T0070907, a Selective Ligand for Peroxisome Proliferator-activated Receptor γ, Functions as an Antagonist of Biochemical and Cellular Activities
Open accessAbstract
The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma (NR1C3)) plays a central role in adipogenesis and is the molecular target for the thiazolidinedione (TZD) class of antidiabetic drugs. In a search for novel non-TZD ligands for PPARgamma, T0070907 was identified as a potent and selective PPARgamma antagonist. With an apparent binding affinity (concentration at 50% inhibition of [(3)H]rosiglitazone binding or IC(50)) of 1 nm, T0070907 covalently modifies PPARgamma on cysteine 313 in helix 3 of human PPARgamma2. T0070907 blocked PPARgamma function in both cell-based reporter gene and adipocyte differentiation assays. Consistent with its role as an antagonist of PPARgamma, T0070907 blocked agonist-induced recruitment of coactivator-derived peptides to PPARgamma in a homogeneous time-resolved fluorescence-based assay and promoted recruitment of the transcriptional corepressor NCoR to PPARgamma in both glutathione S-transferase pull-down assays and a PPARgamma/retinoid X receptor (RXR) alpha-dependent gel shift assay. Studies with mutant receptors suggest that T0070907 modulates the interaction of PPARgamma with these cofactor proteins by affecting the conformation of helix 12 of the PPARgamma ligand-binding domain. Interestingly, whereas the T0070907-induced NCoR recruitment to PPARgamma/RXRalpha heterodimer can be almost completely reversed by the simultaneous treatment with RXRalpha agonist LGD1069, T0070907 treatment has only modest effect…
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T0070907 is a PPARγ antagonist with inverse agonist properties.
“we were interested in the PPARg antagonist 2-chloro-5-nitro-N-4-pyridinyl-benzamide (T0070907) (Lee et al., 2002) with inverse agonist properties (Lee et al., 2002;Brust et al., 2018) as an alternative.”
T0070907 has similar effects to GW9662 on RNA but not necessarily on the protein level.
“Furthermore, the structurally related antagonist or inverse agonist T0070907 (Lee et al., 2002;Hughes et al., 2014;Brust et al., 2018) might be a useful alternative depending on the experimental setup (Supplemental Fig. 13), as we observed similar effects to GW9662 on RNA but not necessarily on the protein level.”
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“To determine whether degradation of sAβ was dependent on the actions of PPARγ and LXRs, microglia and astrocytes were pretreated with antagonists of these receptors (T0 and 22HC, respectively; Lee et al., 2002; Kase et al., 2007).”
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- Authors
- Lee, G., Elwood, F., McNally, J., Weiszmann, J., Lindstrom, M., Amaral, K., Nakamura, M., Miao, S., Cao, P., Learned, R. M., Chen, J.-L., & Li, Y.
- Corresponding author
- Li, Yang
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-05
- Volume
- 277
- Issue
- 22
- Pages
- 19649-19657
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2101460040
- Cited by
- 319
- References
- 0
- Citations by year
- 2026: 12 · 2025: 20 · 2024: 16 · 2023: 6 · 2022: 16 · 2021: 14 · 2020: 11 · 2019: 13 · 2018: 12 · 2017: 14 · 2016: 6 · 2015: 12 · 2014: 15 · 2013: 16 · 2012: 16
- FWCI
- 3.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- T0070907, PPARγ antagonist, PPARγ, thiazolidinediones, coactivator recruitment, NCoR, retinoid X receptor alpha, adipogenesis, corepressors, nuclear receptors
- MeSH terms
- Bexarotene, Allosteric Site, Amino Acid Sequence, Animals, Benzamides, Cell Differentiation, Cell Line, Cysteine, Dose-Response Relationship, Drug, Glutathione Transferase, Humans, Ligands, Molecular Sequence Data, Mutation, Peptides, Plasmids, Protein Binding, Protein Conformation, Pyridines, Recombinant Fusion Proteins, Spectrometry, Fluorescence, Tetrahydronaphthalenes, Time Factors, Transcription Factors, Transcription, Genetic, Transfection, 3T3 Cells, Anticarcinogenic Agents, Protein Structure, Tertiary, Adipocytes, Receptors, Cytoplasmic and Nuclear, Receptors, Retinoic Acid, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Dimerization, Retinoid X Receptors, Mice
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