Amorfrutins are selective PPARγ agonists with potent antidiabetic properties
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PROVIDER: PRJNA139093 | ENA |
REPOSITORIES: ENA
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Project description:Faced by an alarming incidence of metabolic diseases including obesity and type 2 diabetes worldwide, there is an urgent need for effective strategies for preventing and treating these common diseases. The nuclear receptor PPARγ (peroxisome proliferator-activated receptor gamma) plays a crucial role in metabolism. We isolated the amorfrutins from edible parts of the plants Glychyrrhiza foetida and Amorpha fruticosa, and identified these natural products as a new chemical class to treat insulin resistance and diabetes by selectively activating PPARγ. In contrast to existing synthetic PPARγ drugs, the amorfrutins display unique properties by separating insulin sensitization from unwanted side effects. In obese mouse models, amorfrutin treatment significantly improved important metabolic and inflammatory parameters. In summary, PPARγ activation by selective amorfrutins derived from edible biomaterial is a promising approach to combat metabolic diseases and other diseases in which PPARγ is involved in.
2012-05-02 | GSE28384 | GEO
Project description:Faced by an alarming incidence of metabolic diseases including obesity and type 2 diabetes worldwide, there is an urgent need for effective strategies for preventing and treating these common diseases. The nuclear receptor PPARM-NM-3 (peroxisome proliferator-activated receptor gamma) plays a crucial role in metabolism. We isolated the amorfrutins from edible parts of the plants Glychyrrhiza foetida and Amorpha fruticosa, and identified these natural products as a new chemical class to treat insulin resistance and diabetes by selectively activating PPARM-NM-3. In contrast to existing synthetic PPARM-NM-3 drugs, the amorfrutins display unique properties by separating insulin sensitization from unwanted side effects. In obese mouse models, amorfrutin treatment significantly improved important metabolic and inflammatory parameters. In summary, PPARM-NM-3 activation by selective amorfrutins derived from edible biomaterial is a promising approach to combat metabolic diseases and other diseases in which PPARM-NM-3 is involved in. GSM701612-GSM701623: Male DIO C57BL/6 mice (age 18 wks), 3 groups (n=4 each after pooling of 8 samples per group). Mice were fed over 3 wks with high fat diet (HFD) without compound (vehicle), HFD with 4 mg/kg/d rosiglitazone or with 100 mg/kg/d amorfrutin 1. Liver RNA extracted. --> 4 biological replicates, vehicle vs. rosiglitazone or amorfrutin 1 GSM702299-GSM702344: Biological replicates (n = 3-4 each) of human primary adipocytes were treated with the following compounds for 24 hours. 10M-BM-5M rosiglitazone, 10M-BM-5M pioglitazone, 30M-BM-5M telmisartan, 10M-BM-5M nTZDpa, 30M-BM-5M amorfrutin 1, 30M-BM-5M amorfrutin 2, 30M-BM-5M amorfrutin 3 or 30M-BM-5M amorfrutin 4 vs. 0.1% DMSO (vehicle)
2012-05-01 | E-GEOD-28384 | biostudies-arrayexpress
Project description:Cell-targeted PD-1 agonists are potent NK cell inhibitors
| PRJNA1216245 | ENA
Project description:SNPs affecting disease risk often reside in non-coding genomic regions. Here we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, a nuclear receptor for antidiabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors, and functionally regulate nearby genes whose expression is strain-selective and imbalanced in heterozygous F1 mice. Moreover, genetically-determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs, providing proof-of- concept for personalized medicine related to nuclear receptor genomic occupancy. In human fat, motif-altering SNPs cause differential PPARγ binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome- wide association studies. One PPARγ motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPARγ genomic occupancy determines individual disease risk and drug response. 6 ChIP-seq experiments conducted in mice and 5 in human subjects. Deep sequencing carried out using Illumina HiSeq2000 and the Solexa Analysis Pipeline eWAT; epididymal White Adipose Tissue iWAT; inguinal White Adipose Tissue 12wLFD; mice were fed a control low fat diet (Research Diet D12450B) chow; mice were fed standard rodent chow Diet GR; Glucocorticoid receptor
2015-07-02 | E-GEOD-64458 | biostudies-arrayexpress
Project description:Biased signaling and ligand bias, often referred to as functional selectivity or selective nuclear receptor modulation, have been reported for many nuclear receptor partial agonists over the past 20 years. However, whether differences in nuclear receptor signaling produced by partial and full agonists results from less intense partial agonist modulation, off-target effects, or biased signaling remains unclear. To determine whether biased signaling can occur through nuclear receptors we compare the transcriptional effects of two full agonists (which also favor different coactivator peptides) in human adipocytes. We also test the signaling effects of a partial agonist relative to full agonists. Furthermore, whether biased coactivator peptide recruitment translates to biased signaling in cells has not been determined. In a step towards this goal, we show that these same full agonists induce biased recruitment of 100-300 residue regions of coactivators containing all their nuclear receptor binding motifs. Together these data support the idea that nuclear receptor agonists can induce biased signaling through differences in coactivator recruitment.
2025-10-26 | GSE266107 | GEO
Project description:Background: Prostate cancer (PCa) and Type 2 diabetes (T2D) are two major health risks that often occur concurrently in men. Studies predict that diabetic PCa patients have a reduced risk of PCa progression, while other studies show contradicting data. This impedes unraveling the connection between PCa with T2D. Besides other drugs, Peroxisome Proliferator-Activated Receptor (PPAR) agonists have been applied as T2D medication in patients. In publicly available patient datasets high PPARγ expression correlated with advanced PCa and worse survival outcomes. Aim: We investigated the effect of PPAR agonists Bezafibrate (PPARα), Tesaglitazar (PPARα/γ), and Pioglitazone (PPARγ) on PCa tumorigenesis using primary PCa 22RV1 and metastatic PC3 cells. To get an unbiased view on the proteome repertoire of primary and metastatic PCa cells, we analysed their proteome at basal culture conditions and following treatment with PPAR agonists Bezafibrate, Tesaglitazar, and Pioglitazone. As compared to vitality assays, we chose a relatively short (24h) treatment period, assuming that early proteome alterations might provide mechanistic insight to explain the effect of PPAR agonists on vitality and proliferation.
2025-08-11 | PXD060526 | Pride
Project description:SNPs affecting disease risk often reside in non-coding genomic regions. Here we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, a nuclear receptor for antidiabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors, and functionally regulate nearby genes whose expression is strain-selective and imbalanced in heterozygous F1 mice. Moreover, genetically-determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs, providing proof-of- concept for personalized medicine related to nuclear receptor genomic occupancy. In human fat, motif-altering SNPs cause differential PPARγ binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome- wide association studies. One PPARγ motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPARγ genomic occupancy determines individual disease risk and drug response.
2015-07-02 | GSE64459 | GEO
Project description:SNPs affecting disease risk often reside in non-coding genomic regions. Here we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, a nuclear receptor for antidiabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors, and functionally regulate nearby genes whose expression is strain-selective and imbalanced in heterozygous F1 mice. Moreover, genetically-determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs, providing proof-of- concept for personalized medicine related to nuclear receptor genomic occupancy. In human fat, motif-altering SNPs cause differential PPARγ binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome- wide association studies. One PPARγ motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPARγ genomic occupancy determines individual disease risk and drug response.
2015-07-02 | GSE64458 | GEO
Project description:PPARγ is known for its anti-inflammatory actions in macrophages. However, which macrophage populations express PPARγ in vivo and how it regulates tissue homeostasis in the steady state and during inflammation is not completely understood. We show that lung and spleen macrophages constitutively expressed PPARγ, while other macrophage populations did not. Recruitment of monocytes to sites of inflammation was associated with induction of PPARγ as they differentiated to macrophages. Its absence in these macrophages led to failed resolution of inflammation, characterized by persistent, low-level recruitment of leukocytes. Conversely, PPARγ agonists supported an earlier cessation in leukocyte recruitment during resolution of acute inflammation and likewise suppressed monocyte recruitment to chronically inflamed atherosclerotic vessels. In the steady state, PPARγ deficiency in macrophages had no obvious impact in the spleen but profoundly altered cellular lipid homeostasis in lung macrophages. Reminiscent of pulmonary alveolar proteinosis, LysM-Cre x PPARγflox/flox mice displayed mild leukocytic inflammation in the steady-state lung and succumbed faster to mortality upon infection with S. pneumoniae. Surprisingly, this mortality was not due to overly exuberant inflammation, but instead to impaired bacterial clearance. Thus, in addition to its anti-inflammatory role in promoting resolution of inflammation, PPARγ sustains functionality in lung macrophages and thereby has a pivotal role in supporting pulmonary host defense. The two major subsets of monocytes (Ly-6C+ and Ly-6Clo) from 12-week old C57Bl/6 mice were sorted and the RNA extracted and hybridized to Affymetrix GeneChip® 430 2.0 arrays. We pooled leukocytes from 5 mice for each sort and sorted 3 to 4 separate times for 3 to 4 biological replicates.
2012-10-03 | E-GEOD-32034 | biostudies-arrayexpress
Project description:We have generated a novel targeted bispecific PD-1 molecule, to achieve tissue-specific immune suppression for the treatment of immune-mediated inflammatory diseases. These targeted PD-1 agonists have shown potent T cell inhibition and here we describe an additional effect on NK cell activation. We show that PD-1 pathway activation modifies NK cell gene expression and decreases their inflammatory and cytotoxic functions. Targeted PD-1 agonist molecules, inhibiting T cells and NK cells in a tissue-specific manner offer a new promising treatment for autoimmune and inflammatory diseases.
2025-08-28 | GSE288132 | GEO