ArticleProceedings of the National Academy of Sciences of the United States of America2017
Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers, 1 of them a synthesis that pooled it.
What it found
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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.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
63 citing papers in PubMed, 1 synthesis or guideline pooled it, 115 citations in OpenAlex.
- Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document.Thyroid : official journal of the American Thyroid Association · 2021Guideline
- Thyroid dysfunction and cardiovascular disease.European heart journal · 2026Review
- Hypothalamic control of heart rate and body temperature by thyroid hormones.Reviews in endocrine & metabolic disorders · 2026Review
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- Article
- [New ways in interdisciplinarity: internal medicine meets human genetics : When frequent conditions become rare and rare conditions become frequent].Innere Medizin (Heidelberg, Germany) · 2026Review
- Thyroid hormone receptor α signaling shapes innate and adaptive immune responses during viral infection.European thyroid journal · 2025Article
- Transcriptional Cofactors for Thyroid Hormone Receptors.Endocrinology · 2025Review
- Thyroid Hormone Action by Genomic and Nongenomic Molecular Mechanisms.Methods in molecular biology (Clifton, N.J.) · 2025Article
- TRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA.Nature communications · 2024Article
- Lack of canonical thyroid hormone receptor α signaling changes regulatory T cell phenotype in female mice.iScience · 2024Article
- The key roles of thyroid hormone in mitochondrial regulation, at interface of human health and disease.Journal of basic and clinical physiology and pharmacology · 2024Review
- Gene polymorphisms and thyroid hormone signaling: implication for the treatment of hypothyroidism.Endocrine · 2024Review
- Metabolic Messengers: Thyroid Hormones.Nature metabolism · 2024Review
- Effects of roxadustat on thyroid hormone levels and blood lipid metabolism in patients undergoing hemodialysis: a retrospective study.International journal of medical sciences · 2024Article
- Urine Excretion, Organ Distribution, and Placental Transfer of 6PPD and 6PPD-Quinone in Mice and Potential Developmental Toxicity through Nuclear Receptor Pathways.Environmental science & technology · 2023Article
- Thyroid Hormone Regulates the Lipid Content of Muscle Fibers, Thus Affecting Physical Exercise Performance.International journal of molecular sciences · 2023Article
- Uncovering Actions of Type 3 Deiodinase in the Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD).Cells · 2023Article
- Hepatic Energy Metabolism under the Local Control of the Thyroid Hormone System.International journal of molecular sciences · 2023Review
- Article
3 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
28 authors at 10 institutions in 4 countries.
Funding
Abstract
Thyroid hormone (TH) and TH receptors (TRs) α and β act by binding to TH response elements (TREs) in regulatory regions of target genes. This nuclear signaling is established as the canonical or type 1 pathway for TH action. Nevertheless, TRs also rapidly activate intracellular second-messenger signaling pathways independently of gene expression (noncanonical or type 3 TR signaling). To test the physiological relevance of noncanonical TR signaling, we generated knockin mice with a mutation in the TR DNA-binding domain that abrogates binding to DNA and leads to complete loss of canonical TH action. We show that several important physiological TH effects are preserved despite the disruption of DNA binding of TRα and TRβ, most notably heart rate, body temperature, blood glucose, and triglyceride concentration, all of which were regulated by noncanonical TR signaling. Additionally, we confirm that TRE-binding-defective TRβ leads to disruption of the hypothalamic-pituitary-thyroid axis with resistance to TH, while mutation of TRα causes a severe delay in skeletal development, thus demonstrating tissue- and TR isoform-specific canonical signaling. These findings provide in vivo evidence that noncanonical TR signaling exerts physiologically important cardiometabolic effects that are distinct from canonical actions. These data challenge the current paradigm that in vivo physiological TH action is mediated exclusively via regulation of gene transcription at the nuclear level.
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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.