes was associated with the ala12 allele, and susceptibility with the pro12 allele.
In a 'Europid pedigree' in which 5 members in 2 generations had severe insulin resistance and type 2 diabetes, Savage et al. (2002) found double heterozygosity for frameshift mutations in the PPARG gene (601487.0011) and the PPP1RG3A gene (600917.0003).
Familial Partial Lipodystrophy Type 3
In 3 subjects with severe insulin resistance who were later determined to have familial partial lipodystrophy (FPLD3; 604367) (see Savage et al., 2003), Barroso et al. (1999) reported 2 different heterozygous mutations (601487.0007; 601487.0008) in the ligand-binding domain of PPARG. In the PPAR-gamma crystal structure, the mutations destabilized helix 12, which mediates transactivation. Consistent with this observation, both receptor mutants were markedly transcriptionally impaired and, moreover, were able to inhibit the action of coexpressed wildtype PPAR-gamma in a dominant-negative manner. In addition to insulin resistance, all 3 subjects developed type 2 diabetes mellitus and hypertension at an unusually early age. Barroso et al. (1999) concluded that their findings represented the first germline loss-of-function mutations in PPAR-gamma and provided compelling genetic evidence that this receptor is important in the control of insulin sensitivity, glucose homeostasis, and blood pressure in man.
Hegele et al. (2002) identified a transactivation-deficient mutant of the PPARG gene (601487.0012) as the cause of familial partial lipodystrophy type 3.
Cancer
Sarraf et al. (1999) identified 4 somatic mutations (1 nonsense, 1 frameshift, and 2 missense) in the PPARG gene among 55 sporadic colon cancers (114500). Each mutation greatly impaired the function of the PPARG protein. The 472delA mutation (601487.0003) resulted in the deletion of the entire ligand-binding domain. Q286P (601487.0004) and K319X (601487.0005) retained a complete or partial ligand-binding domain but lost the ability to activate transcription through a failure to bind to ligands. R288H (601487.0006) showed a normal response to synthetic ligands but greatly decreased transcription and binding when exposed to natural ligands. These data indicated that colon cancer in humans is associated with loss-of-function mutations in the PPARG gene.
Studies indicating that synthetic ligands such as TZDs can influence the frequency of colonic tumors in mice raised concerns about the role of PPARG in colon cancer. Girnun et al. (2002) analyzed the role of this receptor in mice heterozygous for the Pparg gene with both chemical and genetic models of colon cancer. Heterozygous loss of the gene function caused an increase in beta-catenin (see 116806) levels and a greater incidence of colon cancer when animals were treated with azoxymethane. However, mice with preexisting damage to the Apc gene (611731), a regulator of beta-catenin, developed tumors in a manner insensitive to the status of the Pparg gene. These data showed that PPAR-gamma can suppress beta-catenin levels and colon carcinogenesis but only before damage to the APC/beta-catenin pathway. The authors suggested that PPAR-gamma ligands may be useful as chemopreventive agents in colon cancer.
Kroll et al. (2000) reported that t(2;3)(q13;p25), a translocation identified in a subset of human thyroid follicular carcinomas (188470), results in fusion of the DNA-binding domains of the thyroid transcription factor PAX8 (167415) to domains A to F of PPARG1. PAX8/PPARG1 mRNA and protein were detected in 5 of 8 thyroid follicular carcinomas but not in 20 follicular adenomas, 10 papillary carcinomas, or 10 multinodular hyperplasias. PAX8/PPARG1 inhibited thiazolidinedione-induced transactivation by PPARG1 in a dominant-negative manner. The experiments demonstrated an oncogenic role for PPARG and suggested that PAX8/PPARG1 may be useful in the diagnosis and treatment of thyroid carcinoma.
Marques et al. (2002) combined RT-PCR with primers in exons 4-8 of PAX8 and in exon 1 of PPARG1 with PPARG immunohistochemistry to study PAX8/PPARG1 oncogene activation in 9 follicular thyroid carcinomas (FTCs), 16 follicular thyroid adenomas (FTAs), 9 papillary thyroid carcinomas (PTCs), 4 anaplastic thyroid carcinomas, and 2 multinodular hyperplasias. PAX8/PPAR1G rearrangements were detected by RT-PCR in 5 of 9 (56%) FTCs and in 2 of 16 (13%) FTAs. By contrast, all cases of PTC, anaplastic thyroid carcinomas, and multinodular hyperplasia were RT-PCR-negative. Diffuse nuclear immunoreactivity for PPARG was observed in 7 of 9 (78%) FTCs, 5 of 16 FTAs (31%), and 1 of 9 PTCs (11%). Positivity was focal in 3 cases. The authors concluded that PAX8/PPARG1 rearrangements are present in both follicular carcinomas and adenomas, which suggests that this oncogene is not a reliable marker to differentiate between FTC and FTA in fine-needle aspiration biopsies of follicular neoplasms of the thyroid.
Dwight et al. (2003) detected the PAX8/PPARG rearrangement by RT-PCR, FISH, and/or Western analysis in 10 of 34 (29%) follicular thyroid carcinomas and in 1 of 20 (5%) atypical follicular thyroid adenomas, but not in any of the 20 follicular thyroid adenomas or 13 anaplastic thyroid carcinomas studied. In addition, 7 of 87 thyroid tumors exhibited involvement of PPARG alone. The authors concluded that PAX8/PPARG occurs frequently in follicular thyroid carcinomas, and that the presence of this rearrangement may be highly suggestive of a malignant tumor.
Because of somatic mutations of PPARG in sporadic colorectal cancers and because of the somatic translocation of PAX8 and PPARG in follicular thyroid carcinoma, Smith et al. (2001) examined a broader range of cancers for germline sequence variation in PPARG. They found that P12A alleles (601487.0002) were underrepresented in renal cell carcinoma patients compared to country-of-origin race-matched controls. In contrast, the H449H variant was overrepresented in individuals with endometrial carcinoma compared to controls. The observations were considered consistent with the hypothesis that PPARG serves as a common, low-penetrance susceptibility gene for cancers of several types, especially those cancers epidemiologically associated with obesity and fat intake.
Nikiforova et al. (2003) analyzed a series of 88 conventional follicular and Hurthle cell thyroid tumors for RAS (HRAS, 190020; NRAS, 164790; KRAS, 190070) mutations and PAX8-PPARG rearrangements using molecular methods and for galectin-3 (153619) and mesothelioma antibody HBME-1 expression by immunohistochemistry. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPARG rearrangement, and only 1 (3%) had both. Of follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPARG rearrangement, and 48% had neither. Follicular carcinomas with RAS mutations most often displayed an HBME-1-positive/galectin-3-negative immunophenotype and were either minimally or overtly invasive. Hurthle cell tumors infrequently had PAX8-PPARG rearrangement or RAS mutations.
The nuclear hormone receptor PPARG promotes adipogenesis and macrophage differentiation and is a primary pharmacologic target in the treatment of type 2 diabetes. Barak et al. (1999) showed that PPARG gene knockout in mice resulted in 2 independent lethal phases. Initially, PPARG deficiency interfered with terminal differentiation of the trophoblast and placental vascularization, leading to severe myocardial thinning and death by embryonic day 10.0. Supplementing Pparg-null embryos with wildtype placentas via aggregation with tetraploid embryos corrected the cardiac defect, implicating a previously unrecognized dependence of the developing heart on a functional placenta. A tetraploid-rescued mutant surviving to term exhibited another lethal combination of pathologies, including lipodystrophy and multiple hemorrhages. These findings both confirmed and expanded the current known spectrum of physiologic functions regulated by PPARG.
Kubota et al. (1999) generated homozygous Pparg-deficient mouse embryos, which died at 10.5 to 11.5 days postcoitum due to placental dysfunction. Heterozygous Pparg-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet. These phenotypes were abrogated by PPARG agonist treatment. Heterozygous Pparg-deficient mice showed overexpression and hypersecretion of leptin (LEP; 164160) despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study revealed an unpredicted role for PPARG in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPARG.
Rosen et al. (1999) demonstrated that mice chimeric for wildtype and Pparg-null cells showed little or no contribution of null cells to adipose tissue, whereas most other organs examined did not require PPARG for proper development. In vitro, the differentiation of embryonic stem cells into fat was shown to be dependent on PPARG gene dosage. These data provided direct evidence that PPARG is essential for the formation of fat.
Miles et al. (2000) conducted metabolic studies in Pparg gene knockout mice. Because homozygous Pparg-null mice die in development, they studied glucose metabolism in mice heterozygous for the mutation. They identified no statistically significant differences in body weight, basal glucose, insulin (176730), or free fatty acid levels between the wildtype and heterozygous groups. Nor was there a difference in glucose excursion between the groups of mice during oral glucose tolerance tests. However, insulin concentrations of the wildtype group were greater than those of the heterozygous deficient group, and insulin-induced increase in glucose disposal rate was significantly increased in the heterozygous mice. Likewise, the insulin-induced suppression of hepatic glucose production was significantly greater in the heterozygous mice than in wildtype mice. Taken together, these results indicated that, counterintuitively, although pharmacologic activation of PPAR-gamma improves insulin sensitivity, a similar effect is obtained by genetically reducing the expression levels of the receptor.
Using RNase protection and in situ hybridization, Michalik et al. (2001) showed that the alpha, delta (which they called beta), and gamma isotypes of PPAR are expressed in the mouse epidermis during fetal development and that they disappear progressively from the interfollicular epithelium after birth. Michalik et al. (2001) generated Pparg mutant mice and observed early embryonic lethality of Pparg-null mutants, consistent with the findings of Barak et al. (1999) and Kubota et al. (1999).
Using the Cre/loxP system, Cui et al. (2002) targeted disruption of Pparg to several mouse organs and tissues. They found that Pparg was not required for functional development of the mammary gland during pregnancy or for the establishment of B and T cells. Absence of Pparg did not increase the incidence of mammary tumors. However, the loss of Pparg in oocytes and granulosa cells resulted in impaired fertility. Progesterone levels were decreased and implantation rates were reduced.
Wan et al. (2007) generated hematopoietic and endothelial cell-specific Pparg deletion in mice. Maternal Pparg deletion resulted in the production of 'toxic milk' containing elevated levels of inflammatory lipids. Ingestion of this milk caused inflammation, alopecia, and growth retardation in the nursing wildtype neonates. After weaning, the pups were symptom-free. Genomic profiling revealed that Pparg deficiency led to increased expression of lipid oxidation enzymes in the lactating mammary gland. Metabolic profiling showed increased levels of oxidized free fatty acids in the nursing pups.
To clarify the role of PPAR signaling in tumor development, Saez et al. (2003) generated strains of mice with defined loss-of-function mutations in the Ppar genes. Mice devoid of Pparg die in utero, whereas heterozygotes are viable. To assess how Pparg haploinsufficiency influences the development of prostate cancer, Saez et al. (2003) crossed heterozygous mice with the transgenic adenocarcinoma mouse prostate (TRAMP) model, in which the probasin promoter drives prostate-specific expression of SV40 T antigen, thus recapitulating the progressive stages associated with clinical prostate cancer. TRAMP mice have also been used to examine the role of Ppara (170998), as this Ppar is androgen-responsive and is highly expressed in prostatic adenocarcinoma. Saez et al. (2003) crossed Ppara and Pparg mutants with TRAMP mice to generate mice carrying the TRAMP transgene in a Ppara-null or Pparg hemizygous background. They detected no increase in tumor predisposition in any of the Ppar mutant colonies, even after monitoring enough mice for long enough to be able to detect age-dependent tumor development. No differences in tumor incidence (complete in all cases), latency, size, histopathology, or disease progression were observed in animals carrying any of the Ppar loss-of-function mutations in addition to the TRAMP transgene. Saez et al. (2003) concluded that neither complete loss of Ppara nor hemizygous deletion of Ppara or Pparg has a significant effect on tumor development in this experimental model.
Herzig et al. (2003) generated mice infected with dominant-negative Creb (123810)-expressing adenovirus and showed that, compared with control littermates, the Creb-deficient mice had a fatty liver phenotype and a pronounced increase in hepatic triglyceride content and in plasma triglyceride levels on a high-fat diet. The heterozygotes also displayed higher liver triglyceride contents than wildtype littermates. Creb-deficient mice displayed elevated expression of the nuclear hormone receptor Ppar-gamma. CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the hairy/enhancer of split (HES1; 139605) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo. Herzig et al. (2003) concluded that the coordinate induction of PGC1 (604517) and repression of PPAR-gamma by CREB during fasting provides a molecular rationale for the antagonism between insulin and counter-regulatory hormones, and indicates a potential role for CREB antagonists as therapeutic agents in enhancing insulin sensitivity in the liver.
The thiazolidinediones are insulin-sensitizing drugs that are potent agonists of PPAR-gamma. Although muscle is the major organ responsible for insulin-stimulated glucose disposal, the PPARG gene is more highly expressed in adipose tissue than in muscle. To study this issue, Hevener et al. (2003) used the Cre/loxP system to knock out the Pparg gene in mouse skeletal muscle. As early as 4 months of age, mice with targeted disruption of PPAR-gamma in muscle showed glucose intolerance and progressive insulin resistance. Using the hyperinsulinemic-euglycemic clamp technique, Hevener et al. (2003) found that the in vivo insulin-stimulated glucose disposal rate (IS-GDR) was reduced by approximately 80% and was unchanged by 3 weeks of TZD treatment. These effects revealed a crucial role for muscle PPAR-gamma in the maintenance of skeletal muscle insulin action, the etiology of insulin resistance, and the action of TZDs.
He et al. (2003) found that targeted deletion of Pparg in mouse adipose tissue resulted in decreased adipose tissue mass with a decrease in the number of adipocytes and hypertrophy of remaining adipocytes with associated inflammation. The transgenic mice showed an increase in plasma free fatty acids and triglycerides, indicating lipolysis, and a decrease in circulating leptin. Hepatic effects included insulin resistance with an increase in gluconeogenesis and fatty liver. By contrast, blood glucose and insulin-stimulated skeletal muscle glucose uptake were similar to wildtype mice. Thiazolidinedione treatment reversed hepatic insulin resistance, but did not lower free fatty acids. The findings suggested that there are multiple PPARG-dependent components of metabolism in different tissues.
Rosen et al. (2003) created mice with targeted elimination of Pparg expression in pancreatic beta cells. Mutant mice had significant islet hyperplasia on a normal diet, and the normal expansion of beta-cell mass that occurs in control mice in response to high-fat feeding was blunted in mutant animals. No effect on glucose homeostasis was noted. Rosen et al. (2003) concluded that PPARG is critical in beta-cell proliferation and that the mechanisms controlling beta-cell hyperplasia in obesity are different from those that regulate baseline cell mass in the islet.
Zhang et al. (2004) investigated the functional differences between PPAR-gamma-1 and PPAR-gamma-2 by selectively disrupting the Pparg2 gene in mice. In contrast to the embryonic lethality of Ppar-gamma deficient mice, Pparg2-null mice survived. Although normal development was identified in other tissues, Pparg2-null mice exhibited an overall reduction in white adipose tissue, less lipid accumulation, and decreased expression of adipogenic genes in adipose tissue. In addition, insulin sensitivity was impaired in male Pparg2-null mice, with dramatically decreased expression of insulin receptor substrate-1 (IRS1; 147545) and glucose transporter-4 (GLUT4; 138190) in the skeletal muscle, but thiazolidinediones were able to normalize this insulin resistance. The Pparg2-null mice embryonic fibroblasts showed a dramatically reduced capacity for adipogenesis in vitro compared with wildtype mouse embryonic fibroblasts.
A dominant negative P467L mutation (601487.0007) in the ligand-binding domain of the PPARG gene in humans is associated with severe insulin resistance and hypertension. Tsai et al. (2004) found that P465L homozygous mice died in utero. Heterozygous mice with the same mutation grew normally and had normal total adipose tissue weight. However, they had reduced interscapular brown adipose tissue and intraabdominal fat mass, and increased extraabdominal subcutaneous fat, compared with wildtype mice. They had abnormal plasma glucose levels and insulin sensitivity, and increased glucose tolerance. However, while fed a high-fat diet, their plasma insulin levels were mildly elevated in association with a significant increase in pancreatic islet mass. They were hypertensive, and expression of the angiotensinogen gene (106150) was increased in their subcutaneous adipose tissues. The effects of P465L on blood pressure, fat distribution, and insulin sensitivity were the same in both male and female mice regardless of diet and age. Thus, Tsai et al. (2004) demonstrated that the P465L mutation alone is sufficient to cause abnormal fat distribution and hypertension but not insulin resistance in mice. These results provided genetic evidence for a critical role for PPARG in blood pressure regulation that is not dependent on altered insulin sensitivity. Hegele and Leff (2004) commented on the work of Tsai et al. (2004).
Odegaard et al. (2007) generated macrophage-specific Pparg-knockout BALB/c mice and found that Pparg was required for alternatively activated resident macrophages, but not classically activated and recruited macrophages. Arginase-1 (ARG1; 608313) mRNA and activity, both hallmarks of alternatively activated macrophages, were significantly reduced in Il4 (147780)-stimulated Pparg-knockout bone marrow-derived macrophages. EMSA analysis showed that Ppar/Rxr heterodimers bound a distal enhancer in the Arg1 promoter region after Il4 stimulation. BALB/c mice lacking macrophage Pparg, like wildtype C57BL/6 mice, resisted acute infection with Leishmania major in terms of footpad swelling and necrosis, suggesting that Pparg is required for acquisition and maintenance of alternatively activated macrophages. Administration of a high-fat diet resulted in greater weight gain and adiposity in mutant mice than in control mice. Pparg-knockout adipose tissue macrophages failed to express genes associated with alternative activation. Mice lacking macrophage Pparg were more susceptible to obesity and insulin resistance. Odegaard et al. (2007) proposed that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggested that macrophage polarization towards the alternate state may be beneficial in treatment of type 2 diabetes.
Wan et al. (2007) found that targeted deletion of Pparg in mouse osteoclasts, but not osteoblasts, resulted in osteopetrosis characterized by increased bone mass, reduced medullary cavity space, and extamedullary hematopoiesis in spleen. These defects resulted from impaired osteoclast differentiation and compromised Rankl (TNFSF11; 602642) signaling. Moreover, ligand activation of Pparg exacerbated osteoclast differentiation in a receptor-dependent manner. Wan et al. (2007) concluded that PPARG and its ligands have a role in promoting osteoclast differentiation and bone resorption.
Lu et al. (2011) generated mice with a neuron-specific Pparg knockout (Pparg-BKO mice) and observed that during high-fat diet (HFD) feeding, food intake was reduced and energy expenditure increased in Pparg-BKO mice compared to mice carrying Pparg floxed alleles (Pparg-f/f mice), resulting in reduced weight gain. Pparg-BKO mice also responded better to leptin administration than Pparg-f/f mice. When treated with rosiglitazone, Pparg-BKO mice were resistant to rosiglitazone-induced hyperphagia and weight gain, and experienced only marginal improvement in glucose metabolism relative to rosiglitazone-treated Pparg-f/f mice. Hyperinsulinemic-euglycemic clamp studies showed that the increase in hepatic insulin sensitivity induced by rosiglitazone treatment during HFD feeding was completely abolished in Pparg-BKO mice, an effect associated with the failure of rosiglitazone to improve liver insulin receptor (147670) signal transduction. Lu et al. (2011) concluded that the excess weight gain induced by HFD feeding depends in part on the effect of neuronal PPARG signaling to limit thermogenesis and increase food intake, and that neuronal PPARG signaling is also required for the hepatic insulin-sensitizing effects of thiazolidinediones such as rosiglitazone.
In experiments involving male Long-Evans rats, Ryan et al. (2011) observed that both acute and chronic activation of central nervous system (CNS) Pparg, either by insulin-sensitizing thiazolidinedione drugs or by hypothalamic overexpression of a Pparg fusion protein, led to positive energy balance in rats. Blocking endogenous activation of CNS Pparg with pharmacologic antagonists or reducing its expression with short hairpin RNA (shRNA) led to negative energy balance, restored leptin sensitivity in rats fed a HFD, and blocked the hyperphagic response to oral thiazolidinedione treatment. Ryan et al. (2011) concluded that hypothalamic PPARG plays a role in the central regulation of energy balance, and that CNS mechanisms might underlie at least some of the weight gain observed with PPARG-modulating drugs.
Banks et al. (2015) found that mice with Cdk5 (123831) ablated specifically in adipose tissues had both a paradoxical increase in PPARG phosphorylation at serine-273 and worsened insulin resistance. Unbiased proteomic studies showed that ERK kinases are activated in these knockout animals. Banks et al. (2015) demonstrated that ERK (see 601795) directly phosphorylates serine-273 of PPARG in a robust manner and that Cdk5 suppresses ERKs through direct action on a novel site in MAP kinase/ERK kinase (MEK; see 176872). Pharmacologic inhibition of MEK and ERK markedly improved insulin resistance in both obese wildtype mice and ob/ob mice (see 164160), and also completely reversed the deleterious effects of the Cdk5 ablation. Banks et al. (2015) concluded that these data showed that an ERK/CDK5 axis controls PPARG function and suggested that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes.
In 4 German subjects with severe obesity (601665), Ristow et al. (1998) identified a pro115-to-gln (P115Q) mutation in exon 6 of the PPARG2 gene. Significantly, the mutation was in the codon immediately adjacent to a serine-114 phosphorylation site that negatively regulates transcriptional activity of the protein and is shared by all 3 forms of PPAR-gamma (Wang et al., 1999). Overexpression of the mutant gene in murine fibroblasts led to the production of a protein in which the phosphorylation of serine at position 114 was defective, as well as accelerated differentiation of the cells into adipocytes and greater cellular accumulation of triglyceride than with the wildtype PPARG2. These effects were similar to those of an in vitro mutation created directly at the ser114 phosphorylation site.
In a screening of 26 Caucasians with type 2 diabetes mellitus (125853) with or without obesity (601665), Yen et al. (1997) identified a C-to-G transversion in the PPARG2 gene, resulting in a pro12-to-ala (P12A) substitution. The allele frequency of the ala12 variant ranged from 0.12 in Caucasian Americans to 0.10 in Chinese. The authors noted that the product of the PPARG gene is a nuclear receptor that regulates adipocyte differentiation and possibly lipid metabolism and insulin sensitivity, all of which are relevant to the development of type 2 diabetes mellitus.
Among a group of middle-aged and elderly nondiabetic Finnish individuals, Deeb et al. (1998) found that the ala12 allele was associated with lower insulin levels, lower body mass index (BMI; 606641), higher insulin sensitivity, and higher HDL cholesterol levels. Among a group of Japanese-American individuals, Deeb et al. (1998) found that the ala12 allele was less frequent among those with type 2 diabetes compared to normal controls. Functional studies showed that the ala12 isoform of PPARG2 were less effective in activating transcription, which the authors suggested may lead to lower levels of adipose tissue mass accumulation.
Valve et al. (1999) found that the frequencies of the ala12 allele in exon B and a silent CAC487-to-CAT allele in exon 6 were not significantly different between obese Finnish patients and population-based control subjects (0.14 vs 0.13 and 0.19 vs 0.21, respectively). The polymorphisms were associated with increased BMI, and the 5 women with both ala12ala and CAT478CAT genotypes were significantly more obese compared with the women having both pro12pro and CAC478CAC genotypes. The authors concluded that the pro12-to-ala and CAC478-to-CAT polymorphisms in the PPARG gene are associated with severe overweight and increased fat mass among obese women.
Altshuler et al. (2000) evaluated 16 published genetic associations to type 2 diabetes and related subphenotypes using a family-based design to control for population stratification, and replication samples to increase power. They confirmed only 1 association, that of the common P12A polymorphism in PPAR-gamma with type 2 diabetes. By analyzing over 3,000 individuals, they found a modest (1.25-fold) but significant (P = 0.002) increase in diabetes risk associated with the more common proline allele (approximately 85% frequency). Altshuler et al. (2000) noted that earlier studies had yielded conflicting results. Based on their findings, however, Altshuler et al. (2000) suggested that the risk allele (pro12) occurs at such high frequency that the modest effect may translate into a large population-attributable risk which may influence as much as 25% of type 2 diabetes in the general population.
Hegele et al. (2000) found that the G319S (142410.0008) variant of the transcription factor-1 gene was strongly associated with type 2 diabetes among the Oji-Cree of northern Ontario. However, the majority of subjects with diabetes did not have the HNF1A S319 variant, suggesting that there might be other genetic determinants of diabetes susceptibility. In the course of sequencing candidate genes in diabetic subjects who were homozygous for HNF1A G319/G319, they found that some subjects had the PPARG ala12 variant. After genotyping PPARG in the entire adult Oji-Cree population, they found that PPARG ala12 was strongly associated with type 2 diabetes in women, but not men. Among women, carriers of ala12 had a 2.3 increased odds ratio of being affected with type 2 diabetes, compared with noncarriers, and that affected ala12 carriers had a significantly earlier age of onset and/or age at diagnosis compared with noncarriers. The authors concluded that, when taken together with the previously reported association of diabetes with HNF1A in both men and women, the gender-specific association with PPARG ala12 confirms that type 2 diabetes is etiologically complex in the Oji-Cree and that at least 2 genes are involved in determining susceptibility to the disease in this population.
In 2 independently recruited cohorts of unrelated, nondiabetic, adult Caucasian subjects with either moderate or extreme obesity, Beamer et al. (1998) found that the ala12 allele was associated with higher BMI. The authors suggested that genetic variation at the PPARG locus may influence susceptibility to the multifactorial disorder of obesity in humans. In a study of 552 patients with type I diabetes (222100) and 503 type 2 diabetes, Ringel et al. (1999) found no difference in the ala12 allele between patients and controls. There was also no relationship between dyslipoproteinemia or obesity and the P12A genotype. Among 229 Korean subjects, including 111 obese subjects (BMI greater than 25 kg/m2), Oh et al. (2000) found that allele frequencies of ala12 were not different among those with normal glucose tolerance (111 individuals), those with impaired glucose tolerance (60 individuals), and those with diabetes mellitus (58 individuals). In addition, ala12 allele frequencies were not significantly different between obese and nonobese individuals. Oh et al. (2000) concluded that PPARG P12A is not associated with either diabetes or obesity and may not be an important determinant of obesity or diabetes in Korean subjects.
By genotyping 619 members of 52 familial type 2 diabetes kindreds, Hasstedt et al. (2001) found that BMI, systolic and diastolic blood pressures, triglyceride levels, and glucose concentration were significantly associated with the P12A variant, whereas the effect of P12A on liability for diabetes was not significant. The frequency of the ala12 allele in the study was approximately 0.12, which is within the range observed in random Caucasian samples. The predicted means for each trait and each genotype suggested that the P12A variant acted most like a recessive mutation, with the major effect among homozygous individuals, who comprise only 1 to 2% of the population. The authors concluded that the results confirm an association of the P12A variant with traits commonly ascribed to the insulin resistance syndrome, but not with direct measure of insulin sensitivity. They stated that the tendency for this variant to act in a recessive manner with effects on multiple traits may explain the inconsistent associations reported in previous studies.
Polycystic ovary syndrome (PCOS; 184700) is common in women of reproductive age and is associated with a high risk for development of type 2 diabetes. Insulin resistance, a key component in the pathogenesis of PCOS and glucose intolerance, is ameliorated by the thiazolidinediones, synthetic ligands for PPARG. Hara et al. (2002) examined the relationship of the pro12-to-ala polymorphism in the PPARG gene to clinical and hormonal features of PCOS. Twenty-eight of 218 subjects had the ala allele, all in the heterozygous state. The frequency of the ala allele varied among the groups: 1% in African Americans, 8% in Caucasians, and 15% in Hispanics. Nondiabetic Caucasians with an ala allele (pro/ala group) were more insulin sensitive than those in the pro/pro group, as evidenced by a lower homeostasis model assessment index and lower levels of insulin at both the fasting and 2 hour time points during the oral glucose tolerance test. The authors concluded that the pro12-to-ala polymorphism in the PPARG gene is a modifier of insulin resistance in Caucasian women with PCOS.
Orio et al. (2003) studied the P12A and C161T (601487.0009) polymorphisms of the PPARG gene in 100 PCOS patients and healthy controls matched for age and BMI. They found that the P12A polymorphism was unrelated to BMI and/or leptin (164160) levels in women with PCOS.
Population structure has been presumed to cause many of the disease-marker associations that have been reported but not replicated, yet few actual case-control studies have been evaluated for the presence of structure. Ardlie et al. (2002) examined 4 case-control samples, comprising 3,472 individuals, to determine if a detectable population subdivision was present. The 4 population samples included 500 U.S. whites and 236 African Americans with hypertension, and 500 U.S. whites and 500 Polish whites with type 2 diabetes, all with matched control subjects. Both diabetes populations were typed for the pro12-to-ala polymorphism of the PPARG gene, to replicate this well-supported association (Altshuler et al., 2000). In each of the 4 samples, Ardlie et al. (2002) tested for structure, using the sum of the case-control allele frequency chi square statistics for 9 short tandem repeat (STR) and 35 SNP markers (Pritchard and Rosenberg, 1999). They found weak evidence for population structure in the African American sample only. Further refinement of the sample to include only individuals with U.S.-born parents and grandparents eliminated the stratification. The example provided insight into the factors affecting the replication of association studies and suggested that carefully matched, moderate-sized case-control samples in cosmopolitan U.S. and European populations are unlikely to contain levels of structure that would result in significantly inflated numbers of false-positive associations. They also explored the role that extreme differences in power among studies, due to sample size and risk-allele frequency differences, may play in the replication problem.
In a group of 2,245 nondiabetic Danish subjects, Frederiksen et al. (2002) determined that the frequency of the ala12 allele was 12.6% in a subset of individuals with what they called 'insulin resistance syndrome' and 14.2% among individuals without the syndrome. However, the frequency of the ala12 variant in homozygous form was significantly lower in the group with insulin resistance compared to those without the syndrome: P = 0.02; odds ratio, 0.24 (0.06-0.99). The authors concluded that homozygosity of the ala12 PPARG variant confers a reduced risk of 'insulin resistance syndrome' among Danish Caucasian subjects.
In 476 elderly persons whose birth weights were known, Eriksson et al. (2003) studied the effects of the ala12 allele of the P12A mutation on lipid metabolism in adult life as modified by size at birth, which is an indicator of the intrauterine environment. The ala12 allele was associated with increased total serum low density lipoprotein (LDL) and non-high density lipoprotein (non-HDL) cholesterol concentrations, but only among those who had birth weights below 3,000 grams. These interactions between the effects of the gene on adult traits and the effects of birth weight were interpreted as examples of gene-environment interactions, which underlie plasticity during development.
Masud and Ye (2003) studied the P12A polymorphism in a cohort of 1,170 white British patients with coronary artery disease and found that subjects homozygous for the ala12 allele had significantly higher mean BMI than subjects with other genotypes (p = 0.02). They performed a metaanalysis using data from 30 independent studies, for a total of 19,136 subjects. In the samples with a mean BMI value of 27 or greater, ala12 allele carriers had a significantly higher BMI than noncarriers. This difference was not detected in those with a BMI less than 27. Further analysis using data from the publications studying BMI found that ala12 homozygotes had significantly higher BMI than heterozygotes and pro12 homozygotes. The data supported the hypothesis that the P12A polymorphism is a genetic modifier of obesity and are consistent with a recessive model for the ala12 allele.
In a large metaanalysis, Lohmueller et al. (2003) found a statistically significant association between type 2 diabetes and the P12A variant. Resistance to diabetes was associated with the ala12 allele, and susceptibility with the pro12 allele.
In a study of 2,141 women, Memisoglu et al. (2003) found that associations between the P12A variant and intake of total fat, fat subtypes and BMI were different in ala12 carriers compared with wildtype pro/pro carriers. Among pro/pro individuals, those in the highest quintile of total fat intake had significantly higher mean BMI compared to those in the lowest quintile, whereas among ala12 carriers there was no significant trend observed between dietary fat intake and BMI. In contrast, intake of monounsaturated fat was not associated with BMI among pro/pro carriers but was inversely associated with BMI among ala12 carriers. The relationship between dietary fat intake and plasma lipid concentrations also differed according to PPARG genotype. Memisoglu et al. (2003) suggested that PPARG genotype may be an important factor in physiologic responses to dietary fat in humans.
Kim et al. (2004) examined the effects of the P12A polymorphism on body fat distribution and other obesity-related parameters in 1,051 Korean females. Body weight, fat mass, fat percentage, BMI, and waist-to-hip ratio (WHR) were significantly higher in individuals with the PA or AA genotype than those with PP. Among overweight individuals (BMI greater than 25), PA/AA was associated with significantly higher abdominal subcutaneous fat, abdominal visceral fat, and subcutaneous upper and lower thigh fat; there was no association in individuals with a BMI less than 25. Serum lipid profiles, glucose, and liver function indicators showed no association with PPARG2 genotype. Kim et al. (2004) suggested that the PPARG2 PA/AA genotype is associated with increased subcutaneous and visceral fat areas in overweight Korean females.
Using the homeostasis model of insulin resistance, Buzzetti et al. (2004) investigated the influence of the P12A polymorphism on insulin sensitivity in a large, nondiabetic Italian population. Presence of the ala allele was associated with significantly lower fasting insulin levels compared to the pro-pro genotype (p = 0.01), and significantly lower insulin resistance was observed in ala12 carriers (p = 0.013). There was no significant interaction effect between body mass index and the ala12 polymorphism, nor between gender and ala12 polymorphism in modulating insulin sensitivity. Buzzetti et al. (2004) concluded that the ala12 allele is significantly associated with greater insulin sensitivity.
In 622 subjects aged 40 to 70 years who were at risk for developing type 2 diabetes, Temelkova-Kurktschiev et al. (2004) investigated the relationship of the P12A polymorphism to early atherosclerosis, measured by carotid intimal medial thickness (IMT; 609338). Altogether, 449 of the subjects had the common P12P genotype, 162 had the P12A genotype, and 11 the A12A genotype. IMT was significantly decreased in subjects with the A12A genotype compared with subjects with the other 2 genotypes. Body mass index, free fatty acid levels, and leukocyte count were lower in subjects with the A12A genotype compared with subjects with the P12P or P12A genotypes. In multivariate analysis, the A12A genotype was a significant independent determinant of IMT. The authors also concluded that the A12A genotype of the PPARG2 gene may protect from early atherosclerosis in subjects at risk for diabetes.
Kolehmainen et al. (2003) studied the effect of the P12A polymorphism of PPARG2 gene on the expression of PPARG target genes in adipose tissue. Adipose tissue samples were collected from 30 massively obese subjects, and P12A polymorphism genotype was determined by SSCP analysis. The mRNA expression of p85-alpha phosphatidylinositol 3-kinase (171833) was significantly lower in the omental fat of the P12A carriers than in that of the P12P carriers (P less than 0.01). It also appeared that PPARG2 expression was higher in men with the ala12 allele (P less than 0.01). Interestingly, particularly in women, the expression of both PPARG splice variants was lower in omental than subcutaneous fat independently of genotype (P less than 0.05-0.01). Kolehmainen et al. (2003) concluded that the common P12A polymorphism of the PPARG2 gene has a minor influence on mRNA expression of PPARG target genes in adipose tissue of obese subjects. Expression of both PPARG splice variants is dependent on fat depot: omental fat showed lower mRNA levels compared with subcutaneous fat depots.
Hansen et al. (2005) investigated the separate and combined effects of the PPARG P12A and the KCNJ11 E23K (600937.0014) polymorphisms on risk of type 2 diabetes. The combined analysis involved 1,164 type 2 diabetic patients and 4,733 middle-aged, glucose-tolerant subjects. In the separate analyses, the K allele of KCNJ11 E23K associated with type 2 diabetes (odds ratio, 1.19; P = 0.0002), whereas PPARG P12A showed no significant association with type 2 diabetes. The combined analysis indicated that the 2 polymorphisms acted in an additive manner to increase the risk of type 2 diabetes, and the authors found no evidence for a synergistic interaction between them. Together, the 2 polymorphisms conferred a population-attributable risk for type 2 diabetes of 28%. The authors concluded that their results showed no evidence of a synergistic interaction between the KCNJ11 E23K and PPARG P12A polymorphisms, but indicated that they may act in an additive manner to increase the risk of type 2 diabetes.
Hansen et al. (2006) studied any variation in the PPARG and PPARA gene associated with the risk of fluid retention and development of peripheral edema in patients with type 2 diabetes treated with the dual-acting PPAR-alpha/gamma agonist ragaglitazar. They identified a population-attributable risk of approximately 50% for the P12P genotype and suggested that testing for the P12A substitution in the PPARG gene, in addition to the already identified clinical risk factors, may become a useful tool to further reduce the risk of PPARG agonist-induced fluid retention and edema in patients with type 2 diabetes.
In genomewide association studies of type 2 diabetes involving genotype data from a variety of international consortia, the Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research (2007), Zeggini et al. (2007), and Scott et al. (2007) confirmed association of the P12A polymorphism (rs1801282) with diabetes susceptibility. Although this association was not strongly observed in any single scan, all-data metaanalyses obtained strong evidence (OR = 1.14, P = 1.7 x 10(-6)).
Florez et al. (2007) studied whether the PPARG P12A polymorphism affects progression from impaired glucose tolerance to diabetes, or responses to preventive interventions (lifestyle, metformin, or troglitazone vs placebo) in 3,548 Diabetes Prevention Program participants. They performed Cox regression analysis using genotype at P12A, intervention, and their interactions as predictors of diabetes incidence. Florez et al. (2007) concluded that the P12A allele increases risk for diabetes in persons with impaired glucose tolerance, an effect modified by BMI, but that PPARG P12A has little or no effect on the beneficial response to troglitazone.
In a case-control study in healthy unrelated Caucasians from Italy, Bulotta et al. (2005) tested for an effect of the P12A variant of the PPARG2 gene on diabetes risk influenced by the UCP2 variant -866G/A (601693.0001). After stratifying for the PPARG2 polymorphism, the increased risk conferred by the UCP2 G/G genotype was still evident among P12/P12 homozygous subjects (n = 801; OR = 1.38 ; 95% CI, 1.04-1.83), but seemed to disappear among carriers of the A12 allele (n = 137; OR = 0.87; 95% CI, 0.40-1.91).
In a sporadic colon cancer (114500) tumor, Sarraf et al. (1999) identified a somatic 1-bp deletion (472delA) in the PPARG gene.
In a sporadic colon cancer (114500) tumor, Sarraf et al. (1999) identified a somatic 857A-G transition in the PPARG gene, resulting in a gln286-to-pro (Q286P) substitution.
In a sporadic colon cancer (114500), Sarraf et al. (1999) identified a somatic 955A-T transversion in the PPARG gene, resulting in a lys319-to-ter (K319X) nonsense substitution.
In a sporadic colon cancer (114500) tumor, Sarraf et al. (1999) identified a somatic 863G-A transition in the PPARG gene, resulting in an arg288-to-his (R288H) substitution.
In a patient with severe insulin resistance, type 2 diabetes mellitus, and hypertension beginning in her twenties and characteristic of familial partial lipodystrophy (604367), Barroso et al. (1999) detected a C-to-T transition in the PPARG gene resulting in a proline-to-leucine mutation at codon 467 (P467L). Her son, aged 30 years, who also had a history of early-onset diabetes and hypertension, was also heterozygous for the P467L mutation. All other family members, including both parents of the proband, none of whom were known to have diabetes or hypertension, were homozygous for wildtype receptor sequence. Nonpaternity was excluded, indicating a de novo appearance of the mutation in the proband. In a follow-up of the family reported by Barroso et al. (1999), Savage et al. (2003) found clinical features consistent with familial partial lipodystrophy type 3.
In a 15-year-old patient with primary amenorrhea, hirsutism, acanthosis nigricans, elevated blood pressure, and markedly elevated fasting and postprandial insulin levels characteristic of familial partial lipodystrophy (604367), Barroso et al. (1999) identified a G-to-A transition in the PPARG gene resulting in a valine-to-methionine mutation at codon 290 (V290M). By age 17 the patient had developed type 2 diabetes and had hypertension which required treatment with beta-blockers. Her clinically unaffected mother and sister were both wildtype at this locus; screening of the deceased father was not possible. In a follow-up of the patient reported by Barroso et al. (1999), Savage et al. (2003) found clinical features consistent with familial partial lipodystrophy type 3.
Meirhaeghe et al. (1998) reported a 161C-T substitution in exon 6 of the PPARG gene. Among 820 men and women living in northern France, Meirhaeghe et al. (1998) determined that the frequencies of the C and T alleles were 0.860 and 0.140, respectively. In the whole sample, no association of the polymorphism with several markers of obesity was observed, but there was a statistically significant association (P less than 0.03) between the T allele and plasma leptin levels in obese individuals. Obese subjects bearing at least one T allele had higher plasma leptin levels than obese subjects who did not have a T allele. There was no difference in the nonobese group. The increased plasma leptin levels in obese patients with the T allele were not associated with an increase in BMI. The authors concluded that the PPARG gene may affect the relationship between leptin levels and adipose tissue mass.
Wang et al. (1999) studied this polymorphism in 647 Australian Caucasian patients aged 65 years or less, with or without angiographically documented coronary artery disease. The frequencies of the CC, CT, and TT genotypes were 69.8%, 27.7%, and 2.5%, respectively, and the T allele frequency was 0.163. These frequencies were in Hardy-Weinberg equilibrium and not different between men and women. Wang et al. (1999) found that the T allele carriers (CT and TT genotypes) had significantly reduced coronary artery disease risk compared to the CC homozygotes, with an odds ratio of 0.457. Association with obesity (601665) was not found in these patients. The authors interpreted this to indicate that the PPARG gene may have a significant role in atherogenesis, independent of obesity and of lipid abnormalities, possibly via a direct local vascular wall effect.
Ogawa et al. (1999) examined 404 healthy unrelated postmenopausal Japanese women to determine the effect of the silent 161C-T polymorphism on bone mineral density. Within this population, there were 291 C/C homozygotes, 106 C/T heterozygotes, and 7 T/T homozygotes. Ogawa et al. (1999) found that women with at least 1 T allele had a significant reduction in total body bone mineral density compared with those homozygous for the C allele (p less than 0.05). There was no significant difference in the density of lumbar regions 2 to 4 between the groups.
Song et al. (2003) studied the association of the PPARG 161C-T genotype in IgA nephropathy (IgAN; 161950). They analyzed the association of the polymorphism with renal prognosis in IgAN patients using the Kaplan-Meier method and Cox proportional hazard regression model. The PPARG polymorphism was not associated with renal survival rate. However, when patients were stratified into those either with or without hypertension at the time of diagnosis, the renal survival of the CT/TT genotypes was significantly better in those without hypertension than those with the CC genotype. Thus, Song et al. (2003) concluded that the PPARG 161C-T polymorphism is associated with the survival of IgAN patients without hypertension, and that the T allele of the polymorphism may have a protective effect on the progression of IgAN.
Masud and Ye (2003) examined the 2 common polymorphisms in the PPARG gene, P12A (601487.0002) and C161T, in a cohort of 1,170 white British patients with coronary artery disease; they found that P12A, but not C161T, was associated with BMI.
Orio et al. (2003) studied the P12A and C161T polymorphisms of the PPARG gene in 100 patients with polycystic ovary syndrome (PCOS; 184700) and healthy controls matched for age and BMI. The T allele frequency of the C161T polymorphism was significantly higher (P less than 0.05) in PCOS patients compared with control women. In addition, BMI and leptin (164160) levels were significantly higher (P less than 0.05) in PCOS patients carrying the C-to-T substitution than in controls. The P12A polymorphism was unrelated to BMI and/or leptin levels in PCOS women. The authors concluded that the higher frequency of the C-to-T substitution in exon 6 of the PPARG gene in PCOS women suggests that it plays a role in the complex pathogenetic mechanism of obesity in PCOS.
This variant, formerly titled GLIOMA SUSCEPTIBILITY 1 (137800), has been reclassified as a polymorphism. As of December 2012, the his449-to-his (H449H) variant (C-to-T transition) (rs3856806) had an overall population frequency of 12.85% (Exome Variant Server, 2012). In addition, Zhou et al. (2000) did not find an association between disease and this variant in a German population.
In American patients with sporadic glioblastoma multiforme, Zhou et al. (2000) found overrepresentation of a germline 1347C-T polymorphism in exon 6 of the PPARG gene that resulted in a silent his449-to-his (H449H) change. Among 26 Americans with glioblastoma, 13 (50%) were found to carry the H449H polymorphism in heterozygosity, compared to 10 of 80 (12%) normal controls (P less than 0.001). Among a second set of 25 Americans with glioblastoma, there were 8 variant alleles at codon 449 and 42 wildtype, versus 10 variant and 150 wildtype among controls (P = 0.03). There were no significant differences in allele or genotype frequencies between 44 German glioblastoma cases and 60 German controls.
In a 'Europid family' in which 5 members in 2 generations had severe insulin resistance and type 2 diabetes (125853), Savage et al. (2002) found double heterozygosity for frameshift mutations in the PPARG gene and the PPP1RG3A gene (600917.0003). In the PPARG gene, there was a 3-bp deletion (AAA) and a 1-bp insertion (T) at nucleotide 553, resulting in a premature stop codon. The grandparents had typical late-onset type 2 diabetes with no clinical features of severe insulin resistance. Three of their 6 children and 2 of their grandchildren had acanthosis nigricans and elevated fasting plasma insulin levels. Hypertension was also a feature. The PPARG mutation was present in the grandfather, in all 5 relatives with severe insulin resistance, and in 1 other relative with normal insulin levels. The PPP1R3A mutation was present in the grandmother, in all 5 individuals with severe insulin resistance, and in 1 other relative. Thus, all 5 family members with severe insulin resistance, and no other family members, were double heterozygotes with respect to frameshift mutations. (Although the article by Savage et al. (2002) originally stated that the affected individuals were compound heterozygotes, they were actually double heterozygotes. Compound heterozygosity is heterozygosity at the same locus for each of 2 different mutant alleles; double heterozygosity is heterozygosity at each of 2 separate loci. The use of an incorrect term in the original publication was the result of a 'copy-editing error that was implemented after the authors returned corrected proofs' (Savage et al., 2002).)
In a 3-generation Canadian kindred in which 4 members had autosomal dominant familial partial lipodystrophy (604367) and a normal LMNA (150330) gene sequence, Hegele et al. (2002) identified a mutation in the PPARG gene. All 4 affected members were heterozygous for a 1164T-A transversion in exon 5, predicting a phe388-to-leu (F388L) substitution. The mutation was not found in normal family members or normal unrelated subjects. The mutation altered a highly conserved residue within helix 8 of the predicted ligand-binding pocket of PPAR-gamma. The mutant receptor had significantly decreased basal transcriptional activity and impaired stimulation by a synthetic ligand.
In a woman with familial partial lipodystrophy (604367), Agarwal and Garg (2002) identified a heterozygous 1273C-T mutation in exon 6 of the PPARG gene, resulting in an arg425-to-cys (R425C) substitution. None of the 4 unaffected family members had the mutation.
In 3 affected members of a family segregating partial lipodystrophy (604367), Ludtke et al. (2007) identified heterozygosity for a 568T-A transversion in the PPARG gene, resulting in a cys190-to-ser (C190S) substitution. The mutation is located within zinc finger-2 of the DNA-binding domain and has a significantly lower ability to activate a reporter gene than wildtype PPAR-gamma, in the absence or presence of rosiglitazone. A dominant-negative effect was not observed. The mutation was not found in an unaffected family member or in 124 control subjects.
In a 31-year-old woman with familial partial lipodystrophy (604367), i.e., lipodystrophy and early childhood diabetes with extreme insulin resistance and hypertriglyceridemia leading to recurrent pancreatitis, Monajemi et al. (2007) identified heterozygosity for a 1762 C-to-T transition in the PPARG gene, resulting in an arg194-to-trp (R194W) substitution in the PPAR-gamma isoform-2, a conserved residue located in the zinc finger structure involved in DNA binding. The mutation was not found in 100 healthy Caucasians. In vitro analysis of the mutated protein showed that R194W (R166W in the PPAR-gamma isoform-1) could not bind to DNA and had no transcriptional activity. Furthermore, R194W had no dominant-negative activity. Monajemi et al. (2007) concluded that the R194W mutation disrupts DNA-binding activity and through haploinsufficiency leads to the clinical manifestations of FPLD3 and the associated metabolic disturbances.
Agarwal, A. K., Garg, A. A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J. Clin. Endocr. Metab. 87: 408-411, 2002. [PubMed: 11788685] [Full Text: https://doi.org/10.1210/jcem.87.1.8290]
Akiyama, T. E., Sakai, S., Lambert, G., Nicol, C. J., Matsusue, K., Pimprale, S., Lee, Y.-H., Ricote, M., Glass, C. K., Brewer, H. B., Jr., Gonzalez, F. J. Conditional disruption of the peroxisome proliferator-activated receptor gamma gene in mice results in lowered expression of ABCA1, ABCG1, and apoE in macrophages and reduced cholesterol efflux. Molec. Cell. Biol. 22: 2607-2619, 2002. [PubMed: 11909955] [Full Text: https://doi.org/10.1128/MCB.22.8.2607-2619.2002]
Akune, T., Ohba, S., Kamekura, S., Yamaguchi, M., Chung, U., Kubota, N., Terauchi, Y., Harada, Y., Azuma, Y., Nakamura, K., Kadowaki, T., Kawaguchi, H. PPAR-gamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J. Clin. Invest. 113: 846-855, 2004. [PubMed: 15067317] [Full Text: https://doi.org/10.1172/JCI19900]
Aljada, A., Ghanim, H., Friedman, J., Garg, R., Mohanty, P., Dandona, P. Troglitazone reduces the expression of PPAR-gamma while stimulating that of PPAR-alpha in mononuclear cells in obese subjects. J. Clin. Endocr. Metab. 86: 3130-3133, 2001. [PubMed: 11443177] [Full Text: https://doi.org/10.1210/jcem.86.7.7624]
Almeida, P. E., Silva, A. R., Maya-Monteiro, C. M., Torocsik, D., D'Avila, H., Dezso, B., Magalhaes, K. G., Castro-Faria-Neto, H. C., Nagy, L., Bozza, P. T. Mycobacterium bovis bacillus Calmette-Guerin infection induces TLR2-dependent peroxisome proliferator-activated receptor gamma expression and activation: functions in inflammation, lipid metabolism, and pathogenesis. J. Immun. 183: 1337-1345, 2009. [PubMed: 19561094] [Full Text: https://doi.org/10.4049/jimmunol.0900365]
Altshuler, D., Hirschhorn, J. N., Klannemark, M., Lindgren, C. M., Vohl, M.-C., Nemesh, J., Lane, C. R., Schaffner, S. F., Bolk, S., Brewer, C., Tuomi, T., Gaudet, D., Hudson, T. J., Daly, M., Groop, L., Lander, E. S. The common PPAR-gamma pro12ala polymorphism is associated with decreased risk of type 2 diabetes. Nature Genet. 26: 76-80, 2000. [PubMed: 10973253] [Full Text: https://doi.org/10.1038/79216]
Ameshima, S., Golpon, H., Cool, C. D., Chan, D., Vandivier, R. W., Gardai, S. J., Wick, M., Nemenoff, R. A., Geraci, M. W., Voelkel, N. F. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ. Res. 92: 1162-1169, 2003. [PubMed: 12714563] [Full Text: https://doi.org/10.1161/01.RES.0000073585.50092.14]
Aprile, M., Cataldi, S., Ambrosio, M. R., D'Esposito, V., Lim, K., Dietrich, A., Bluher, M., Bousfield Savage, D., Formisano, P., Ciccodicola, A., Costa, V. PPAR-gamma-delta-5, a naturally occurring dominant-negative splice isoform, impairs PPAR-gamma function and adipocyte differentiation. Cell Rep. 25: 1577-1592, 2018. [PubMed: 30404011] [Full Text: https://doi.org/10.1016/j.celrep.2018.10.035]
Ardlie, K. G., Lunetta, K. L., Seielstad, M. Testing for population subdivision and association in four case-control studies. Am. J. Hum. Genet. 71: 304-311, 2002. [PubMed: 12096349] [Full Text: https://doi.org/10.1086/341719]
Are, A., Aronsson, L., Wang, S., Greicius, G., Lee, Y. K., Gustafsson, J.-A., Pettersson, S., Arulampalam, V. Enterococcus faecalis from newborn babies regulate endogenous PPAR-gamma activity and IL-10 levels in colonic epithelial cells. Proc. Nat. Acad. Sci. 105: 1943-1948, 2008. [PubMed: 18234854] [Full Text: https://doi.org/10.1073/pnas.0711734105]
Banks, A. S., McAllister, F. E., Camporez, J. P. G., Zushin, P.-J. H., Jurczak, M. J., Laznik-Bogoslavski, D., Shulman, G. I., Gygi, S. P., Spiegelman, B. M. An ERK/Cdk5 axis controls the diabetogenic actions of PPAR-gamma. Nature 517: 391-395, 2015. [PubMed: 25409143] [Full Text: https://doi.org/10.1038/nature13887]
Barak, Y., Nelson, M. C., Ong, E. S., Jones, Y. Z., Ruiz-Lozano, P., Chien, K. R., Koder, A., Evans, R. M. PPAR-gamma is required for placental, cardiac, and adipose tissue development. Molec. Cell 4: 585-595, 1999. [PubMed: 10549290] [Full Text: https://doi.org/10.1016/s1097-2765(00)80209-9]
Barroso, I., Gurnell, M., Crowley, V. E. F., Agostini, M., Schwabel, J. W., Soos, M. A., Masien, G. L., Williams, T. D. M., Lewis, H., Schafer, A. J., Chatterjee, V. K. K., O'Rahilly, S. Dominant negative mutations in human PPAR-gamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402: 880-883, 1999. [PubMed: 10622252] [Full Text: https://doi.org/10.1038/47254]
Beamer, B. A., Negri, C., Yen, C.-J., Gavrilova, O., Rumberger, J. M., Durcan, M. J., Yarnall, D. P., Hawkins, A. L., Griffin, C. A., Burns, D. K., Roth, J., Reitman, M., Shuldiner, A. R. Chromosomal localization and partial genomic structure of the human peroxisome proliferator activated receptor-gamma (hPPAR-gamma) gene. Biochem. Biophys. Res. Commun. 233: 756-759, 1997. [PubMed: 9168928] [Full Text: https://doi.org/10.1006/bbrc.1997.6540]
Beamer, B. A., Yen, C.-J., Andersen, R. E., Muller, D., Elahi, D., Cheskin, L. J., Andres, R., Roth, J., Shuldiner, A. R. Association of the pro12ala variant in the peroxisome proliferator-activated receptor-gamma-2 gene with obesity in two Caucasian populations. Diabetes 47: 1806-1808, 1998. [PubMed: 9792554] [Full Text: https://doi.org/10.2337/diabetes.47.11.1806]
Bruemmer, D., Yin, F., Liu, J., Berger, J. P., Sakai, T., Blaschke, F., Fleck, E., Van Herle, A. J., Forman, B. M., Law, R. E. Regulation of the growth arrest and DNA damage-inducible gene 45 (GADD45) by peroxisome proliferator-activated receptor gamma in vascular smooth muscle cells. Circ. Res. 93: e38-e47, 2003. [PubMed: 12881480] [Full Text: https://doi.org/10.1161/01.RES.0000088344.15288.E6]
Bulotta, A., Ludovico, O., Coco, A., Di Paola, R., Quattrone, A., Carella, M., Pellegrini, F., Prudente, S., Trischitta, V. The common -866G/A polymorphism in the promoter region of the UCP-2 gene is associated with reduced risk of type 2 diabetes in Caucasians from Italy. J. Clin. Endocr. Metab. 90: 1176-1180, 2005. [PubMed: 15562023] [Full Text: https://doi.org/10.1210/jc.2004-1072]
Buzzetti, R., Petrone, A., Ribaudo, M. C., Alemanno, I., Zavarella, S., Mein, C. A., Maiani, F., Tiberti, C., Baroni, M. G., Vecci, E., Arca, M., Leonetti, F., Di Mario, U. The common PPAR-gamma-2 pro12-to-ala variant is associated with greater insulin sensitivity. Europ. J. Hum. Genet. 12: 1050-1054, 2004. [PubMed: 15367918] [Full Text: https://doi.org/10.1038/sj.ejhg.5201283]
Byndloss, M. X., Olsan, E. E., Rivera-Chavez, F., Tiffany, C. R., Cevallos, S. A., Lokken, K. L., Torres, T. P., Byndloss, A. J., Faber, F., Gao, Y., Litvak, Y., Lopez, C. A., Xu, G., Napoli, E., Giulivi, C., Tsolis, R. M., Revzin, A., Lebrilla, C. B., Baumler, A. J. Microbiota-activated PPAR-gamma signaling inhibits dysbiotic Enterobacteriaceae expansion. Science 357: 570-575, 2017. [PubMed: 28798125] [Full Text: https://doi.org/10.1126/science.aam9949]
Chandra, V., Huang, P., Hamuro, Y., Raghuram, S., Wang, Y., Burris, T. P., Rastinejad, F. Structure of the intact PPAR-gamma-RXR-alpha nuclear receptor complex on DNA. Nature 456: 350-356, 2008. [PubMed: 19043829] [Full Text: https://doi.org/10.1038/nature07413]
Chawla, A., Boisvert, W. A., Lee, C.-H., Laffitte, B. A., Barak, Y., Joseph, S. B., Liao, D., Nagy, L., Edwards, P. A., Curtiss, L. K., Evans, R. M., Tontonoz, P. A PPAR-gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Molec. Cell 7: 161-171, 2001. [PubMed: 11172721] [Full Text: https://doi.org/10.1016/s1097-2765(01)00164-2]
Chiang, M.-C., Chen, C.-M., Lee, M.-R., Chen, H.-W., Chen, H.-M., Wu, Y.-S., Hung, C.-H., Kang, J.-J., Chang, C.-P., Chang, C., Wu, Y.-R., Tsai, Y.-S., Chern, Y. Modulation of energy deficiency in Huntington's disease via activation of the peroxisome proliferator-activated receptor gamma. Hum. Molec. Genet. 19: 4043-4058, 2010. [PubMed: 20668093] [Full Text: https://doi.org/10.1093/hmg/ddq322]
Choi, J. H., Banks, A. S., Estall, J. L., Kajimura, S., Bostrom, P., Laznik, D., Ruas, J. L., Chalmers, M. J., Kamenecka, T. M., Bluher, M., Griffin, P. R., Spiegelman, B. M. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPAR-gamma by Cdk5. Nature 466: 451-456, 2010. [PubMed: 20651683] [Full Text: https://doi.org/10.1038/nature09291]
Choi, J. H., Banks, A. S., Kamenecka, T. M., Busby, S. A., Chalmers, M. J., Kumar, N., Kuruvilla, D. S., Shin, Y., He, Y., Bruning, J. B., Marciano, D. P., Cameron, M. D., Laznik, D., Jurczak, M. J., Schurer, S. C., Vidovic, D., Shulman, G. I., Spiegelman, B. M., Griffin, P. R. Antidiabetic actions of a non-agonist PPAR-gamma ligand blocking Cdk5-mediated phosphorylation. Nature 477: 477-481, 2011. [PubMed: 21892191] [Full Text: https://doi.org/10.1038/nature10383]
Cipolletta, D., Feuerer, M., Li, A., Kamei, N., Lee, J., Shoelson, S. E., Benoist, C., Mathis, D. PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue T(reg) cells. Nature 486: 549-553, 2012. [PubMed: 22722857] [Full Text: https://doi.org/10.1038/nature11132]
Cui, Y., Miyoshi, K., Claudio, E., Siebenlist, U. K., Gonzalez, F. J., Flaws, J., Wagner, K.-U., Henninghausen, L. Loss of the peroxisome proliferation-activated receptor gamma (PPAR-gamma) does not affect mammary development and propensity for tumor formation but leads to reduced fertility. J. Biol. Chem. 277: 17830-17835, 2002. [PubMed: 11884400] [Full Text: https://doi.org/10.1074/jbc.M200186200]
Deeb, S. S., Fajas, L., Nemoto, M., Pihlajamaki, J., Mykkanen, L., Kuusisto, J., Laakso, M., Fujimoto, W., Auwerx, J. A pro12ala substitution in PPAR-gamma-2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nature Genet. 20: 284-287, 1998. [PubMed: 9806549] [Full Text: https://doi.org/10.1038/3099]
Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316: 1331-1336, 2007. [PubMed: 17463246] [Full Text: https://doi.org/10.1126/science.1142358]
Dutchak, P. A., Katafuchi, T., Bookout, A. L., Choi, J. H., Yu, R. T., Mangelsdorf, D. J., Kliewer, S. A. Fibroblast growth factor-21 regulates PPAR-gamma activity and the antidiabetic actions of thiazolidinediones. Cell 148: 556-567, 2012. [PubMed: 22304921] [Full Text: https://doi.org/10.1016/j.cell.2011.11.062]
Dwight, T., Thoppe, S. R., Foukakis, T., Lui, W. O., Wallin, G., Hoog, A., Frisk, T., Larsson, C., Zedenius, J. Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rearrangement in follicular thyroid tumors. J. Clin. Endocr. Metab. 88: 4440-4445, 2003. [PubMed: 12970322] [Full Text: https://doi.org/10.1210/jc.2002-021690]
Elbrecht, A., Chen, Y., Cullinan, C. A., Hayes, N., Leibowitz, M. D., Moller, D. E., Berger, J. Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors gamma-1 and gamma-2. Biochem. Biophys. Res. Commun. 224: 431-437, 1996. [PubMed: 8702406] [Full Text: https://doi.org/10.1006/bbrc.1996.1044]
Eriksson, J., Lindi, V., Uusitupa, M., Forsen, T., Laakso, M., Osmond, C., Barker, D. The effects of the pro12ala polymorphism of the PPAR-gamma-2 gene on lipid metabolism interact with body size at birth. Clin. Genet. 64: 366-370, 2003. [PubMed: 12974743] [Full Text: https://doi.org/10.1034/j.1399-0004.2003.00150.x]
Evans, R. M., Barish, G. D., Wang, Y. X. PPARs and the complex journey to obesity. Nature Med. 10: 355-361, 2004. [PubMed: 15057233] [Full Text: https://doi.org/10.1038/nm1025]
Exome Variant Server. NHLBI GO Exome Sequencing Project (ESP), Seattle, WA. http://evs.gs.washington.edu/EVS/ , 12/2012.
Fajas, L., Auboeuf, D., Raspe, E., Schoonjans, K., Lefebvre, A. M., Saladin, R., Najib, J., Laville, M., Fruchart, J.-C., Deeb, S., Vidal-Puig, A., Flier, J., Briggs, M. R., Staels, B., Vidal, H., Auwerx, J. The organization, promoter analysis, and expression of the human PPAR-gamma gene. J. Biol. Chem. 272: 18779-18789, 1997. [PubMed: 9228052] [Full Text: https://doi.org/10.1074/jbc.272.30.18779]
Fajas, L., Egler, V., Reiter, R., Hansen, J., Kristiansen, K., Debril, M.-B., Miard, S., Auwerx, J. The retinoblastoma-histone deacetylase 3 complex inhibits PPAR-gamma and adipocyte differentiation. Dev. Cell 3: 903-910, 2002. [PubMed: 12479814] [Full Text: https://doi.org/10.1016/s1534-5807(02)00360-x]
Fajas, L., Fruchart, J.-C., Auwerx, J. PPAR-gamma-3 mRNA: a distinct PPAR-gamma mRNA subtype transcribed from an independent promoter. FEBS Lett. 438: 55-60, 1998. [PubMed: 9821958] [Full Text: https://doi.org/10.1016/s0014-5793(98)01273-3]
Fajas, L., Landsberg, R. L., Huss-Garcia, Y., Sardet, C., Lees, J. A., Auwerx, J. E2Fs regulate adipocyte differentiation. Dev. Cell 3: 39-49, 2002. [PubMed: 12110166] [Full Text: https://doi.org/10.1016/s1534-5807(02)00190-9]
Fan, L., Li, H., Wang, W. Long non-coding RNA PRRT3-AS1 silencing inhibits prostate cancer cell proliferation and promotes apoptosis and autophagy. Exp. Physiol. 105: 793-808, 2020. [PubMed: 32086850] [Full Text: https://doi.org/10.1113/EP088011]
Florez, J. C., Jablonski, K. A., Sun, M. W., Bayley, N., Kahn, S. E., Shamoon, H., Hamman, R. F., Knowler, W. C., Nathan, D. N., Altshuler, D. Effects of the type 2 diabetes-associated PPARG P12A polymorphism on progression to diabetes and response to troglitazone. J. Clin. Endocr. Metab. 92: 1502-1509, 2007. [PubMed: 17213274] [Full Text: https://doi.org/10.1210/jc.2006-2275]
Frederiksen, L., Brodbaek, K., Fenger, M., Jorgensen, T., Borch-Johnsen, K., Madsbad, S., Urhammer, S. A. Studies of the pro12-to-ala polymorphism of the PPAR-gamma gene in the Danish MONICA cohort: homozygosity of the ala allele confers a decreased risk of the insulin resistance syndrome. J. Clin. Endocr. Metab. 87: 3989-3992, 2002. [PubMed: 12161548] [Full Text: https://doi.org/10.1210/jcem.87.8.8732]
Gampe, R. T., Jr., Montana, V. G., Lambert, M. H., Miller, A. B., Bledsoe, R. K., Milburn, M. V., Kliewer, S. A., Willson, T. M., Xu, H. E. Asymmetry in the PPAR-gamma/RXR-alpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Molec. Cell 5: 545-555, 2000. [PubMed: 10882139] [Full Text: https://doi.org/10.1016/s1097-2765(00)80448-7]
Ge, K., Guermah, M., Yuan, C.-X., Ito, M., Wallberg, A. E., Spiegelman, B. M., Roeder, R. G. Transcription coactivator TRAP220 is required for PPAR-gamma-2-stimulated adipogenesis. Nature 417: 563-567, 2002. [PubMed: 12037571] [Full Text: https://doi.org/10.1038/417563a]
Girnun, G. D., Smith, W. M., Drori, S., Sarraf, P., Mueller, E., Eng, C., Nambiar, P., Rosenberg, D. W., Bronson, R. T., Edelmann, W., Kucherlapati, R., Gonzalez, F. J., Spiegelman, B. M. APC-dependent suppression of colon carcinogenesis by PPAR-gamma. Proc. Nat. Acad. Sci. 99: 13771-13776, 2002. [PubMed: 12370429] [Full Text: https://doi.org/10.1073/pnas.162480299]
Greene, M. E., Blumberg, B., McBride, O. W., Yi, H. F., Kronquist, K., Kwan, K., Hsieh, L., Greene, G., Nimer, S. D. Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Expr. 4: 281-299, 1995. [PubMed: 7787419]
Guan, Y., Hao, C., Cha, D. R., Rao, R., Lu, W., Kohan, D. E., Magnuson, M. A., Redha, R., Zhang, Y., Breyer, M. D. Thiazolidinediones expand body fluid volume through PPAR-gamma stimulation of ENaC-mediated renal salt absorption. Nature Med. 11: 861-866, 2005. [PubMed: 16007095] [Full Text: https://doi.org/10.1038/nm1278]
Gupta, R. K., Arany, Z., Seale, P., Mepani, R. J., Ye, L., Conroe, H. M., Roby, Y. A., Kulaga, H., Reed, R. R., Spiegelman, B. M. Transcriptional control of preadipocyte determination by Zfp423. Nature 464: 619-623, 2010. [PubMed: 20200519] [Full Text: https://doi.org/10.1038/nature08816]
Hansen, L., Ekstrom, C. T., Palacios, R. T., Anant, M., Wassermann, K., Reinhardt, R. R. The pro12-to-ala variant of the PPARG gene is a risk factor for peroxisome proliferator-activated receptor-gamma/alpha agonist-induced edema in type 2 diabetic patients. J. Clin. Endocr. Metab. 91: 3446-3450, 2006. [PubMed: 16822823] [Full Text: https://doi.org/10.1210/jc.2006-0590]
Hansen, S. K., Nielsen, E.-M. D., Ek, J., Andersen, G., Glumer, C., Carstensen, B., Mouritzen, P., Drivsholm, T., Borch-Johnsen, K., Jorgensen, T., Hansen, T., Pedersen, O. Analysis of separate and combined effects of common variation in KCNJ11 and PPARG on risk of type 2 diabetes. J. Clin. Endocr. Metab. 90: 3629-3637, 2005. [PubMed: 15797964] [Full Text: https://doi.org/10.1210/jc.2004-1942]
Hara, M., Alcoser, S. Y., Qaadir, A., Beiswenger, K. K., Cox, N. J., Ehrmann, D. A. Insulin resistance is attenuated in women with polycystic ovary syndrome with the Pro12Ala polymorphism in the PPAR-gamma gene. J. Clin. Endocr. Metab. 87: 772-775, 2002. [PubMed: 11836319] [Full Text: https://doi.org/10.1210/jcem.87.2.8255]
Harris, S. G., Phipps, R. P. Prostaglandin D2, its metabolite 15-d-PGJ2, and peroxisome proliferator activated receptor-gamma agonists induce apoptosis in transformed, but not normal, human T lineage cells. Immunology 105: 23-34, 2002. [PubMed: 11849312] [Full Text: https://doi.org/10.1046/j.0019-2805.2001.01340.x]
Hasstedt, S. J., Ren, Q.-F., Teng, K., Elbein, S. C. Effect of the peroxisome proliferator-activated receptor-gamma-2 Pro12Ala variant on obesity, glucose homeostasis, and blood pressure in members of familial type 2 diabetic kindreds. J. Clin. Endocr. Metab. 86: 536-541, 2001. [PubMed: 11158005] [Full Text: https://doi.org/10.1210/jcem.86.2.7205]
He, W., Barak, Y., Hevener, A., Olson, P., Liao, D., Le, J., Nelson, M., Ong, E., Olefsky, J. M., Evans, R. M. Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. Proc. Nat. Acad. Sci. 100: 15712-15717, 2003. [PubMed: 14660788] [Full Text: https://doi.org/10.1073/pnas.2536828100]
Heaney, A. P., Fernando, M., Yong, W. H., Melmed, S. Functional PPAR-gamma receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas. Nature Med. 8: 1281-1287, 2002. [PubMed: 12379847] [Full Text: https://doi.org/10.1038/nm784]
Hegele, R. A., Cao, H., Frankowski, C., Mathews, S. T., Leff, T. PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. Diabetes 51: 3586-3590, 2002. [PubMed: 12453919] [Full Text: https://doi.org/10.2337/diabetes.51.12.3586]
Hegele, R. A., Cao, H., Harris, S. B., Zinman, B., Hanley, A. J. G., Anderson, C. M. Peroxisome proliferator-activated receptor-gamma2 P12A and type 2 diabetes in Canadian Oji-Cree. J. Clin. Endocr. Metab. 85: 2014-2019, 2000. [PubMed: 10843190] [Full Text: https://doi.org/10.1210/jcem.85.5.6610]
Hegele, R. A., Leff, T. Unbuckling lipodystrophy from insulin resistance and hypertension. (Commentary) J. Clin. Invest. 114: 163-165, 2004. [PubMed: 15254581] [Full Text: https://doi.org/10.1172/JCI22382]
Herzig, S., Hedrick, S., Morantte, I., Koo, S.-H., Galimi, F., Montminy, M. CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-gamma. Nature 426: 190-193, 2003. [PubMed: 14614508] [Full Text: https://doi.org/10.1038/nature02110]
Hevener, A. L., He, W., Barak, Y., Le, J., Bandyopadhyay, G., Olson, P., Wilkes, J., Evans, R. M., Olefsky, J. Muscle-specific Pparg deletion causes insulin resistance. Nature Med. 9: 1491-1497, 2003. [PubMed: 14625542] [Full Text: https://doi.org/10.1038/nm956]
Jonker, J. W., Suh, J. M., Atkins, A. R., Ahmadian, M., Li, P., Whyte, J., He, M., Juguilon, H., Yin, Y.-Q., Phillips, C. T., Yu, R. T., Olefsky, J. M., Henry, R. R., Downes, M., Evans, R. M. A PPAR-gamma-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis. Nature 485: 391-394, 2012. [PubMed: 22522926] [Full Text: https://doi.org/10.1038/nature10998]
Kelly, D., Campbell, J. I., King, T. P., Grant, G., Jansson, E. A., Coutts, A. G. P., Pettersson, S., Conway, S. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA. Nature Immun. 5: 104-112, 2004. [PubMed: 14691478] [Full Text: https://doi.org/10.1038/ni1018]
Kersten, S., Desvergne, B., Wahli, W. Roles of PPARs in health and disease. Nature 405: 421-424, 2000. [PubMed: 10839530] [Full Text: https://doi.org/10.1038/35013000]
Kim, K. S., Choi, S. M., Shin, S. U., Yang, H. S., Yoon, Y. Effects of peroxisome proliferator-activated receptor-gamma-2 pro12ala polymorphism on body fat distribution in female Korean subjects. Metabolism 53: 1538-1543, 2004. [PubMed: 15562396] [Full Text: https://doi.org/10.1016/j.metabol.2004.06.019]
Kolehmainen, M., Uusitupa, M. I. J., Alhava, E., Laakso, M., Vidal, H. Effect of the pro12ala polymorphism in the peroxisome proliferator-activated receptor (PPAR) gamma-2 gene on the expression of PPAR-gamma target genes in adipose tissue of massively obese subjects. J. Clin. Endocr. Metab. 88: 1717-1722, 2003. [PubMed: 12679463] [Full Text: https://doi.org/10.1210/jc.2002-020603]
Kroll, T. G., Sarraf, P., Pecciarini, L., Chen, C.-J., Mueller, E., Splegelman, B. M., Fletcher, J. A. PAX8-PPAR-gamma-1 fusion oncogene in human thyroid carcinoma. Science 289: 1357-1360, 2000. Note: Erratum: Science 1474, 2000. [PubMed: 10958784] [Full Text: https://doi.org/10.1126/science.289.5483.1357]
Kubota, N., Terauchi, Y., Miki, H., Tamemoto, H., Yamauchi, T., Komeda, K., Satoh, S., Nakano, R., Ishii, C., Sugiyama, T., Eto, K., Tsubamoto, Y., and 17 others. PPAR-gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Molec. Cell 4: 597-609, 1999. [PubMed: 10549291] [Full Text: https://doi.org/10.1016/s1097-2765(00)80210-5]
Lapsys, N. M., Kriketos, A. D., Lim-Fraser, M., Poynten, A. M., Lowy, A., Furler, S. M., Chisholm, D. J., Cooney, G. J. Expression of genes involved in lipid metabolism correlate with peroxisome proliferator-activated receptor gamma expression in human skeletal muscle. J. Clin. Endocr. Metab. 85: 4293-4297, 2000. [PubMed: 11095470] [Full Text: https://doi.org/10.1210/jcem.85.11.6973]
Lefebvre, B., Benomar, Y., Guedin, A., Langlois, A., Hennuyer, N., Dumont, J., Bouchaert, E., Dacquet, C., Penicaud, L., Casteilla, L., Pattou, F., Ktorza, A., Staels, B., Lefebvre, P. Proteasomal degradation of retinoid X receptor alpha reprograms transcriptional activity of PPAR-gamma in obese mice and humans. J. Clin. Invest. 120: 1454-1468, 2010. [PubMed: 20364085] [Full Text: https://doi.org/10.1172/JCI38606]
Lehmann, J. M., Moore, L. B., Smith-Oliver, T. A., Wilkison, W. O., Willson, T. M., Kliewer, S. A. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J. Biol. Chem. 270: 12953-12956, 1995. [PubMed: 7768881] [Full Text: https://doi.org/10.1074/jbc.270.22.12953]
Lohmueller, K. E., Pearce, C. L., Pike, M., Lander, E. S., Hirschhorn, J. N. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nature Genet. 33: 177-182, 2003. [PubMed: 12524541] [Full Text: https://doi.org/10.1038/ng1071]
Lowell, B. B. PPAR-gamma: an essential regulator of adipogenesis and modulator of fat cell function. Cell 99: 239-242, 1999. [PubMed: 10555139] [Full Text: https://doi.org/10.1016/s0092-8674(00)81654-2]
Lu, M., Sarruf, D. A., Talukdar, S., Sharma, S., Li, P., Bandyopadhyay, G., Nalbandian, S., Fan, W., Gayen, J. R., Mahata, S. K., Webster, N. J., Schwartz, M. W., Olefsky, J. M. Brain PPAR-gamma promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. Nature Med. 17: 618-622, 2011. [PubMed: 21532596] [Full Text: https://doi.org/10.1038/nm.2332]
Ludtke, A., Buettner, J., Wu, W., Muchir, A., Schroeter, A., Zinn-Justin, S., Spuler, S., Schmidt, H. H.-J., Worman, H. J. Peroxisome proliferator-activated receptor-gamma C190S mutation causes partial lipodystrophy. J. Clin. Endocr. Metab. 92: 2248-2255, 2007. [PubMed: 17356052] [Full Text: https://doi.org/10.1210/jc.2005-2624]
Marques, A. R., Espadinha, C., Catarino, A. L., Moniz, S., Pereira, T., Sobrinho, L. G., Leite, V. Expression of PAX8-PPAR-gamma-1 rearrangements in both follicular thyroid carcinomas and adenomas. J. Clin. Endocr. Metab. 87: 3947-3952, 2002. [PubMed: 12161538] [Full Text: https://doi.org/10.1210/jcem.87.8.8756]
Martin, G., Schoonjans, K., Staels, B., Auwerx, J. PPAR-gamma activators improve glucose homeostasis by stimulating fatty acid uptake in the adipocytes. Atherosclerosis 137: S75-S80, 1998. [PubMed: 9694545] [Full Text: https://doi.org/10.1016/s0021-9150(97)00315-8]
Masud, S., Ye, S. Effect of the peroxisome proliferator activated receptor-gamma gene pro12ala variant on body mass index: a meta-analysis. J. Med. Genet. 40: 773-780, 2003. [PubMed: 14569127] [Full Text: https://doi.org/10.1136/jmg.40.10.773]
Meirhaeghe, A., Fajas, L., Helbecque, N., Cottel, D., Lebel, P., Dallongeville, J., Deeb, S., Auwerx, J., Amouyel, P. A genetic polymorphism of the peroxisome proliferator-activated receptor gamma gene influences plasma leptin levels in obese tumors. Hum. Molec. Genet. 7: 435-440, 1998. [PubMed: 9467001] [Full Text: https://doi.org/10.1093/hmg/7.3.435]
Memisoglu, A., Hu, F. B., Hankinson, S. E., Manson, J. E., De Vivo, I., Willett, W. C., Hunter, D. J. Interaction between a peroxisome proliferator-activated receptor gamma gene polymorphism and dietary fat intake in relation to body mass. Hum. Molec. Genet. 12: 2923-2929, 2003. [PubMed: 14506127] [Full Text: https://doi.org/10.1093/hmg/ddg318]
Michalik, L., Desvergne, B., Tan, N. S., Basu-Modak, S., Escher, P., Rieusset, J., Peters, J. M., Kaya, G., Gonzalez, F. J., Zakany, J., Metzger, D., Chambon, P., Duboule, D., Wahli, W. Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-beta mutant mice. J. Cell Biol. 154: 799-814, 2001. [PubMed: 11514592] [Full Text: https://doi.org/10.1083/jcb.200011148]
Miles, P. D. G., Barak, Y., He, W., Evans, R. M., Olefsky, J. M. Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. J. Clin. Invest. 105: 287-292, 2000. [PubMed: 10675354] [Full Text: https://doi.org/10.1172/JCI8538]
Monajemi, H., Zhang, L., Li, G., Jeninga, E. H., Cao, H., Maas, M., Brouwer, C. B., Kalkhoven, E., Stroes, E., Hegele, R. A., Leff, T. Familial partial lipodystrophy phenotype resulting from a single-base mutation in deoxyribonucleic acid-binding domain of peroxisome proliferator-activated receptor-gamma. J. Clin. Endocr. Metab. 92: 1606-1612, 2007. [PubMed: 17299075] [Full Text: https://doi.org/10.1210/jc.2006-1807]
Mueller, E., Sarraf, P., Tontonoz, P., Evans, R. M., Martin, K. J., Zhang, M., Fletcher, C., Singer, S., Spiegelman, B. M. Terminal differentiation of human breast cancer through PPAR-gamma. Molec. Cell. 1: 465-470, 1998. [PubMed: 9660931] [Full Text: https://doi.org/10.1016/s1097-2765(00)80047-7]
Mueller, E., Smith, M., Sarraf, P., Kroll, T., Aiyer, A., Kaufman, D. S., Oh, W., Demetri, G., Figg, W. D., Zhou, X.-P., Eng, C., Spiegelman, B. M., Kantoff, P. W. Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. Proc. Nat. Acad. Sci. 97: 10990-10995, 2000. [PubMed: 10984506] [Full Text: https://doi.org/10.1073/pnas.180329197]
Mukherjee, R., Jow, L., Croston, G. E., Paterniti, J. R., Jr. Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPAR-gamma-2 versus PPAR-gamma-1 and activation with retinoid X receptor agonists and antagonists. J. Biol. Chem. 272: 8071-8076, 1997. [PubMed: 9065481] [Full Text: https://doi.org/10.1074/jbc.272.12.8071]
Nagy, L., Tontonoz, P., Alvarez, J. G. A., Chen, H., Evans, R. M. Oxidized LDL regulates macrophage gene expression through ligand activation of PPAR-gamma. Cell 93: 229-240, 1998. [PubMed: 9568715] [Full Text: https://doi.org/10.1016/s0092-8674(00)81574-3]
Nakamichi, Y., Kikuta, T., Ito, E., Ohara-Imaizumi, M., Nishiwaki, C., Ishida, H., Nagamatsu, S. PPAR-gamma overexpression suppresses glucose-induced proinsulin biosynthesis and insulin release synergistically with pioglitazone in MIN6 cells. Biochem. Biophys. Res. Commun. 306: 832-836, 2003. [PubMed: 12821117] [Full Text: https://doi.org/10.1016/s0006-291x(03)01045-3]
Nikiforova, M. N., Lynch, R. A., Biddinger, P. W., Alexander, E. K., Dorn, G. W., II, Tallini, G., Kroll, T. G., Nikiforov, Y. E. RAS point mutations and PAX8-PPAR-gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J. Clin. Endocr. Metab. 88: 2318-2326, 2003. [PubMed: 12727991] [Full Text: https://doi.org/10.1210/jc.2002-021907]
Odegaard, J. I., Ricardo-Gonzalez, R. R., Goforth, M. H., Morel, C. R., Subramanian, V., Mukundan, L., Eagle, A. R., Vats, D., Brombacher, F., Ferrante, A. W., Chawla, A. Macrophage-specific PPAR-gamma controls alternative activation and improves insulin resistance. Nature 447: 1116-1120, 2007. [PubMed: 17515919] [Full Text: https://doi.org/10.1038/nature05894]
Ogawa, S., Urano, T., Hosoi, T., Miyao, M., Hoshino, S., Fujita, M., Shiraki, M., Orimo, H., Ouchi, Y., Inoue, S. Association of bone mineral density with a polymorphism of the peroxisome proliferator-activated receptor gamma gene: PPAR-gamma expression in osteoblasts. Biochem. Biophys. Res. Commun. 260: 122-126, 1999. [PubMed: 10381354] [Full Text: https://doi.org/10.1006/bbrc.1999.0896]
Oh, E. Y., Min, K. M., Chung, J. H., Min, Y.-K., Lee, M.-S., Kim, K.-W., Lee, M.-K. Significance of pro12ala mutation in peroxisome proliferator-activated receptor-gamma2 in Korean diabetic and obese subjects. J. Clin. Endocr. Metab. 85: 1801-1804, 2000. [PubMed: 10843155] [Full Text: https://doi.org/10.1210/jcem.85.5.6499]
Orio, F., Jr., Matarese, G., Di Biase, S., Palomba, S., Labella, D., Sanna, V., Savastano, S., Zullo, F., Colao, A., Lombardi, G. Exon 6 and 2 peroxisome proliferator-activated receptor-gamma polymorphisms in polycystic ovary syndrome. J. Clin. Endocr. Metab. 88: 5887-5892, 2003. [PubMed: 14671186] [Full Text: https://doi.org/10.1210/jc.2002-021816]
Pascual, G., Fong, A. L., Ogawa, S., Gamliel, A., Li, A. C., Perissi, V., Rose, D. W., Willson, T. M., Rosenfeld, M. G., Glass, C. K. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. (Letter) Nature 437: 759-763, 2005. [PubMed: 16127449] [Full Text: https://doi.org/10.1038/nature03988]
Patsouris, D., Mandard, S., Voshol, P. J., Escher, P., Tan, N. S., Havekes, L. M., Koenig, W., Marz, W., Tafuri, S., Wahli, W., Muller, M., Kersten, S. PPAR-alpha governs glycerol metabolism. J. Clin. Invest. 114: 94-103, 2004. [PubMed: 15232616] [Full Text: https://doi.org/10.1172/JCI20468]
Pawliczak, R., Han, C., Huang, X.-L., Demetris, A. J., Shelhamer, J. H., Wu, T. 85-kDa cytosolic phospholipase A-2 mediates peroxisome proliferator-activated receptor gamma activation in human lung epithelial cells. J. Biol. Chem. 277: 33153-33163, 2002. [PubMed: 12077117] [Full Text: https://doi.org/10.1074/jbc.M200246200]
Picard, F., Kurtev, M., Chung, N,, Topark-Ngarm, A., Senawong, T., Machado de Oliveira, R., Leid, M., McBurney, M. W., Guarente, L. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429: 771-776, 2004. Note: Erratum: Nature 430: 921 only, 2004. [PubMed: 15175761] [Full Text: https://doi.org/10.1038/nature02583]
Pritchard, J. K., Rosenberg, N. A. Use of unlinked genetic markers to detect population stratification in association studies. Am. J. Hum. Genet. 65: 220-228, 1999. [PubMed: 10364535] [Full Text: https://doi.org/10.1086/302449]
Qi, C., Surapureddi, S., Zhu, Y.-J., Yu, S., Kashireddy, P., Rao, M. S., Reddy, J. K. Transcriptional coactivator PRIP, the peroxisome proliferator-activated receptor gamma (PPAR-gamma)-interacting protein, is required for PPAR-gamma-mediated adipogenesis. J. Biol. Chem. 278: 25281-25284, 2003. [PubMed: 12754253] [Full Text: https://doi.org/10.1074/jbc.C300175200]
Ren, D., Collingwood, T. N., Rebar, E. J., Wolffe, A. P., Camp, H. S. PPAR-gamma knockdown by engineered transcription factors: exogenous PPAR-gamma-2 but not PPAR-gamma-1 reactivates adipogenesis. Genes Dev. 16: 27-32, 2002. [PubMed: 11782442] [Full Text: https://doi.org/10.1101/gad.953802]
Ricote, M., Huang, J., Fajas, L., Li, A., Welch, J., Najib, J., Witztum, J. L., Auwerx, J., Palinski, W., Glass, C. K. Expression of the peroxisome proliferator-activated receptor gamma (PPAR-gamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc. Nat. Acad. Sci. 95: 7614-7619, 1998. [PubMed: 9636198] [Full Text: https://doi.org/10.1073/pnas.95.13.7614]
Ringel, J., Engeli, S., Distler, A., Sharma, A. M. Pro12-to-ala missense mutation of the peroxisome proliferator activated receptor gamma and diabetes mellitus. Biochem. Biophys. Res. Commun. 254: 450-453, 1999. [PubMed: 9918859] [Full Text: https://doi.org/10.1006/bbrc.1998.9962]
Ristow, M., Muller-Wieland, D., Pfeiffer, A., Krone, W., Kahn, C. R. Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. New Eng. J. Med. 339: 953-959, 1998. [PubMed: 9753710] [Full Text: https://doi.org/10.1056/NEJM199810013391403]
Rocchi, S., Picard, F., Vamecq, J., Gelman, L., Potier, N., Zeyer, D., Dubuquoy, L., Bac, P., Champy, M.-F., Plunket, K. D., Leesnitzer, L. M., Blanchard, S. G., Desreumaux, P., Moras, D., Renaud, J.-P., Auwerx, J. A unique PPAR-gamma ligand with potent insulin-sensitizing yet weak adipogenic activity. Molec. Cell 8: 737-747, 2001. [PubMed: 11684010] [Full Text: https://doi.org/10.1016/s1097-2765(01)00353-7]
Rosen, E. D., Hsu, C.-H., Wang, X., Sakai, S., Freeman, M. W., Gonzalez, F. J., Spiegelman, B. M. C/EBP-alpha induces adipogenesis through PPAR-gamma: a unified pathway. Genes Dev. 16: 22-26, 2002. [PubMed: 11782441] [Full Text: https://doi.org/10.1101/gad.948702]
Rosen, E. D., Kulkarni, R. N., Sarraf, P., Ozcan, U., Okada, T., Hsu, C.-H., Eisenman, D., Magnuson, M. A., Gonzalez, F. J., Kahn, C. R., Spiegelman, B. M. Targeted elimination of peroxisome proliferator-activated receptor gamma in beta cells leads to abnormalities in islet mass without compromising glucose homeostasis. Molec. Cell. Biol. 23: 7222-7229, 2003. [PubMed: 14517292] [Full Text: https://doi.org/10.1128/MCB.23.20.7222-7229.2003]
Rosen, E. D., Sarraf, P., Troy, A. E., Bradwin, G., Moore, K., Milstone, D. S., Spiegelman, B. M., Mortensen, R. M. PPAR-gamma is required for the differentiation of adipose tissue in vivo and in vitro. Molec. Cell 4: 611-617, 1999. [PubMed: 10549292] [Full Text: https://doi.org/10.1016/s1097-2765(00)80211-7]
Ryan, K. K., Li, B., Grayson, B. E., Matter, E. K., Woods, S. C., Seeley, R. J. A role for central nervous system PPAR-gamma in the regulation of energy balance. Nature Med. 17: 623-626, 2011. [PubMed: 21532595] [Full Text: https://doi.org/10.1038/nm.2349]
Saez, E., Olson, P., Evans, R. M. Genetic deficiency in Pparg does not alter development of experimental prostate cancer. Nature Med. 9: 1265-1266, 2003. [PubMed: 12960963] [Full Text: https://doi.org/10.1038/nm928]
Sahin, E., Colla, S., Liesa, M., Moslehi, J., Muller, F. L., Guo, M., Cooper, M., Kotton, D., Fabian, A. J., Walkey, C., Maser, R. S., Tonon, G., and 18 others. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470: 359-365, 2011. Note: Erratum: Nature 475: 254 only, 2011. [PubMed: 21307849] [Full Text: https://doi.org/10.1038/nature09787]
Sarraf, P., Mueller, E., Smith, W. M., Wright, H. M., Kum, J. B., Aaltonen, L. A., de la Chapelle, A., Spiegelman, B. M., Eng, C. Loss-of-function mutations in PPAR-gamma associated with human colon cancer. Molec. Cell 3: 799-804, 1999. [PubMed: 10394368] [Full Text: https://doi.org/10.1016/s1097-2765(01)80012-5]
Savage, D. B., Agostini, M., Barroso, I., Gurnell, M., Luan, J., Meirhaeghe, A., Harding, A.-H., Ihrke, G., Rajanayagam, O., Soos, M. A., George, S., Berger, D., and 9 others. Digenic inheritance of severe insulin resistance in a human pedigree. Nature Genet. 31: 379-384, 2002. Note: Erratum: Nature Genet. 32: 211 only, 2002. [PubMed: 12118251] [Full Text: https://doi.org/10.1038/ng926]
Savage, D. B., Tan, G. D., Acerini, C. L., Jebb, S. A., Agostini, M., Gurnell, M., Williams, R. L., Umpleby, A. M., Thomas, E. L., Bell, J. D., Dixon, A. K., Dunne, F., Boiani, R., Cinti, S., Vidal-Puig, A., Karpe, F., Chatterjee, V. K. K., O'Rahilly, S. Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. Diabetes 52: 910-917, 2003. [PubMed: 12663460] [Full Text: https://doi.org/10.2337/diabetes.52.4.910]
Scott, L. J., Mohlke, K. L., Bonnycastle, L. L., Willer, C. J., Li, Y., Duren, W. L., Erdos, M. R., Stringham, H. M., Chines, P. S., Jackson, A. U., Prokunina-Olsson, L., Ding, C.-J., and 29 others. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316: 1341-1345, 2007. [PubMed: 17463248] [Full Text: https://doi.org/10.1126/science.1142382]
Sewter, C., Blows, F., Considine, R., Vidal-Puig, A., O'Rahilly, S. Differential effects of adiposity on peroxisomal proliferator-activated receptor gamma-1 and gamma-2 messenger ribonucleic acid expression in human adipocytes. J. Clin. Endocr. Metab. 87: 4203-4207, 2002. [PubMed: 12213872] [Full Text: https://doi.org/10.1210/jc.2002-011511]
Smith, W. M., Zhou, X.-P., Kurose, K., Gao, X., Latif, F., Kroll, T., Sugano, K., Cannistra, S. A., Clinton, S. K., Maher, E. R., Prior, T. W., Eng, C. Opposite association of two PPARG variants with cancer: overrepresentation of H449H in endometrial carcinoma cases and underrepresentation of P12A in renal cell carcinoma cases. Hum. Genet. 109: 146-151, 2001. [PubMed: 11511919] [Full Text: https://doi.org/10.1007/s004390100563]
Song, J., Sakatsume, M., Narita, I., Goto, S., Omori, K., Takada, T., Saito, N., Ueno, M., Gejyo, F. Peroxisome proliferator-activated receptor gamma C161T polymorphisms and survival of Japanese patients with immunoglobulin A nephropathy. Clin. Genet. 64: 398-403, 2003. [PubMed: 14616762] [Full Text: https://doi.org/10.1034/j.1399-0004.2003.00154.x]
Tang, W., Zeve, D., Suh, J. M., Bosnakovski, D., Kyba, M., Hammer, R. E., Tallquist, M. D., Graff, J. M. White fat progenitor cells reside in the adipose vasculature. Science 322: 583-586, 2008. [PubMed: 18801968] [Full Text: https://doi.org/10.1126/science.1156232]
Tarrade, A., Schoonjans, K., Pavan, L., Auwerx, J., Rochette-Egly, C., Evain-Brion, D., Fournier, T. PPAR-gamma/RXR-alpha heterodimers control human trophoblast invasion. J. Clin. Endocr. Metab. 86: 5017-5024, 2001. [PubMed: 11600579] [Full Text: https://doi.org/10.1210/jcem.86.10.7924]
Temelkova-Kurktschiev, T., Hanefeld, M., Chinetti, G., Zawadzki, C., Haulon, S., Kubaszek, A., Koehler, C., Leonhardt, W., Staels, B., Laakso, M. Ala12Ala genotype of the peroxisome proliferator-activated receptor gamma-2 protects against atherosclerosis. J. Clin. Endocr. Metab. 89: 4238-4242, 2004. [PubMed: 15356014] [Full Text: https://doi.org/10.1210/jc.2003-032120]
Tong, Q., Dalgin, G., Xu, H., Ting, C.-N., Leiden, J. M., Hotamisligil, G. S. Function of GATA transcription factors in preadipocyte-adipocyte transition. Science 290: 134-138, 2000. [PubMed: 11021798] [Full Text: https://doi.org/10.1126/science.290.5489.134]
Tontonoz, P., Hu, E., Devine, J., Beale, E. G., Spiegelman, B. M. PPAR gamma 2 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene. Molec. Cell. Biol. 15: 351-357, 1995. [PubMed: 7799943] [Full Text: https://doi.org/10.1128/MCB.15.1.351]
Tontonoz, P., Hu, E., Graves, R. A., Budavari, A. I., Spiegelman, B. M. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 8: 1224-1234, 1994. [PubMed: 7926726] [Full Text: https://doi.org/10.1101/gad.8.10.1224]
Tontonoz, P., Hu, E., Spiegelman, B. M. Stimulation of adipogenesis in fibroblasts by PPAR-gamma-2, a lipid-activated transcription factor. Cell 79: 1147-1156, 1994. Note: Erratum: Cell 80: page following 957 only, 1995. [PubMed: 8001151] [Full Text: https://doi.org/10.1016/0092-8674(94)90006-x]
Tontonoz, P., Nagy, L., Alvarez, J. G. A., Thomazy, V. A., Evans, R. M. PPAR-gamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93: 241-252, 1998. [PubMed: 9568716] [Full Text: https://doi.org/10.1016/s0092-8674(00)81575-5]
Tsai, Y.-S., Kim, H.-J., Takahashi, N., Kim, H.-S., Hagaman, J. R., Kim, J. K., Maeda, N. Hypertension and abnormal fat distribution but not insulin resistance in mice with P465L PPAR-gamma. J. Clin. Invest. 114: 240-249, 2004. [PubMed: 15254591] [Full Text: https://doi.org/10.1172/JCI20964]
Uno, K., Katagiri, H., Yamada, T., Ishigaki, Y., Ogihara, T., Imai, J., Hasegawa, Y., Gao, J., Kaneko, K., Iwasaki, H., Ishihara, H., Sasano, H., Inukai, K., Mizuguchi, H., Asano, T., Shiota, M., Nakazato, M., Oka, Y. Neuronal pathway from the liver modulates energy expenditure and systemic insulin sensitivity. Science 312: 1656-1659, 2006. [PubMed: 16778057] [Full Text: https://doi.org/10.1126/science.1126010]
Valve, R., Sivenius, K., Miettinen, R., Pihlajamaki, J., Rissanen, A., Deeb, S. S., Auwerx, J., Uusitupa, M., Laakso, M. Two polymorphisms in the peroxisome proliferator-activated receptor-gamma gene are associated with severe overweight among obese women. J. Clin. Endocr. Metab. 84: 3708-3712, 1999. [PubMed: 10523018] [Full Text: https://doi.org/10.1210/jcem.84.10.6061]
Vidal-Puig, A. J, Considine, R. V., Jimenez-Linan, M., Werman, A., Pories, W. J., Caro, J. F., Flier, J. S. Peroxisome Proliferator-activated receptor gene expression in human tissues: effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J. Clin. Invest. 99: 2416-2422, 1997. [PubMed: 9153284] [Full Text: https://doi.org/10.1172/JCI119424]
Wan, Y., Chong, L.-W., Evans, R. M. PPAR-gamma regulates osteoclastogenesis in mice. Nature Med. 13: 1496-1503, 2007. [PubMed: 18059282] [Full Text: https://doi.org/10.1038/nm1672]
Wan, Y., Saghatelian, A., Chong, L.-W., Zhang, C.-L., Cravatt, B. F., Evans, R. M. Maternal PPAR-gamma protects nursing neonates by suppressing the production of inflammatory milk. Genes Dev. 21: 1895-1908, 2007. [PubMed: 17652179] [Full Text: https://doi.org/10.1101/gad.1567207]
Wang, C., Pattabiraman, N., Zhou, J. N., Fu, M., Sakamaki, T., Albanese, C., Li, Z., Wu, K., Hulit, J., Neumeister, P., Novikoff, P. M., Brownlee, M., Scherer, P. E., Jones, J. G., Whitney, K. D., Donehower, L. A., Harris, E. L., Rohan, T., Johns, D. C., Pestell, R. G. Cyclin D1 repression of peroxisome proliferator-activated receptor gamma expression and transactivation. Molec. Cell. Biol. 23: 6159-6173, 2003. [PubMed: 12917338] [Full Text: https://doi.org/10.1128/MCB.23.17.6159-6173.2003]
Wang, X. L., Oosterhof, J., Duarte, N. Peroxisome proliferator-activated receptor gamma C161-T polymorphism and coronary artery disease. Cardiovasc. Res. 44: 588-594, 1999. [PubMed: 10690291] [Full Text: https://doi.org/10.1016/s0008-6363(99)00256-4]
Welch, J. S., Ricote, M., Akiyama, T. E., Gonzalez, F. J., Glass, C. K. PPAR-gamma and PPAR-delta negatively regulate specific subsets of lipopolysaccharide and IFN-gamma target genes in macrophages. Proc. Nat. Acad. Sci. 100: 6712-6717, 2003. [PubMed: 12740443] [Full Text: https://doi.org/10.1073/pnas.1031789100]
Wisloff, U., Najjar, S. M., Ellingsen, O., Haram, P. M., Swoap, S., Al-Share, Q., Fernstrom, M., Rezaei, K., Lee, S. J., Koch, L. G., Britton, S. L. Cardiovascular risk factors emerge after artificial selection for low aerobic capacity. Science 307: 418-420, 2005. [PubMed: 15662013] [Full Text: https://doi.org/10.1126/science.1108177]
Yen, C.-J., Beamer, B. A., Negri, C., Silver, K., Brown, K. A., Yarnall, D. P., Burns, D. K., Roth, J., Shuldiner, A. R. Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR-gamma) gene in diabetic Caucasians: identification of a pro12ala PPAR-gamma-2 missense mutation. Biochem. Biophys. Res. Commun. 241: 270-274, 1997. [PubMed: 9425261] [Full Text: https://doi.org/10.1006/bbrc.1997.7798]
Yu, S., Matsusue, K., Kashireddy, P., Cao, W.-Q., Yeldandi, V., Yeldandi, A. V., Rao, M. S., Gonzalez, F. J., Reddy, J. K. Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor gamma-1 (PPAR-gamma-1) overexpression. J. Biol. Chem. 278: 498-505, 2003. [PubMed: 12401792] [Full Text: https://doi.org/10.1074/jbc.M210062200]
Yun, Z., Maecker, H. L., Johnson, R. S., Giaccia, A. J. Inhibition of PPAR-gamma-2 gene expression by the HIF-1-regulated gene DEC1/Stra13: a mechanism for regulation of adipogenesis by hypoxia. Dev. Cell 2: 331-341, 2002. [PubMed: 11879638] [Full Text: https://doi.org/10.1016/s1534-5807(02)00131-4]
Zeggini, E., Weedon, M. N., Lindgren, C. M., Frayling, T. M., Elliott, K. S., Lango, H., Timpson, N. J., Perry, J. R. B., Rayner, N. W., Freathy, R. M., Barrett, J. C., Shields, B., and 15 others. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316: 1336-1341, 2007. Note: Erratum: Science 317: 1036 only, 2007. [PubMed: 17463249] [Full Text: https://doi.org/10.1126/science.1142364]
Zhang, J., Fu, M., Cui, T., Xiong, C., Xu, K., Zhong, W., Xiao, Y., Floyd, D., Liang, J., Li, E., Song, Q., Chen, Y. E. Selective disruption of PPAR-gamma-2 impairs the development of adipose tissue and insulin sensitivity. Proc. Nat. Acad. Sci. 101: 10703-10708, 2004. [PubMed: 15249658] [Full Text: https://doi.org/10.1073/pnas.0403652101]
Zhang, L., Guerrero-Juarez, C. F., Hata, T., Bapat, S. P., Ramos, R., Plikus, M. V., Gallo, R. L. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection. Science 347: 67-71, 2015. [PubMed: 25554785] [Full Text: https://doi.org/10.1126/science.1260972]
Zhou, X.-P., Smith, W. M., Gimm, O., Mueller, E., Gao, X., Sarraf, P., Prior, T. W., Plass, C., van Deimling, A., Black, P. M., Yates, A. J., Eng, C. Over-representation of PPAR-gamma sequence variants in sporadic cases of glioblastoma multiforme: preliminary evidence for common low penetrance modifiers for brain tumour risk in the general population. J. Med. Genet. 37: 410-414, 2000. [PubMed: 10851250] [Full Text: https://doi.org/10.1136/jmg.37.6.410]