ArticleDiabetes2011
Metformin inhibits nuclear receptor TR4-mediated hepatic stearoyl-CoA desaturase 1 gene expression with altered insulin sensitivity.
Article in Diabetes, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
48 citing papers in PubMed, 96 citations in OpenAlex.
- Coregulatory Networks Remodel the Disease-Specific Functions of Orphan Nuclear Receptor TR4.Cells · 2026Review
- The Molecular Mechanisms of Metformin's Action on Blood Lipid Profile in Diabetic Patients.International journal of molecular sciences · 2026Review
- Orphan Nuclear Receptors TR2 and TR4 in Erythropoiesis: From Mechanisms to Therapies.Biomolecules · 2025Review
- Comparative Evaluation and Profiling of Chemical Tools for the Nuclear Hormone Receptor Family 2.ACS pharmacology & translational science · 2025Article
- Review
- Metformin and the Liver: Unlocking the Full Therapeutic Potential.Metabolites · 2024Review
- TR4 worsen urosepsis by regulating GSDMD.European journal of medical research · 2024Article
- Biguanides and glucagon like peptide 1 receptor agonists in the amelioration of post liver transplant weight gain; a scoping review of the mechanism of action, safety and efficacy.Gastroenterology and hepatology from bed to bench · 2024Article
- Efficacy Confirmation Test of Black Cumin (Metabolites · 2023Article
- Structures of human TR4LBD-JAZF1 and TR4DBD-DNA complexes reveal the molecular basis of transcriptional regulation.Nucleic acids research · 2023Article
- Metformin: update on mechanisms of action on liver diseases.Frontiers in nutrition · 2023Review
- Metabolomic profiles of metformin in breast cancer survivors: a pooled analysis of plasmas from two randomized placebo-controlled trials.Journal of translational medicine · 2022Article
- Testicular orphan receptor 4 (TR4) promotes papillary thyroid cancer invasion via activating circ-FNLA/miR-149-5p/MMP9 signaling.Molecular therapy. Nucleic acids · 2021Article
- Targeting Energy Expenditure-Drugs for Obesity Treatment.Pharmaceuticals (Basel, Switzerland) · 2021Review
- The role of FATP1 in lipid accumulation: a review.Molecular and cellular biochemistry · 2021Review
- Targeting the TR4 nuclear receptor with antagonist bexarotene can suppress the proopiomelanocortin signalling in AtT-20 cells.Journal of cellular and molecular medicine · 2021Article
- Identification of Small-Molecule Regulators of Testicular Receptor 4 via a Drug Repurposing Screening.ACS omega · 2020Article
- Review
- Identification of MicroRNA-Target Gene-Transcription Factor Regulatory Networks in Colorectal Adenoma Using Microarray Expression Data.Frontiers in genetics · 2020Article
- Beta-catenin inhibits TR4-mediated lipid accumulation in 3T3-L1 adipocytes via induction of Slug.Cell & bioscience · 2020Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 3 countries.
Funding
Abstract
objectiveTR4 is a nuclear receptor without clear pathophysiological roles. We investigated the roles of hepatic TR4 in the regulation of lipogenesis and insulin sensitivity in vivo and in vitro. RESEARCH DESIGN AND
methodsTR4 activity and phosphorylation assays were carried out using hepatocytes and various TR4 wild-type and mutant constructs. Liver tissues from TR4 knockout, C57BL/6, and db/db mice were examined to investigate TR4 target gene stearoyl-CoA desaturase (SCD) 1 regulation.
resultsTR4 transactivation is inhibited via phosphorylation by metformin-induced AMP-activated protein kinase (AMPK) at the amino acid serine 351, which results in the suppression of SCD1 gene expression. Additional mechanistic dissection finds TR4-transactivated SCD1 promoter activity via direct binding to the TR4-responsive element located at -243 to -255 on the promoter region. The pathophysiological consequences of the metformin→AMPK→TR4→SCD1 pathway are examined via TR4 knockout mice and primary hepatocytes with either knockdown or overexpression of TR4. The results show that the suppression of SCD1 via loss of TR4 resulted in reduced fat mass and increased insulin sensitivity with increased β-oxidation and decreased lipogenic gene expression.
conclusionsThe pathway from metformin→AMPK→TR4→SCD1→insulin sensitivity suggests that TR4 may function as an important modulator to control lipid metabolism, which sheds light on the use of small molecules to modulate TR4 activity as a new alternative approach to battle the metabolic syndrome.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.