Disease relevance of Pparg

• Genetic deficiency in Pparg does not alter development of experimental prostate cancer [1].
• Similar effects of fasting on PPAR gamma mRNAs were noted in all three models of obesity [2].
• CONCLUSIONS: Our studies provide molecular evidence in vivo, suggesting that CLA ameliorates colitis through a PPAR gamma-dependent mechanism [3].
• Activation of PPAR gamma and delta by conjugated linoleic acid mediates protection from experimental inflammatory bowel disease [3].
• Peroxisome proliferator-activated receptor-gamma agonist 15-deoxy-Delta(12,14)-prostaglandin J(2) ameliorates experimental autoimmune encephalomyelitis [4].
• Our study demonstrated that the PPARgamma agonist, rosiglitazone, promoted hematoma resolution, decreased neuronal damage, and improved functional recovery in a mouse ICH model [5].
• These studies demonstrate that PPAR-gamma-expressing, but not PPAR-gamma null Treg, prevent colitis induced by transfer of naive CD4+ T cells into SCID recipients [6].
• PPARgamma expression in the liver was upregulated after reperfusion following ischemia [7].
• These results suggest that hyperglycemia enhances the adipogenic induction of lipid accumulation through an ERK1/2-activated PI3K/Akt-regulated PPAR gamma pathway [8].
• Overall, these data demonstrate that IL-13 or PPARgamma ligands attenuate C. albicans infection of the GI tract through PPARgamma activation and hence suggest that PPARgamma ligands may be of therapeutic value in esophageal and GI candidiasis in immunocompromised patients [9].

High impact information on Pparg

• Here, we report the PGJ2 and its derivatives are efficacious activators of peroxisome proliferator-activated receptors alpha and gamma (PPAR alpha and PPAR gamma, respectively), orphan nuclear receptors implicated in lipid homeostasis and adipocyte differentiation [10].
• A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation [10].
• The PGJ2 metabolite 15-deoxy-delta 12,14-PGJ2 binds directly to PPAR gamma and promotes efficient differentiation of C3H10T1/2 fibroblasts to adipocytes [10].
• This suggests that an endogenous PPAR gamma ligand may be an important regulator of adipogenesis [11].
• Similarly, the thiazolidinedione class of antidiabetic drugs also bind to PPAR gamma and act as potent regulators of adipocyte development [11].

Psychiatry related information on Pparg

• There was a decrease in the metabolic rate and physical activity of the PPARgamma(+/-) mice, which was abolished by thiazolidinedione treatment, thereby linking regulation of the metabolic rate and physical activity to PPARgamma [12].

Chemical compound and disease context of Pparg

• In a model of contact allergen-induced LC migration, PPAR gamma activation not only impedes LC emigration, and their subsequent accumulation as DCs in the DLNs, but also dramatically prevents the contact hypersensitivity responses after challenge [13].
• Up-regulation of peroxisome proliferator-activated receptors (PPAR-alpha) and PPAR-gamma messenger ribonucleic acid expression in the liver in murine obesity: troglitazone induces expression of PPAR-gamma-responsive adipose tissue-specific genes in the liver of obese diabetic mice [14].
• Diet restriction caused a 45% weight loss, an upregulation of PPAR-alpha and PPAR-gamma, and a change in the expression of genes regulating glucose transport and insulin sensitivity, lipid metabolism, oxidative stress, and inflammation, most of which are under the transcriptional control of these PPARs [15].
• The peroxisome proliferator-activated receptor gamma ligand rosiglitazone delays the onset of inflammatory bowel disease in mice with interleukin 10 deficiency [16].
• In the present study, we investigated the synergistic effect of PPAR-gamma and its agonist, pioglitazone, on proinsulin biosynthesis and insulin release in a glucose-responsible insulinoma cell line, MIN6 cells [17].
• We conclude that AM/AMBP-1 is protective in sepsis due to its vasoactive properties and direct anti-inflammatory effects mediated through both the cAMP-dependent pathway and Pyk-2-ERK1/2-dependent induction of PPAR-gamma [18].
• Deletion of PPARgamma resulted in enhanced susceptibility to bleomycin-induced skin fibrosis, as indicated by increases in all measures of skin fibrosis and enhanced sensitivity of fibroblasts to TGFbeta1 in PPAR-deficient mice [19].

Biological context of Pparg

• Muscle-specific Pparg deletion causes insulin resistance [20].
• Adipogenesis (lipid accumulation, Pparg expression) is inhibited by Msx2 [21].
• The potential for regulation of PPAR gamma gene expression in vivo is unknown [2].
• Together, these data indicate that PPAR gamma plays a critical 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 [22].
• Cyclin D1 repression of peroxisome proliferator-activated receptor gamma expression and transactivation [23].

Anatomical context of Pparg

• To address this issue, we used the Cre-loxP system to knock out Pparg, the gene encoding PPAR-gamma, in mouse skeletal muscle [20].
• Ovulatory human chorionic gonadotropin downregulated expression of Pparg and Ppara in EMR1+ ovarian macrophages, but no hormonal responsiveness was observed in H2+ cells [24].
• Isolation of immune cells (EMR1+ or H2+) showed that Pparg and Ppara were expressed in ovarian macrophages at much higher levels than in peritoneal macrophages [24].
• These findings demonstrate in vivo modulation of PPAR gamma mRNA levels over a fourfold range and provide an additional level of regulation for the control of adipocyte development and function [2].
• Levels of adipose tissue PPAR gamma 2 mRNA were increased by 50% in normal mice exposed to a high fat diet [2].

Associations of Pparg with chemical compounds

• Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor selectively activated by ligands of the thiazolidinedione class [23].
• 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 [22].
• We demonstrated that Insig-1 is regulated by peroxisome proliferator-activated receptor gamma (PPARgamma) providing a link between insulin sensitization/glucose homeostasis and lipid homeostasis [25].
• Using an experimental murine model of LC migration induced by TNF-alpha, we show that the highly potent PPAR gamma agonist rosiglitazone specifically impairs the departure of LCs from the epidermis [13].
• To determine whether increased PPAR-gamma expression in the liver has any functional consequences, we examined the effect of troglitazone treatment on the hepatic mRNA levels of several PPAR-gamma-responsive adipose tissue-specific genes that have either no detectable or very low basal expression in the liver [14].
• Our results demonstrated that PPARgamma is required to maintain normal adiposity and insulin sensitivity in adult mice [26].
• These findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs [27].
• Both pioglitazone and ciglitazone (PPARgamma agonists; 0.5-5.0 microg, intracerebroventricularly (i.c.v.), once daily) prevented the expression of behavioral sensitization to METH challenge on withdrawal day 7, but not the sensitization that occurred during repeated administration of METH [28].
• PPARgamma activation by rosiglitazone prevented the mitochondrial dysfunction and oxidative stress that occurred when mutant striatal cells were challenged with pathological increases in calcium [29].
• Although these modifications were also found in TNFalpha-treated adipocytes, rosiglitazone and 9-cis retinoic acid (PPARgamma and RXR ligands) were unable to prevent triglyceride loss in FCCP-treated cells [30].
• The innate FoxO1 transrepression function enables insulin to augment PPARgamma activity, which in turn leads to insulin sensitization, and this feed-forward cycle represents positive reinforcing connections between insulin and PPARgamma signaling [31].

Physical interactions of Pparg

• Thus activation of PPAR-gamma by 15d-PGJ2 inhibits DNA-binding activity of the transcription factors Cbfa1 and NF-kappaB, leading to diminished expression of osteoblast/stromal differentiation markers [32].
• An intact DNA-binding domain is not required for peroxisome proliferator-activated receptor gamma (PPARgamma) binding and activation on some PPAR response elements [33].
• For adipocyte differentiation, independent lines of evidence show that the transcription factors peroxisome proliferator activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (C/EBPalpha) as well as the tumor suppressor retinoblastoma (Rb) protein are essential [34].
• CHIR 99021 stabilizes free cytosolic beta-catenin and inhibits adipogenesis by blocking induction of CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma [35].
• Furthermore, Northern analysis clearly indicated that transcript levels of peroxisome proliferator-activated receptor gamma (PPARgamma) and adipose-type fatty acid binding protein (A-FABP) were well correlated with the levels of fat accumulation [36].

Regulatory relationships of Pparg

• Peroxisome proliferator-activated receptor gamma controls Muc1 transcription in trophoblasts [37].
• Activation of peroxisome proliferator-activated receptor-gamma inhibits the Runx2-mediated transcription of osteocalcin in osteoblasts [38].
• Under these conditions, hepatic PPAR gamma expression increased in both the control and PPAR alpha-deficient mice [39].
• The peroxisome proliferator-activated receptor gamma regulates expression of the perilipin gene in adipocytes [40].
• In this study, the pro-adipocytic and anti-osteoblastic activities of netoglitazone were evaluated in vitro, using both U-33/gamma2 cells as a model of marrow mesenchymal cell differentiation under the control of PPAR-gamma2 and primary bone marrow cultures, and in vivo in C57BL/6 mice [41].

Other interactions of Pparg

• Neither hemizygous deletion of Pparg nor complete ablation of Ppara influenced the development of prostate cancer in our experimental context [1].
• Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists [42].
• In contrast, Msx2 diminished peroxisome proliferator-activated receptor gamma (PPARgamma) expression and adipogenesis of the preadipocytic cell line 3T3-F442A [43].
• Differential expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) and its coactivators steroid receptor coactivator-1 and PPAR-binding protein PBP in the brown fat, urinary bladder, colon, and breast of the mouse [44].
• Adipose tissue expression of the lipid droplet-associating proteins S3-12 and perilipin is controlled by peroxisome proliferator-activated receptor-gamma [45].
• We demonstrate that when expressed on a hyperphagic ob/ob background, the P465L PPARgamma mutant grossly exacerbates the insulin resistance and metabolic disturbances associated with leptin deficiency, yet reduces whole-body adiposity and adipocyte size [46].
• Bcl-2 knockdown by small interfering RNA in cells overexpressing PPARgamma results in increased sensitivity to Abeta and oxidative stress, further suggesting that Bcl-2 up-regulation mediates PPARgamma protective effects [47].

Analytical, diagnostic and therapeutic context of Pparg

• Western blot analysis demonstrated a marked effect of fasting to reduce PPAR gamma protein levels in adipose tissue [2].
• METHODS: The expression of PPAR gamma, delta, and their target genes in the colon of mice fed control or CLA-supplemented diets was assayed after a 7-day dextran sodium sulfate (DSS) challenge by quantitative real-time polymerase chain reaction (PCR) [3].
• Furthermore, tissue-selective binding of PPAR alpha and PPAR gamma to the PPRE was demonstrated in hepatocytes and adipocytes, respectively, by chromatin immunoprecipitation assay [48].
• The PPRE sequence specifically bound to the heterodimer of RXR alpha and PPAR alpha or PPAR gamma 2, as assessed by electrophoretic gel mobility shift assays [48].
• In this study we examined the role of PPAR-gamma in experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis [4].

References