Bis-Indole–Derived NR4A1 Ligands and Metformin Exhibit NR4A1-Dependent Glucose Metabolism and Uptake in C2C12 Cells
Open accessAbstract
Treatment of C2C12 muscle cells with metformin or the NR4A1 ligand 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) induced NR4A1 and Glut4 messenger RNA and protein expression. Similar results were observed with buttressed (3- or 3,5-substituted) analogs of DIM-C-pPhOH, including 1,1-bis(3'-indolyl)-1-(3-chloro-4-hydroxy-5-methoxyphenyl)methane (DIM-C-pPhOH-3-Cl-5-OCH3), and the buttressed analogs were more potent than DIM-C-pPhOH NR4A1 agonists. Metformin and the bis-indole substituted analogs also induced expression of several glycolytic genes and Rab4, which has previously been linked to enhancing cell membrane accumulation of Glut4 and overall glucose uptake in C2C12 cells, and these responses were also observed after treatment with metformin and the NR4A1 ligands. The role of NR4A1 in mediating the responses induced by the bis-indoles and metformin was determined by knockdown of NR4A1, and this resulted in attenuating the gene and protein expression and enhanced glucose uptake responses induced by these compounds. Our results demonstrate that the bis-indole-derived NR4A1 ligands represent a class of drugs that enhance glucose uptake in C2C12 muscle cells, and we also show that the effects of metformin in this cell line are NR4A1-dependent.
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Nur77 regulates LKB1 localization and is important for regulation of glucose uptake into C212 mouse muscle cells.
“the orphan receptor, Nur77, regulates LKB1 localization and is also important for the regulation of glucose uptake into C212 mouse muscle cells (184, 185).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [185]
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Research works printed but not linked: 1
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- Authors
- Mohankumar, K., Lee, J., Wu, C. S., Sun, Y., & Safe, S.
- Affiliations
- Texas A&M University (US)
- Corresponding author
- Safe, Stephen
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2018-03-14
- Volume
- 159
- Issue
- 5
- Pages
- 1950-1963
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC5888234
- OpenAlex
- W2792342319
- Cited by
- 24
- References
- 43
- Citations by year
- 2025: 5 · 2024: 4 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 3
- FWCI
- 0.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Environmental Health Sciences (P30-ES023512)
- Texas AgriLife Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- Nur77, metformin, glucose uptake, glucose metabolism, GLUT4, C2C12 muscle cells, Rab4, glycolytic genes, muscle glucose transport
- MeSH terms
- Animals, Cell Line, Cell Membrane, Glucose, Glycolysis, Hypoglycemic Agents, Indoles, Metformin, Phenols, Gene Expression, rab4 GTP-Binding Proteins, Myoblasts, Glucose Transporter Type 4, Mice, Gene Knockdown Techniques, Nuclear Receptor Subfamily 4, Group A, Member 1
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