T3

cross_nutrient

An iodine-containing hormone binds THRB in a complex with the retinoid receptor RXRA; no nutritional vitamin A manipulation.

evidence_locator

Figure 2a and Results: structural characterization; Methods: protein production and crystallography

evidence_spans

[{"source_document": "artifacts/iodine-metabolism-sources/26289479.txt", "locator": "Figure 2a and Results: structural characterization; Methods: protein production and crystallography", "start_char": 10702, "end_char": 12152}]

experimental_model

Human TR beta/RXR alpha ligand-binding-domain crystallography; full-length human receptors in CV-1 reporter assays

exposure

Human THRB residues 202–461 and RXRA residues 223–462; threefold molar excess of T3 and synthetic HKILHRLL SRC-2 peptide; structure refined at anisotropic 3.2–3.8 angstrom resolution.

limitations

Isolated domains and an eight-residue peptide, not full-length coactivator recruitment in tissue. The structure establishes binding geometry, not a physiological T3 threshold.

nutrient_topic

Iodine research collection; topical membership is not evidence of a direct dietary effect. · Iodine

organism

Human receptor domains produced in Escherichia coli; synthetic coactivator peptide

plain_language

T3 physically occupies its receptor, which presents a docking surface for a transcription coactivator.

primary_references

[i-met-26289479] Structural mechanism for signal transduction in RXR nuclear receptor heterodimers. (2015). https://pubmed.ncbi.nlm.nih.gov/26289479/ DOI: 10.1038/ncomms9013

tissue_or_cell_type

Purified receptor-domain complex

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 1172–1185

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human TR beta/RXR alpha ligand-binding-domain crystallography; full-length human receptors in CV-1 reporter assays · source_derived_draft · unverified_draft

### i-met-t3-thrb-ligand-binding T3 was bound within the human THRB ligand-binding domain in the crystallized THRB–RXRA domain heterodimer, with the THRB activation surface accommodating an SRC-2-derived peptide. Condition category: normal nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: T3 physically occupies its receptor, which presents a docking surface for a transcription coactivator. organism: Human receptor domains produced in Escherichia coli; synthetic coactivator peptide tissue_or_cell_type: Purified receptor-domain complex experimental_model: Human TR beta/RXR alpha ligand-binding-domain crystallography; full-length human receptors in CV-1 reporter assays limitations: Isolated domains and an eight-residue peptide, not full-length coactivator recruitment in tissue. The structure establishes binding geometry, not a physiological T3 threshold. exposure: Human THRB residues 202–461 and RXRA residues 223–462; threefold molar excess of T3 and synthetic HKILHRLL SRC-2 peptide; structure refined at anisotropic 3.2–3.8 angstrom resolution. cross_nutrient: An iodine-containing hormone binds THRB in a complex with the retinoid receptor RXRA; no nutritional vitamin A manipulation. evidence_locator: Figure 2a and Results: structural characterization; Methods: protein production and crystallography evidence_spans: [{"source_document": "artifacts/iodine-metabolism-sources/26289479.txt", "locator": "Figure 2a and Results: structural characterization; Methods: protein production and crystallography", "start_char": 10702, "end_char": 12152}] [i-met-26289479] Structural mechanism for signal transduction in RXR nuclear receptor heterodimers. (2015). https://pubmed.ncbi.nlm.nih.gov/26289479/ DOI: 10.1038/ncomms9013

cross_nutrient

Human thyroid and retinoid receptor machinery jointly support the measured iodine-containing-hormone response; this does not establish dietary vitamin A dependence.

evidence_locator

Figure 1b and legend; Methods: Cell-based assays

evidence_spans

[{"source_document": "artifacts/iodine-metabolism-sources/26289479.txt", "locator": "Figure 1b and legend; Methods: Cell-based assays", "start_char": 45264, "end_char": 46014}]

experimental_model

Human TR beta/RXR alpha ligand-binding-domain crystallography; full-length human receptors in CV-1 reporter assays

exposure

1 micromolar T3 for 24 hours versus vehicle, with THRB/RXRA expression plasmids and a DR4 thyroid-response luciferase reporter; quadruplicate wells and at least two experiments.

limitations

Engineered reporter and receptor overexpression; cannot infer that every endogenous gene is activated by T3 or that dietary iodine or vitamin A improves this signal.

nutrient_topic

Iodine research collection; topical membership is not evidence of a direct dietary effect. · Iodine

organism

Full-length human receptors expressed in African green monkey CV-1 cells

plain_language

Binding of the hormone can be translated into a gene-regulatory signal through its receptor.

primary_references

[i-met-26289479] Structural mechanism for signal transduction in RXR nuclear receptor heterodimers. (2015). https://pubmed.ncbi.nlm.nih.gov/26289479/ DOI: 10.1038/ncomms9013

tissue_or_cell_type

CV-1 reporter assay

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 1187–1200

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human TR beta/RXR alpha ligand-binding-domain crystallography; full-length human receptors in CV-1 reporter assays · source_derived_draft · unverified_draft

### i-met-t3-thrb-transcription T3 increased thyroid-response-element luciferase activity in CV-1 cells transfected with full-length human THRB and RXRA. Condition category: normal nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Binding of the hormone can be translated into a gene-regulatory signal through its receptor. organism: Full-length human receptors expressed in African green monkey CV-1 cells tissue_or_cell_type: CV-1 reporter assay experimental_model: Human TR beta/RXR alpha ligand-binding-domain crystallography; full-length human receptors in CV-1 reporter assays limitations: Engineered reporter and receptor overexpression; cannot infer that every endogenous gene is activated by T3 or that dietary iodine or vitamin A improves this signal. exposure: 1 micromolar T3 for 24 hours versus vehicle, with THRB/RXRA expression plasmids and a DR4 thyroid-response luciferase reporter; quadruplicate wells and at least two experiments. cross_nutrient: Human thyroid and retinoid receptor machinery jointly support the measured iodine-containing-hormone response; this does not establish dietary vitamin A dependence. evidence_locator: Figure 1b and legend; Methods: Cell-based assays evidence_spans: [{"source_document": "artifacts/iodine-metabolism-sources/26289479.txt", "locator": "Figure 1b and legend; Methods: Cell-based assays", "start_char": 45264, "end_char": 46014}] [i-met-26289479] Structural mechanism for signal transduction in RXR nuclear receptor heterodimers. (2015). https://pubmed.ncbi.nlm.nih.gov/26289479/ DOI: 10.1038/ncomms9013

evidence_span

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experimental_model

Sixteen men given oral T3 before, during and after 80 cold air exposures, with and without T3 replacement

exposure

Eighty exposures to 4 degrees C air, ten per week

limitations

Cold air rather than water immersion, recorded because it isolates the thyroid hormone kinetics. The pharmacological oral T3 dose is not physiological.

nutrient_topic

Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Cold water immersion

organism

Human

plain_language

Cold makes the body consume active thyroid hormone faster, independently of the usual feedback loop.

primary_references

[cold-p1636702] Multiple cold air exposures change oral triiodothyronine kinetics in normal men. (1992). https://pubmed.ncbi.nlm.nih.gov/1636702/ DOI: 10.1152/ajpendo.1992.263.1.e85

tissue_or_cell_type

Whole body thyroid hormone kinetics

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 676–687

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Sixteen men given oral T3 before, during and after 80 cold air exposures, with and without T3 replacement · source_derived_draft · unverified_draft

### cold-cold-t3-clearance Repeated cold air exposure increased the oral metabolic clearance rate of T3 by 5.4 l/day/m2 and the disposal rate by 10.2 nmol/day/m2, and these increases were not dependent on thyrotropin or thyroxine, since they were unchanged in men given replacement T3 whose TSH and T4 fell by about half. Condition category: normal nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Cold makes the body consume active thyroid hormone faster, independently of the usual feedback loop. organism: Human tissue_or_cell_type: Whole body thyroid hormone kinetics experimental_model: Sixteen men given oral T3 before, during and after 80 cold air exposures, with and without T3 replacement limitations: Cold air rather than water immersion, recorded because it isolates the thyroid hormone kinetics. The pharmacological oral T3 dose is not physiological. exposure: Eighty exposures to 4 degrees C air, ten per week evidence_span: {"source_cache": "artifacts/cold-research/1636702.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4e0d8127d3ebb682588afd84b635d2607dce9ebec4e7573d25e7baae58fc9301", "start_char": 0, "end_char": 1183, "text_sha256": "4e0d8127d3ebb682588afd84b635d2607dce9ebec4e7573d25e7baae58fc9301"} [cold-p1636702] Multiple cold air exposures change oral triiodothyronine kinetics in normal men. (1992). https://pubmed.ncbi.nlm.nih.gov/1636702/ DOI: 10.1152/ajpendo.1992.263.1.e85

evidence_span

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experimental_model

Mice with targeted disruption of the Dio2 gene, with brown adipocyte assays and T3 rescue

exposure

Cold stress, with norepinephrine, CL316,243 or forskolin stimulation, and a single T3 injection

limitations

The selenoenzyme is the link between thyroid hormone and sympathetic signalling. Plasma T3 was normal in the knockouts, so the defect is local hormone generation, not circulating hormone.

nutrient_topic

Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Cold water immersion

organism

Mouse

plain_language

Two receptors need different amounts of hormone, and only local production reaches the hungrier one.

primary_references

[cold-p11696583] The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. (2001). https://pubmed.ncbi.nlm.nih.gov/11696583/ DOI: 10.1172/jci13803

tissue_or_cell_type

Brown adipose tissue

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 416–427

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mice with targeted disruption of the Dio2 gene, with brown adipocyte assays and T3 rescue · source_derived_draft · unverified_draft

### cold-dio2-thyroid-sympathetic-synergy The authors propose that intracellularly generated T3 is required to saturate thyroid hormone receptor alpha, which has an approximately fourfold lower T3-binding affinity than receptor beta, making the deiodinase an essential component of the thyroid-sympathetic synergism required for thermal homeostasis. Condition category: normal nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Two receptors need different amounts of hormone, and only local production reaches the hungrier one. organism: Mouse tissue_or_cell_type: Brown adipose tissue experimental_model: Mice with targeted disruption of the Dio2 gene, with brown adipocyte assays and T3 rescue limitations: The selenoenzyme is the link between thyroid hormone and sympathetic signalling. Plasma T3 was normal in the knockouts, so the defect is local hormone generation, not circulating hormone. exposure: Cold stress, with norepinephrine, CL316,243 or forskolin stimulation, and a single T3 injection evidence_span: {"source_cache": "artifacts/cold-research/11696583.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "adbd82ff8c43d8a2718cfa752c9a0607c367648d6573b968eb885c883376dc68", "start_char": 0, "end_char": 1332, "text_sha256": "adbd82ff8c43d8a2718cfa752c9a0607c367648d6573b968eb885c883376dc68"} [cold-p11696583] The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. (2001). https://pubmed.ncbi.nlm.nih.gov/11696583/ DOI: 10.1172/jci13803

evidence_span

{"source_cache": "artifacts/cold-research/7628361.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ee7ba7cfa7ae3387c067f33a03ad9c212801437175f6cb656d5e86b482ed8d64", "start_char": 0, "end_char": 2080, "text_sha256": "ee7ba7cfa7ae3387c067f33a03ad9c212801437175f6cb656d5e86b482ed8d64"}

experimental_model

Brown and white adipose tissue of hypothyroid and T3-treated rats

exposure

Hypothyroidism, T3 replacement and T3 excess

limitations

The reciprocal regulation in the two tissues is the informative part. A post-receptor cAMP defect persisted after receptor numbers were corrected, so receptor count is not the whole story.

nutrient_topic

Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Cold water immersion

organism

Rat

plain_language

Thyroid hormone tunes how loudly each fat depot hears the nerve signal, in opposite directions.

primary_references

[cold-p7628361] Thyroid hormone and norepinephrine signaling in brown adipose tissue. II: Differential effects of thyroid hormone on beta 3-adrenergic receptors in brown and white adipose tissue. (1995). https://pubmed.ncbi.nlm.nih.gov/7628361/ DOI: 10.1210/endo.136.8.7628361

tissue_or_cell_type

Brown and white adipose tissue

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 429–440

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Brown and white adipose tissue of hypothyroid and T3-treated rats · source_derived_draft · unverified_draft

### cold-thyroid-beta3-regulation In brown adipose tissue of hypothyroid rats beta-3 adrenergic receptor number and mRNA increased 4- to 6-fold while both fell in white adipose tissue, T3 injection reverted the changes within 24 hours, and T3 excess caused a greater than 90% reduction of beta-3 receptor mRNA in brown fat but a 5-fold increase in white fat. Condition category: normal nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Thyroid hormone tunes how loudly each fat depot hears the nerve signal, in opposite directions. organism: Rat tissue_or_cell_type: Brown and white adipose tissue experimental_model: Brown and white adipose tissue of hypothyroid and T3-treated rats limitations: The reciprocal regulation in the two tissues is the informative part. A post-receptor cAMP defect persisted after receptor numbers were corrected, so receptor count is not the whole story. exposure: Hypothyroidism, T3 replacement and T3 excess evidence_span: {"source_cache": "artifacts/cold-research/7628361.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ee7ba7cfa7ae3387c067f33a03ad9c212801437175f6cb656d5e86b482ed8d64", "start_char": 0, "end_char": 2080, "text_sha256": "ee7ba7cfa7ae3387c067f33a03ad9c212801437175f6cb656d5e86b482ed8d64"} [cold-p7628361] Thyroid hormone and norepinephrine signaling in brown adipose tissue. II: Differential effects of thyroid hormone on beta 3-adrenergic receptors in brown and white adipose tissue. (1995). https://pubmed.ncbi.nlm.nih.gov/7628361/ DOI: 10.1210/endo.136.8.7628361

evidence_locator

Results: T3 recognition, Figure 3; Methods

evidence_spans

[{"source_document": "artifacts/iodine-metabolism-sources/40140416.txt", "locator": "Results: T3 recognition, Figure 3; Methods", "start_char": 679, "end_char": 2779}]

experimental_model

Purified tagged human MCT8 from HEK293F cells; cryo-EM and cell-based mutagenesis

exposure

Cryo-EM preparation: 1.5 mM T3. HeLa uptake assay: human MCT8 and CRYM coexpression; 1 nM unlabeled T3 plus 0.02 microcuries 125I-T3 for 30 minutes at 37 C.

limitations

Purified structural occupancy is not a physiological concentration threshold. Individual mutations and their effects are not identical.

nutrient_topic

Iodine research collection; topical membership is not evidence of a direct dietary effect. · Iodine

organism

Human

plain_language

The transporter recognizes the shape and chemical groups of iodine-containing T3.

primary_references

[i-met-40140416] Structural insights into thyroid hormone transporter MCT8. (2025). https://pubmed.ncbi.nlm.nih.gov/40140416/ DOI: 10.1038/s41467-025-58131-8

tissue_or_cell_type

HeLa cells for transport; HEK293F cells for protein production

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 912–924

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified tagged human MCT8 from HEK293F cells; cryo-EM and cell-based mutagenesis · source_derived_draft · unverified_draft

### i-met-mct8-t3-recognition Human MCT8 structure places the T3 carboxylate against Arg371 and its iodine atoms in hydrophobic pockets; substitutions of substrate-contact residues reduce cellular T3 uptake. Condition category: normal nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The transporter recognizes the shape and chemical groups of iodine-containing T3. organism: Human tissue_or_cell_type: HeLa cells for transport; HEK293F cells for protein production experimental_model: Purified tagged human MCT8 from HEK293F cells; cryo-EM and cell-based mutagenesis limitations: Purified structural occupancy is not a physiological concentration threshold. Individual mutations and their effects are not identical. exposure: Cryo-EM preparation: 1.5 mM T3. HeLa uptake assay: human MCT8 and CRYM coexpression; 1 nM unlabeled T3 plus 0.02 microcuries 125I-T3 for 30 minutes at 37 C. evidence_locator: Results: T3 recognition, Figure 3; Methods evidence_spans: [{"source_document": "artifacts/iodine-metabolism-sources/40140416.txt", "locator": "Results: T3 recognition, Figure 3; Methods", "start_char": 679, "end_char": 2779}] [i-met-40140416] Structural insights into thyroid hormone transporter MCT8. (2025). https://pubmed.ncbi.nlm.nih.gov/40140416/ DOI: 10.1038/s41467-025-58131-8

evidence_span

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experimental_model

Mice with targeted disruption of the Dio2 gene, with brown adipocyte assays and T3 rescue

exposure

Cold stress, with norepinephrine, CL316,243 or forskolin stimulation, and a single T3 injection

limitations

The selenoenzyme is the link between thyroid hormone and sympathetic signalling. Plasma T3 was normal in the knockouts, so the defect is local hormone generation, not circulating hormone.

nutrient_topic

Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Cold water immersion

organism

Mouse

plain_language

Cold makes brown fat build a selenium enzyme that manufactures active thyroid hormone on the spot.

primary_references

[cold-p11696583] The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. (2001). https://pubmed.ncbi.nlm.nih.gov/11696583/ DOI: 10.1172/jci13803

tissue_or_cell_type

Brown adipose tissue

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 377–388

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mice with targeted disruption of the Dio2 gene, with brown adipocyte assays and T3 rescue · source_derived_draft · unverified_draft

### cold-dio2-selenoenzyme Type 2 iodothyronine deiodinase is a selenoenzyme, the product of the cAMP-dependent Dio2 gene, which increases 10- to 50-fold during cold stress only in brown adipose tissue. Condition category: normal nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Cold makes brown fat build a selenium enzyme that manufactures active thyroid hormone on the spot. organism: Mouse tissue_or_cell_type: Brown adipose tissue experimental_model: Mice with targeted disruption of the Dio2 gene, with brown adipocyte assays and T3 rescue limitations: The selenoenzyme is the link between thyroid hormone and sympathetic signalling. Plasma T3 was normal in the knockouts, so the defect is local hormone generation, not circulating hormone. exposure: Cold stress, with norepinephrine, CL316,243 or forskolin stimulation, and a single T3 injection evidence_span: {"source_cache": "artifacts/cold-research/11696583.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "adbd82ff8c43d8a2718cfa752c9a0607c367648d6573b968eb885c883376dc68", "start_char": 0, "end_char": 1332, "text_sha256": "adbd82ff8c43d8a2718cfa752c9a0607c367648d6573b968eb885c883376dc68"} [cold-p11696583] The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. (2001). https://pubmed.ncbi.nlm.nih.gov/11696583/ DOI: 10.1172/jci13803

experimental_model

Human liver/kidney cDNA cloning and heterologous enzyme expression.

limitations

This reaction alone cannot diagnose hidden tissue hypothyroidism from normal blood tests or quantify benefit from selenium intake.

organism

Human protein in a heterologous expression system

Selenium: literature corrections and mechanism additions · lines 998–1007

Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Human liver/kidney cDNA cloning and heterologous enzyme expression. · secondary_verified · secondary_verified

## dio1-t4-to-t3 DIO1 converts T4 into the active thyroid hormone T3. DIO1 catalyzes outer-ring deiodination of T4 to T3 in functional enzyme-expression experiments. Experimental model: Human liver/kidney cDNA cloning and heterologous enzyme expression. Organism: Human protein in a heterologous expression system Limitations: This reaction alone cannot diagnose hidden tissue hypothyroidism from normal blood tests or quantify benefit from selenium intake. Primary reference: [Cloning and in vitro expression of the human selenoprotein, type I iodothyronine deiodinase](https://pubmed.ncbi.nlm.nih.gov/1400883/)

experimental_model

Rat and human DIO2 cDNA characterization and functional expression.

limitations

This reaction alone cannot diagnose hidden tissue hypothyroidism from normal blood tests or quantify benefit from selenium intake.

organism

Human and rat

Selenium: literature corrections and mechanism additions · lines 1009–1018

Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Rat and human DIO2 cDNA characterization and functional expression. · secondary_verified · secondary_verified

## dio2-t4-to-t3 DIO2 converts T4 into the active thyroid hormone T3. DIO2 catalyzes outer-ring deiodination of T4 to T3 in functional enzyme-expression experiments. Experimental model: Rat and human DIO2 cDNA characterization and functional expression. Organism: Human and rat Limitations: This reaction alone cannot diagnose hidden tissue hypothyroidism from normal blood tests or quantify benefit from selenium intake. Primary reference: [Cloning of the mammalian type II iodothyronine deiodinase](https://www.jci.org/articles/view/118806)

evidence_access

Primary abstract

experimental_model

Human HepG2 uptake assay; high millimolar exposures.

limitations

No direct inhibition of T3 binding to isolated nuclei was observed; not proof of iodine depletion or routine-dose hypothyroidism.

nutrient_topic

L-Carnitine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnitine

plain_language

Carnitine can affect thyroid-hormone access to the nucleus in cell experiments.

primary_references

Carnitine is a naturally occurring inhibitor of thyroid hormone nuclear uptake. · 2000 · https://pubmed.ncbi.nlm.nih.gov/11201848/ · DOI 10.1089/thy.2000.10.1043

L-Carnitine: synthesis, acyl-group transport, fuel selection and nutrient interactions (2026-09-19) · lines 298–304

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human HepG2 uptake assay; high millimolar exposures. · source_derived_draft · unverified_draft

## l-carnitine-thyroid-nuclear Carnitine can affect thyroid-hormone access to the nucleus in cell experiments. Adding 10 mM carnitine reduced nuclear T3 uptake in human HepG2 cells by about 35%; 50 mM produced a larger reduction. Model: Human HepG2 uptake assay; high millimolar exposures. Limitations: No direct inhibition of T3 binding to isolated nuclei was observed; not proof of iodine depletion or routine-dose hypothyroidism. Evidence access: Primary abstract Carnitine is a naturally occurring inhibitor of thyroid hormone nuclear uptake. · 2000 · https://pubmed.ncbi.nlm.nih.gov/11201848/ · DOI 10.1089/thy.2000.10.1043

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_locator

Results: serum hormone levels, Figure 7; Methods page 2146: Assays for Serum T4, T3 and TSH.

evidence_spans

[{"source_document": "artifacts/iodine-metabolism-sources/11731615.txt", "locator": "Primary article Results, Figures 7 and 9; Methods: Assays for Serum T4, T3 and TSH, page 2146", "start_char": 17896, "end_char": 18546}, {"source_document": "artifacts/iodine-metabolism-sources/11731615.txt", "locator": "Methods page 2146, total-T3 assay identity and mouse-serum correction", "start_char": 29655, "end_char": 31355}]

experimental_model

Dio2-null mice and wild-type littermates, including hormone challenge after hypothyroidism

exposure

Adult mice aged 10–12 weeks; total-T3 Coat-A-Count radioimmunoassay with correction for a nonspecific mouse-serum effect.

limitations

Specific mouse compensation; not a diagnostic rule for hidden tissue hypothyroidism in humans.

nutrient_topic

Iodine research collection; topical membership is not evidence of a direct dietary effect. · Iodine

organism

Mus musculus

plain_language

A normal circulating T3 result did not mean that the deleted enzyme was functioning.

primary_references

[i-met-11731615] Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4. (2001). https://pubmed.ncbi.nlm.nih.gov/11731615/ DOI: 10.1210/mend.15.12.0740

tissue_or_cell_type

Serum and surveyed tissues

trigger_kind

machinery_impairment Imported condition classification; unverified.

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 1040–1052

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dio2-null mice and wild-type littermates, including hormone challenge after hypothyroidism · source_derived_draft · unverified_draft

### i-met-dio2-ko-serum-t3 Adult Dio2-null mice had serum total T3 comparable to wild type despite complete loss of measured D2 activity and elevated serum T4 and TSH. Condition category: machinery_impairment nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: A normal circulating T3 result did not mean that the deleted enzyme was functioning. organism: Mus musculus tissue_or_cell_type: Serum and surveyed tissues experimental_model: Dio2-null mice and wild-type littermates, including hormone challenge after hypothyroidism limitations: Specific mouse compensation; not a diagnostic rule for hidden tissue hypothyroidism in humans. exposure: Adult mice aged 10–12 weeks; total-T3 Coat-A-Count radioimmunoassay with correction for a nonspecific mouse-serum effect. evidence_locator: Results: serum hormone levels, Figure 7; Methods page 2146: Assays for Serum T4, T3 and TSH. evidence_spans: [{"source_document": "artifacts/iodine-metabolism-sources/11731615.txt", "locator": "Primary article Results, Figures 7 and 9; Methods: Assays for Serum T4, T3 and TSH, page 2146", "start_char": 17896, "end_char": 18546}, {"source_document": "artifacts/iodine-metabolism-sources/11731615.txt", "locator": "Methods page 2146, total-T3 assay identity and mouse-serum correction", "start_char": 29655, "end_char": 31355}] [i-met-11731615] Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4. (2001). https://pubmed.ncbi.nlm.nih.gov/11731615/ DOI: 10.1210/mend.15.12.0740

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Selenoenzyme D2 activates an iodine-containing hormone for feedback; knockout is a machinery experiment.

evidence_locator

Results: TSH Suppression Studies and Figure 9; pages 2140–2141.

evidence_spans

[{"source_document": "artifacts/iodine-metabolism-sources/11731615.txt", "locator": "Primary article Results, Figures 7 and 9; Methods: Assays for Serum T4, T3 and TSH, page 2146", "start_char": 20490, "end_char": 22790}]

experimental_model

Dio2-null mice and wild-type littermates, including hormone challenge after hypothyroidism

exposure

Male mice made hypothyroid for four weeks with methimazole/perchlorate; PTU inhibited D1. Subcutaneous T4 3 micrograms/100 g body weight or T3 1.2 micrograms/100 g; serum collected five hours later.

limitations

Pharmacologic hormone challenge after thyroid synthesis blockade and D1 inhibition; not a human dosing rule or dietary selenium-deficiency experiment.

nutrient_topic

Iodine research collection; topical membership is not evidence of a direct dietary effect. · Iodine

organism

Mus musculus

plain_language

T3 bypassed the missing local T4-activation step in this feedback experiment.

primary_references

[i-met-11731615] Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4. (2001). https://pubmed.ncbi.nlm.nih.gov/11731615/ DOI: 10.1210/mend.15.12.0740

tissue_or_cell_type

Pituitary feedback and serum TSH

trigger_kind

machinery_impairment Imported condition classification; unverified.

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 1025–1038

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dio2-null mice and wild-type littermates, including hormone challenge after hypothyroidism · source_derived_draft · unverified_draft

### i-met-dio2-t4-feedback T4 suppressed serum TSH in hypothyroid wild-type mice but not Dio2-null mice; administered T3 suppressed TSH in both genotypes. Condition category: machinery_impairment nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: T3 bypassed the missing local T4-activation step in this feedback experiment. organism: Mus musculus tissue_or_cell_type: Pituitary feedback and serum TSH experimental_model: Dio2-null mice and wild-type littermates, including hormone challenge after hypothyroidism limitations: Pharmacologic hormone challenge after thyroid synthesis blockade and D1 inhibition; not a human dosing rule or dietary selenium-deficiency experiment. exposure: Male mice made hypothyroid for four weeks with methimazole/perchlorate; PTU inhibited D1. Subcutaneous T4 3 micrograms/100 g body weight or T3 1.2 micrograms/100 g; serum collected five hours later. cross_nutrient: Selenoenzyme D2 activates an iodine-containing hormone for feedback; knockout is a machinery experiment. evidence_locator: Results: TSH Suppression Studies and Figure 9; pages 2140–2141. evidence_spans: [{"source_document": "artifacts/iodine-metabolism-sources/11731615.txt", "locator": "Primary article Results, Figures 7 and 9; Methods: Assays for Serum T4, T3 and TSH, page 2146", "start_char": 20490, "end_char": 22790}] [i-met-11731615] Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4. (2001). https://pubmed.ncbi.nlm.nih.gov/11731615/ DOI: 10.1210/mend.15.12.0740

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_locator

Figure 3B and Results: Analysis of TH content and metabolism in the brain

evidence_spans

[{"source_document": "artifacts/iodine-metabolism-sources/24691440.txt", "locator": "Figure 3B and Results: Analysis of TH content and metabolism in the brain", "start_char": 26251, "end_char": 27951}]

experimental_model

Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays

exposure

P21, n=8 per genotype; hormone content measurements.

limitations

The content result is local to mouse forebrain and this developmental time.

nutrient_topic

Iodine research collection; topical membership is not evidence of a direct dietary effect. · Iodine

organism

Mus musculus

plain_language

Losing both transport routes overwhelms the compensation seen after one loss.

primary_references

[i-met-24691440] Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. (2014). https://pubmed.ncbi.nlm.nih.gov/24691440/ DOI: 10.1172/jci70324

tissue_or_cell_type

Perfused forebrain

trigger_kind

machinery_impairment Imported condition classification; unverified.

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 996–1008

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays · source_derived_draft · unverified_draft

### i-met-double-ko-brain-t3 At postnatal day 21, double-knockout forebrain T3 content was approximately 10% of wild type, whereas Oatp1c1 single-knockout forebrain T3 was preserved. Condition category: machinery_impairment nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Losing both transport routes overwhelms the compensation seen after one loss. organism: Mus musculus tissue_or_cell_type: Perfused forebrain experimental_model: Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays limitations: The content result is local to mouse forebrain and this developmental time. exposure: P21, n=8 per genotype; hormone content measurements. evidence_locator: Figure 3B and Results: Analysis of TH content and metabolism in the brain evidence_spans: [{"source_document": "artifacts/iodine-metabolism-sources/24691440.txt", "locator": "Figure 3B and Results: Analysis of TH content and metabolism in the brain", "start_char": 26251, "end_char": 27951}] [i-met-24691440] Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. (2014). https://pubmed.ncbi.nlm.nih.gov/24691440/ DOI: 10.1172/jci70324

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Selenium-containing D2 processes iodine-containing T4; genetic transport failure persists despite increased enzyme activity.

evidence_locator

Figure 4A and Results: Analysis of TH content and metabolism in the brain

evidence_spans

[{"source_document": "artifacts/iodine-metabolism-sources/24691440.txt", "locator": "Figure 4A and Results: Analysis of TH content and metabolism in the brain", "start_char": 26902, "end_char": 28402}]

experimental_model

Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays

exposure

P21 double knockout versus wild type; D2 activity assay.

limitations

This is compensatory enzyme activity, not demonstration that selenium supplementation repairs transporter loss.

nutrient_topic

Iodine research collection; topical membership is not evidence of a direct dietary effect. · Iodine

organism

Mus musculus

plain_language

The brain increases local hormone activation machinery, but this cannot replace missing substrate delivery.

primary_references

[i-met-24691440] Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. (2014). https://pubmed.ncbi.nlm.nih.gov/24691440/ DOI: 10.1172/jci70324

tissue_or_cell_type

Forebrain and cerebellum homogenates

trigger_kind

machinery_impairment Imported condition classification; unverified.

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 1010–1023

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays · source_derived_draft · unverified_draft

### i-met-double-ko-dio2-response D2 activity in P21 forebrain and cerebellum rose almost tenfold in Mct8/Oatp1c1 double-knockout mice despite persistent severe brain hormone depletion. Condition category: machinery_impairment nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The brain increases local hormone activation machinery, but this cannot replace missing substrate delivery. organism: Mus musculus tissue_or_cell_type: Forebrain and cerebellum homogenates experimental_model: Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays limitations: This is compensatory enzyme activity, not demonstration that selenium supplementation repairs transporter loss. exposure: P21 double knockout versus wild type; D2 activity assay. cross_nutrient: Selenium-containing D2 processes iodine-containing T4; genetic transport failure persists despite increased enzyme activity. evidence_locator: Figure 4A and Results: Analysis of TH content and metabolism in the brain evidence_spans: [{"source_document": "artifacts/iodine-metabolism-sources/24691440.txt", "locator": "Figure 4A and Results: Analysis of TH content and metabolism in the brain", "start_char": 26902, "end_char": 28402}] [i-met-24691440] Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. (2014). https://pubmed.ncbi.nlm.nih.gov/24691440/ DOI: 10.1172/jci70324

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_locator

Figure 3A and Results: In vivo T4 transport studies

evidence_spans

[{"source_document": "artifacts/iodine-metabolism-sources/24691440.txt", "locator": "Figure 3A and Results: In vivo T4 transport studies", "start_char": 23660, "end_char": 25360}]

experimental_model

Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays

exposure

Adults received 1.2 microcuries 125I-T4 intraperitoneally; n=3 per genotype and time point.

limitations

Tracer accumulation is a transport measurement; murine redundancy is not proof of equivalent human compensation.

nutrient_topic

Iodine research collection; topical membership is not evidence of a direct dietary effect. · Iodine

organism

Mus musculus

plain_language

The two mouse transporters provide partly overlapping routes into the brain.

primary_references

[i-met-24691440] Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. (2014). https://pubmed.ncbi.nlm.nih.gov/24691440/ DOI: 10.1172/jci70324

tissue_or_cell_type

Brain after systemic tracer injection

trigger_kind

machinery_impairment Imported condition classification; unverified.

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 982–994

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays · source_derived_draft · unverified_draft

### i-met-double-ko-t4-entry Brain uptake of injected radiolabeled T4 was strongly reduced in Mct8/Oatp1c1 double-knockout mice; either single knockout retained roughly half the wild-type uptake. Condition category: machinery_impairment nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The two mouse transporters provide partly overlapping routes into the brain. organism: Mus musculus tissue_or_cell_type: Brain after systemic tracer injection experimental_model: Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays limitations: Tracer accumulation is a transport measurement; murine redundancy is not proof of equivalent human compensation. exposure: Adults received 1.2 microcuries 125I-T4 intraperitoneally; n=3 per genotype and time point. evidence_locator: Figure 3A and Results: In vivo T4 transport studies evidence_spans: [{"source_document": "artifacts/iodine-metabolism-sources/24691440.txt", "locator": "Figure 3A and Results: In vivo T4 transport studies", "start_char": 23660, "end_char": 25360}] [i-met-24691440] Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. (2014). https://pubmed.ncbi.nlm.nih.gov/24691440/ DOI: 10.1172/jci70324

evidence_locator

Primary abstract

evidence_spans

[{"source_document": "artifacts/iodine-metabolism-sources/12871948.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1490}]

experimental_model

Rat MCT8 cRNA expressed in Xenopus laevis oocytes

exposure

MCT8 cRNA; assay three days later with 10 nM 125I-labeled hormone; uptake linear for less than four minutes.

limitations

Rat transporter in an expression host; this is hormone transport, not intestinal iodide uptake.

nutrient_topic

Iodine research collection; topical membership is not evidence of a direct dietary effect. · Iodine

organism

Rat protein in Xenopus laevis

plain_language

MCT8 carries T3 across the cell membrane.

primary_references

[i-met-12871948] Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. (2003). https://pubmed.ncbi.nlm.nih.gov/12871948/ DOI: 10.1074/jbc.m300909200

tissue_or_cell_type

Oocyte plasma membrane

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 898–910

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat MCT8 cRNA expressed in Xenopus laevis oocytes · source_derived_draft · unverified_draft

### i-met-rat-t3 Rat MCT8 expression increased uptake of 10 nM radiolabeled T3 approximately tenfold in Xenopus oocytes. Condition category: normal nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: MCT8 carries T3 across the cell membrane. organism: Rat protein in Xenopus laevis tissue_or_cell_type: Oocyte plasma membrane experimental_model: Rat MCT8 cRNA expressed in Xenopus laevis oocytes limitations: Rat transporter in an expression host; this is hormone transport, not intestinal iodide uptake. exposure: MCT8 cRNA; assay three days later with 10 nM 125I-labeled hormone; uptake linear for less than four minutes. evidence_locator: Primary abstract evidence_spans: [{"source_document": "artifacts/iodine-metabolism-sources/12871948.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1490}] [i-met-12871948] Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. (2003). https://pubmed.ncbi.nlm.nih.gov/12871948/ DOI: 10.1074/jbc.m300909200

cross_nutrient

false

evidence_span

{"source_cache": "artifacts/iodine-synthesis-sources/10433193.json", "json_field": "abstractText", "text_sha256": "edf82df926d65731111d3f6b8005965a95e9928421170aa4cb5cef0709adc924", "text_characters": 2339, "note": "Exact publisher passage retained in the cited local source cache; locator and digest supplied here."}

experimental_model

Rat oral and intraperitoneal sodium iodide experiments

exposure

0.05% sodium iodide in drinking water for 1 or 6 days.

limitations

Rodent pharmacological exposure; recovery time and susceptibility cannot be imposed on humans.

nutrient_topic

Iodine research collection; topical membership is not evidence of a direct dietary effect. · Iodine

organism

Rattus norvegicus

plain_language

The initial hormone suppression wore off despite continued high iodide exposure.

primary_references

[iodine-syn-escape1999] Escape from the acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter messenger ribonucleic acid and protein. (1999). https://pubmed.ncbi.nlm.nih.gov/10433193/ DOI: 10.1210/endo.140.8.6893

tissue_or_cell_type

Serum

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 786–798

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat oral and intraperitoneal sodium iodide experiments · source_derived_draft · unverified_draft

### iodine-syn-escape-hormone-recovery During continued 0.05% NaI exposure, rat serum T4 and T3 fell at day 1 but returned to normal by day 6. Condition category: normal nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The initial hormone suppression wore off despite continued high iodide exposure. organism: Rattus norvegicus tissue_or_cell_type: Serum experimental_model: Rat oral and intraperitoneal sodium iodide experiments limitations: Rodent pharmacological exposure; recovery time and susceptibility cannot be imposed on humans. exposure: 0.05% sodium iodide in drinking water for 1 or 6 days. cross_nutrient: false evidence_span: {"source_cache": "artifacts/iodine-synthesis-sources/10433193.json", "json_field": "abstractText", "text_sha256": "edf82df926d65731111d3f6b8005965a95e9928421170aa4cb5cef0709adc924", "text_characters": 2339, "note": "Exact publisher passage retained in the cited local source cache; locator and digest supplied here."} [iodine-syn-escape1999] Escape from the acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter messenger ribonucleic acid and protein. (1999). https://pubmed.ncbi.nlm.nih.gov/10433193/ DOI: 10.1210/endo.140.8.6893

cross_nutrient

false

evidence_span

{"source_cache": "artifacts/iodine-synthesis-sources/7372636.txt", "start_char": 6216, "end_char": 8536, "text_sha256": "753e684061b9063528196c840b23404015abc2b7b836a3887497aea0f8fe20a6", "text_characters": 2320, "note": "Exact publisher passage retained in the cited local source cache; locator and digest supplied here."}

experimental_model

Purified hog TPO with human goiter TG or tyrosine-radiolabeled hog TG; chromatographic hormone and dehydroalanine analyses

exposure

Human goiter TG initially 0.04% iodine, iodinated for 90 minutes to approximately 60 iodine atoms per TG; the same preparation contained 2.6 T4 residues per molecule.

limitations

Reconstituted mixed-species experiment. Hormone residues are protein-bound before hydrolysis; the assay is not evidence that free MIT and DIT are routinely coupled in blood.

nutrient_topic

Iodine research collection; topical membership is not evidence of a direct dietary effect. · Iodine

organism

Sus scrofa enzyme; Homo sapiens substrate

plain_language

TPO-driven chemistry can make T3 directly within TG, before the hormone is released.

primary_references

[iodine-syn-tpo-coupling1980] Formation of dehydroalanine residues during thyroid hormone synthesis in thyroglobulin. (1980). https://pubmed.ncbi.nlm.nih.gov/7372636/ DOI: 10.1016/S0021-9258(19)70782-0

tissue_or_cell_type

Purified TPO and human goiter TG

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 856–868

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified hog TPO with human goiter TG or tyrosine-radiolabeled hog TG; chromatographic hormone and dehydroalanine analyses · source_derived_draft · unverified_draft

### iodine-syn-tpo-t3-formation Iodinating human goiter TG with hog TPO for 90 minutes produced 0.3 T3 residues per TG molecule, measured after enzymatic hydrolysis. Condition category: normal nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: TPO-driven chemistry can make T3 directly within TG, before the hormone is released. organism: Sus scrofa enzyme; Homo sapiens substrate tissue_or_cell_type: Purified TPO and human goiter TG experimental_model: Purified hog TPO with human goiter TG or tyrosine-radiolabeled hog TG; chromatographic hormone and dehydroalanine analyses limitations: Reconstituted mixed-species experiment. Hormone residues are protein-bound before hydrolysis; the assay is not evidence that free MIT and DIT are routinely coupled in blood. exposure: Human goiter TG initially 0.04% iodine, iodinated for 90 minutes to approximately 60 iodine atoms per TG; the same preparation contained 2.6 T4 residues per molecule. cross_nutrient: false evidence_span: {"source_cache": "artifacts/iodine-synthesis-sources/7372636.txt", "start_char": 6216, "end_char": 8536, "text_sha256": "753e684061b9063528196c840b23404015abc2b7b836a3887497aea0f8fe20a6", "text_characters": 2320, "note": "Exact publisher passage retained in the cited local source cache; locator and digest supplied here."} [iodine-syn-tpo-coupling1980] Formation of dehydroalanine residues during thyroid hormone synthesis in thyroglobulin. (1980). https://pubmed.ncbi.nlm.nih.gov/7372636/ DOI: 10.1016/S0021-9258(19)70782-0

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/cold-research/11696583.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "adbd82ff8c43d8a2718cfa752c9a0607c367648d6573b968eb885c883376dc68", "start_char": 0, "end_char": 1332, "text_sha256": "adbd82ff8c43d8a2718cfa752c9a0607c367648d6573b968eb885c883376dc68"}

experimental_model

Mice with targeted disruption of the Dio2 gene, with brown adipocyte assays and T3 rescue

exposure

Cold stress, with norepinephrine, CL316,243 or forskolin stimulation, and a single T3 injection

limitations

The selenoenzyme is the link between thyroid hormone and sympathetic signalling. Plasma T3 was normal in the knockouts, so the defect is local hormone generation, not circulating hormone.

nutrient_topic

Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Cold water immersion

organism

Mouse

plain_language

Without locally made hormone the cell cannot even hear the nerve signal properly.

primary_references

[cold-p11696583] The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. (2001). https://pubmed.ncbi.nlm.nih.gov/11696583/ DOI: 10.1172/jci13803

tissue_or_cell_type

Brown adipose tissue

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 403–414

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mice with targeted disruption of the Dio2 gene, with brown adipocyte assays and T3 rescue · source_derived_draft · unverified_draft

### cold-dio2-camp-defect In Dio2-null brown adipocytes the acute norepinephrine-, CL316,243- or forskolin-induced increases in lipolysis, UCP1 mRNA and oxygen consumption were all reduced because of impaired cAMP generation, and all were completely reversed by a single T3 injection 14 hours earlier. Condition category: nutrient_deficiency nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Without locally made hormone the cell cannot even hear the nerve signal properly. organism: Mouse tissue_or_cell_type: Brown adipose tissue experimental_model: Mice with targeted disruption of the Dio2 gene, with brown adipocyte assays and T3 rescue limitations: The selenoenzyme is the link between thyroid hormone and sympathetic signalling. Plasma T3 was normal in the knockouts, so the defect is local hormone generation, not circulating hormone. exposure: Cold stress, with norepinephrine, CL316,243 or forskolin stimulation, and a single T3 injection evidence_span: {"source_cache": "artifacts/cold-research/11696583.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "adbd82ff8c43d8a2718cfa752c9a0607c367648d6573b968eb885c883376dc68", "start_char": 0, "end_char": 1332, "text_sha256": "adbd82ff8c43d8a2718cfa752c9a0607c367648d6573b968eb885c883376dc68"} [cold-p11696583] The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. (2001). https://pubmed.ncbi.nlm.nih.gov/11696583/ DOI: 10.1172/jci13803

cross_nutrient

Vitamin A-iodine: shared receptor machinery for an iodine-containing hormone; not evidence of iodine repletion.

evidence_locator

Figure 3

experimental_model

Recombinant receptors, gel shifts, coimmunoprecipitation and CV-1 reporters.

exposure

Reconstituted TR beta/RXRA

limitations

No iodine nutritional manipulation.

nutrient_topic

Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A

organism

Recombinant receptors

plain_language

A receptor used by retinoids also supports thyroid-hormone DNA recognition.

primary_references

[va-kliewer-1992] Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling (1992). https://pubmed.ncbi.nlm.nih.gov/1310351/ DOI: 10.1038/355446a0

tissue_or_cell_type

Cell-free DNA-binding assay

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1109–1121

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant receptors, gel shifts, coimmunoprecipitation and CV-1 reporters. · source_derived_draft · unverified_draft

### va-sig-rxra-thrb-partnership RXRA complexed with TR beta and enhanced thyroid-response-element binding. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: A receptor used by retinoids also supports thyroid-hormone DNA recognition. organism: Recombinant receptors tissue_or_cell_type: Cell-free DNA-binding assay experimental_model: Recombinant receptors, gel shifts, coimmunoprecipitation and CV-1 reporters. limitations: No iodine nutritional manipulation. evidence_locator: Figure 3 cross_nutrient: Vitamin A-iodine: shared receptor machinery for an iodine-containing hormone; not evidence of iodine repletion. exposure: Reconstituted TR beta/RXRA [va-kliewer-1992] Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling (1992). https://pubmed.ncbi.nlm.nih.gov/1310351/ DOI: 10.1038/355446a0

experimental_model

Human placental DIO3 cloning and functional expression.

limitations

This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit.

organism

Human placental protein in an expression system

Selenium: literature corrections and mechanism additions · lines 1031–1040

Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Human placental DIO3 cloning and functional expression. · secondary_verified · secondary_verified

## dio3-triiodothyronine-inactivation DIO3 lowers thyroid-hormone activity by converting T3 to 3,3-prime-T2. DIO3 catalyzes inner-ring deiodination of T3 to 3,3-prime-T2 in functional placental-enzyme studies. Experimental model: Human placental DIO3 cloning and functional expression. Organism: Human placental protein in an expression system Limitations: This experiment-specific relationship does not establish a human dietary-deficiency threshold or supplementation benefit. Primary reference: [Type 3 iodothyronine deiodinase: cloning, in vitro expression, and functional analysis of the placental selenoenzyme](https://www.jci.org/articles/view/118299)