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Cited by 60Thyroid Disorders and TreatmentsAdipose Tissue and MetabolismThyroid Cancer Diagnosis and Treatment

Similarities and differences in the peripheral actions of thyroid hormones and their metabolites

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Louzada, Ruy A., Carvalho, Denise P.·2018·Frontiers in Endocrinology
DOI 10.3389/fendo.2018.00394PMC PMC6060242
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Abstract

Thyroxine (T4) and 3,5,3'-triiodothyronine (T3) are secreted by the thyroid gland, while T3 is also generated from the peripheral metabolism of T4 by iodothyronine deiodinases types I and II. Several conditions like stress, diseases, and physical exercise can promote changes in local TH metabolism, leading to different target tissue effects that depend on the presence of tissue-specific enzymatic activities. The newly discovered physiological and pharmacological actions of T4 and T3 metabolites, such as 3,5-diiodothyronine (3,5-T2), and 3-iodothyronamine (T1AM) are of great interest. A classical thyroid hormone effect is the ability of T3 to increase oxygen consumption in almost all cell types studied. Approximately 30 years ago, a seminal report has shown that 3,5-T2 increased oxygen consumption more rapidly than T3 in hepatocytes. Other studies demonstrated that exogenous 3,5-T2 administration was able to increase whole body energy expenditure in rodents and humans. In fact, 3,5-T2 treatment prevents diabetic nephropathy, hepatic steatosis induced by high fat diet, insulin resistance, and weight gain during aging in Wistar male rats. The regulation of mitochondria is likely one of the most important actions of T3 and its metabolite 3,5-T2, which was able to restore the thermogenic program of brown adipose tissue (BAT) in hypothyroid rats, just as T3 does, while T1AM administration induced rapid hypothermia. T3 increases heart rate and cardiac contractility, which are hallmark effects of hyperthyroidism involved in cardiac arrhythmia. These deleterious cardiac effects were not observed with the use of 3,5-T2 pharmacological doses, and in contrast T1AM was shown to promote a negative inotropic and chronotropic action at micromolar concentrations in isolated hearts. Furthermore, T1AM has a cardioprotective effect in a model of ischemic/reperfusion injury in isolated hearts, such as occurs with T3 administration. Despite the encouraging possible therapeutic use of TH metabolites, further studies are needed to better understand their peripheral effects, when compared to T3 itself, in order to establish their risk and benefit. On this basis, the main peripheral effects of thyroid hormones and their metabolites in tissues, such as heart, liver, skeletal muscle, and BAT are discussed herein.

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  • T3 exerts the majority of known thyroid hormone effects at the tissue and cellular level, including hypothalamic and pituitary negative feedback regulation of the HPTP axis.

    “T3 exerts the majority of known thyroid hormone (TH) effects at the tissue and cellular level, including hypothalamic and pituitary negative feedback regulation of the hypothalamus-pituitary-thyroid-periphery (HPTP) axis (4–6).”

    From 3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action (2020) · cites this paper as [6]

    The section ‘Thyroid hormones, their metabolites and the hypothalamus-pituitary-thyroid axis’ (page not available) states that T3 reduces hypothalamic TRH and pituitary TSH secretion, supporting the negative-feedback claim. The ‘Genomic and non-genomic actions’ section describes T3’s cellular mechanism, but the copy does not establish that T3 exerts the majority of all known thyroid-hormone effects. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • 3,5-T2, in addition to its thyromimetic action at the classical T3 receptors at high concentrations, exerts rapid direct effects on mitochondria.

    “Various groups have demonstrated that 3,5-T2, in addition to its thyromimetic action at the classical T3 receptors at high concentrations, exerts rapid direct effects on mitochondria (6, 16–19)”

    From 3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action (2020) · cites this paper as [6]

    In “Genomic and non-genomic actions of thyroid hormones” (page unavailable), the review says 3,5-T2 interacts weakly with classical thyroid hormone receptors compared with T3, consistent with action at higher concentrations. It also identifies mitochondria as a target, but says 3,5-T2 *may* stimulate respiration through direct mitochondrial action; the citing sentence presents that direct effect as established. The “Regulation of oxygen consumption” section (page unavailable) supports the rapid-effect component. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Several other teams reported that administration of 3,5-T2 in rodent models dose-dependently resulted in significant suppression of the HPT axis as reflected by decreased TSH serum concentrations and/or pituitary beta-TSH transcript levels.

    “several other teams reported that administration of 3,5-T2 in rodent models (rat and mice, regular or high-fat diet, euthyroid or hypothyroid) dose-dependently resulted in significant suppression of the HPT axis as reflected by decreased TSH serum concentrations and/or pituitary beta-TSH transcript levels (6, 39, 87, 94, 95).”

    From 3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action (2020) · cites this paper as [6]

    The section on the hypothalamus-pituitary-thyroid axis reports that 3,5-T2 lowers serum TSH in rats, with the effect also confirmed in mice. It does not state that HPT-axis suppression was dose-dependent or establish the full range of diet and thyroid-status conditions described in the citing sentence. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Louzada, R. A., & Carvalho, D. P.
Affiliations
Universidade Federal do Rio de Janeiro (BR)
Corresponding author
Carvalho, Denise P.
ORCID
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2018-07-19
Volume
9
Pages
394-394
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2018.00394
PMC
PMC6060242
OpenAlex
W2884725941
Cited by
60
References
5
Citations by year
2026: 3 · 2025: 7 · 2024: 4 · 2023: 4 · 2022: 8 · 2021: 13 · 2020: 10 · 2019: 11
FWCI
1.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (E-02/2017)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (404150/2016-0)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
Keywords
thyroid hormones, thyroid hormone metabolites, thyroxine, triiodothyronine, 3,5-diiodothyronine, 3-iodothyronamine, iodothyronine deiodinase, oxygen consumption, energy expenditure, brown adipose tissue thermogenesis, mitochondrial regulation, cardiac effects, cardioprotection, ischemia-reperfusion injury, insulin resistance, diabetic nephropathy, hepatic steatosis, hypothyroidism

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