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Metabolic Effects of the Intracellular Regulation of Thyroid Hormone

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A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (15 March 2022) | Viewed by 22989

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Prof. Dr. Monica Dentice

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Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80131 Naples, Italy
Interests: thyroid hormones; nuclear receptors; deiodinases; hormone-sensitive cancer; skeletal muscle
Special Issues, Collections and Topics in MDPI journals

Dr. Annunziata Gaetana Cicatiello

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Department of Clinical Medicine and Surgery, Università degli Studi di Napoli Federico II, Naples, Italy
Interests: thyroid hormone; deiodinase; energy metabolism; endocrine physiology

Special Issue Information

Dear Colleagues,

Although thyroid hormone (TH) synthesis and release are regulated by the hypothalamic–pituitary–thyroid axis through the secretion of thyroid-releasing hormone and thyroid-stimulating hormone in the presence of low circulating TH concentrations, research over the last decades has shown that peripheral tissues play a critical contribution to the modification of TH signaling in time and space. Indeed, while the plasma concentrations of TH are relatively stable, tissues can control TH levels through the cell-autonomous regulation of TH transporters, deiodinases, and TH receptors. According to this paradigm of TH action, the local regulation of TH at the intracellular level enables wide fluctuations of TH concentration in local tissues and is a powerful mechanism to modulate TH action without perturbing systemic TH levels.

This Special Issue is devoted to reviewing the current knowledge and novel discoveries on the role of the local control of TH by deiodinases, TH receptors, and TH transporters, with a special focus on the possible therapeutic consequences of such regulation.

We therefore invite reviews, viewpoint manuscripts, and research articles devoted to various aspects of the peripheral regulation of TH action, aiming at identify the mechanisms linking alterations in cell-specific TH metabolism to tissue homeostasis and to the physiopatological regulation of body functioning in humans and animal models and of cell processes in cellular systems.

Prof. Dr. Monica Dentice
Dr. Annunziata Gaetana Cicatiello
Guest Editors

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Keywords

Thyroid hormone metabolism
Deiodinases
Nuclear Receptors
Hypothalamus–Pituitary–Thyroid Axis
Transcriptional Regulation
Metabolic Regulation

Published Papers (10 papers)

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12 pages, 2141 KiB

Open AccessArticle

Divergent Thyroid Hormone Levels in Plasma and Left Ventricle of the Heart in Compensated and Decompensated Cardiac Hypertrophy Induced by Chronic Adrenergic Stimulation in Mice

by Warner Simonides, Alice Tijsma, Anita Boelen, Rutchanna Jongejan, Yolanda de Rijke, Robin Peeters, Monica Dentice, Domenico Salvatore and Alice Muller

Metabolites 2023, 13(2), 308; https://doi.org/10.3390/metabo13020308 - 20 Feb 2023

Cited by 3 | Viewed by 1492

Abstract

Chronic hemodynamic overload of the heart induces ventricular hypertrophy that may be either compensatory or progress to decompensation and heart failure. The gradual impairment of ventricular function is, at least in part, the result of a reduction of cardiac thyroid-hormone (TH) action. Here, we examined the proposed roles of increased cardiac expression of the TH-inactivating enzyme deiodinase type 3 (D3) and reduced plasma TH levels in diminishing cardiac TH levels. Using minipumps, mice were infused for one and two weeks with isoproterenol (ISO) alone or in combination with phenylephrine (PE). Remodeling of the heart induced by these adrenergic agonists was assessed by echocardiography. Left ventricular (LV) tissue and plasma TH levels (T4 and T3) were determined using liquid chromatography-tandem mass spectrometry. LV D3 activity was determined by conversion of radiolabeled substrate and quantification following HPLC. The results show that ISO induced compensated LV hypertrophy with maintained cardiac output. Plasma levels of T4 and T3 remained normal, but LV hormone levels were reduced by approximately 30% after two weeks, while LV D3 activity was not significantly increased. ISO + PE induced decompensated LV hypertrophy with diminished cardiac output. Plasma levels of T4 and T3 were substantially reduced after one and two weeks, together with a more than 50% reduction of hormone levels in the LV. D3 activity was increased after one week and returned to control levels after two weeks. These data show for the first time that relative to controls, decompensated LV hypertrophy with diminished cardiac output is associated with a greater reduction of cardiac TH levels than compensated hypertrophy with maintained cardiac output. LV D3 activity is unlikely to account for these reductions after two weeks in either condition. Whereas the mechanism of the mild reduction in compensated hypertrophy is unclear, changes in systemic TH homeostasis appear to determine the marked drop in LV TH levels and associated impairment of ventricular function in decompensated hypertrophy. Full article

(This article belongs to the Special Issue Metabolic Effects of the Intracellular Regulation of Thyroid Hormone)

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14 pages, 1352 KiB

Open AccessArticle

Age Worsens the Cognitive Phenotype in Mice Carrying the Thr92Ala-DIO2 Polymorphism

by Fernanda B. Lorena, Juliana M. Sato, Beatriz Martin Coviello, Alexandre J. T. Arnold, Alice Batistuzzo, Laís M. Yamanouchi, Eduardo Dias Junior, Bruna P. P. do Nascimento, Tatiana de L. Fonseca, Antonio C. Bianco and Miriam O. Ribeiro

Metabolites 2022, 12(7), 629; https://doi.org/10.3390/metabo12070629 - 8 Jul 2022

Cited by 1 | Viewed by 1832

Abstract

The Thr92Ala-Dio2 polymorphism has been associated with reduced cognition in 2-month-old male mice and increased risk for cognitive impairment and Alzheimer’s disease in African Americans. This has been attributed to reduced thyroid hormone (TH) signaling and endoplasmic reticulum (ER) stress in the brain. Here we studied the Thr92Ala-Dio2 mouse model and saw that older male mice (7–8-month-old) exhibited a more severe cognition impairment, which extended to different aspects of declarative and working memories. A similar phenotype was observed in 4–5-month-old female mice. There were no structural alterations in the prefrontal cortex (PFC) and hippocampus of the Thr92Ala-Dio2 mouse. Nonetheless, in both male and female PFC, there was an enrichment in genes associated with TH-dependent processes, ER stress, and Golgi apparatus, while in the hippocampus there was additional enrichment in genes associated with inflammation and apoptosis. Reduced TH signaling remains a key mechanism of disease given that short-term treatment with L-T3 rescued the cognitive phenotype observed in males and females. We conclude that in mice, age is an additional risk factor for cognitive impairment associated with the Thr92Ala-Dio2 polymorphism. In addition to reduced TH signaling, ER-stress, and involvement of the Golgi apparatus, hippocampal inflammation and apoptosis were identified as potentially important mechanisms of a disease. Full article

(This article belongs to the Special Issue Metabolic Effects of the Intracellular Regulation of Thyroid Hormone)

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9 pages, 3394 KiB

Open AccessArticle

Modulation of Deiodinase Types 2 and 3 during Skeletal Muscle Regeneration

by Ashley Ogawa-Wong, Colleen Carmody, Katherine Le, Rafael Aguiar Marschner, P. Reed Larsen, Ann Marie Zavacki and Simone Magagnin Wajner

Metabolites 2022, 12(7), 612; https://doi.org/10.3390/metabo12070612 - 1 Jul 2022

Cited by 4 | Viewed by 2037

Abstract

The muscle stem-cell niche comprises numerous cell types, which coordinate the regeneration process after injury. Thyroid hormones are one of the main factors that regulate genes linked to skeletal muscle. In this way, deiodinase types 2 and 3 are responsible for the fine-tuning regulation of the local T3 amount. Although their expression and activity have already been identified during muscle regeneration, it is of utmost importance to identify the cell type and temporal pattern of expression after injury to thoroughly comprehend their therapeutic potential. Here, we confirmed the expression of Dio2 and Dio3 in the whole tibialis anterior muscle. We identified, on a single-cell basis, that Dio2 is present in paired box 7 (PAX7)-positive cells starting from day 5 after injury. Dio2 is present in platelet derived growth factor subunit A (PDGFA)-expressing fibro-adipogenic progenitor cells between days 7 and 14 after injury. Dio3 is detected in myogenic differentiation (MYOD)-positive stem cells and in macrophages immediately post injury and thereafter. Interestingly, Dio2 and Dio3 RNA do not appear to be present in the same type of cell throughout the process. These results provide further insight into previously unseen aspects of the crosstalk and synchronized regulation of T3 in injured muscle mediated by deiodinases. The set of findings described here further define the role of deiodinases in muscle repair, shedding light on potential new forms of treatment for sarcopenia and other muscular diseases. Full article

(This article belongs to the Special Issue Metabolic Effects of the Intracellular Regulation of Thyroid Hormone)

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10 pages, 838 KiB

Open AccessArticle

Low Inflammatory Stimulus Increases D2 Activity and Modulates Thyroid Hormone Metabolism during Myogenesis In Vitro

by Thamires Siqueira de Oliveira, Marilia Kimie Shimabukuro, Victoria Regina Siqueira Monteiro, Cherley Borba Vieira Andrade, Anita Boelen, Simone Magagnin Wajner, Ana Luiza Maia, Tania Maria Ortiga-Carvalho and Flavia Fonseca Bloise

Metabolites 2022, 12(5), 416; https://doi.org/10.3390/metabo12050416 - 6 May 2022

Cited by 2 | Viewed by 1819

Abstract

Thyroid hormone (TH) signaling controls muscle progenitor cells differentiation. However, inflammation can alter muscle TH signaling by modulating the expression of TH transporters (Slc16a2), receptors (Thra1), and deiodinase enzymes (Dio2 and Dio3). Thus, a proinflammatory environment could affect myogenesis. The role of a low-grade inflammatory milieu in TH signaling during myogenesis needs further investigation. Herein, we aimed to study the impact of the bacterial lipopolysaccharide (LPS)-induced inflammatory stimulus on the TH signaling during myogenesis. C2C12 myoblasts differentiation was induced without (CTR) or with 10 ng/mL LPS presence. The myoblasts under LPS stimulus release the proinflammatory cytokines (IL-6 and IL-1β) and chemokines (CCL2 and CXCL-1). LPS decreases Myod1 expression by 28% during the initial myogenesis, thus reducing the myogenic stimulus. At the same time, LPS reduced the expression of Dio2 by 41% but doubled the D2 enzymatic activity. The late differentiation was not affected by inflammatory milieu, which only increased the Slc16a2 gene expression by 38%. LPS altered the intracellular metabolism of TH and reduced the initial myogenic stimulus. However, it did not affect late differentiation. Increased intracellular TH activation may be the compensatory pathway involved in the recovery of myogenic differentiation under a low-grade inflammatory milieu. Full article

(This article belongs to the Special Issue Metabolic Effects of the Intracellular Regulation of Thyroid Hormone)

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19 pages, 9147 KiB

Open AccessArticle

Thyroid Hormone Receptor Isoforms Alpha and Beta Play Convergent Roles in Muscle Physiology and Metabolic Regulation

by Annarita Nappi, Melania Murolo, Annunziata Gaetana Cicatiello, Serena Sagliocchi, Emery Di Cicco, Maddalena Raia, Mariano Stornaiuolo, Monica Dentice and Caterina Miro

Metabolites 2022, 12(5), 405; https://doi.org/10.3390/metabo12050405 - 29 Apr 2022

Cited by 10 | Viewed by 2284

Abstract

Skeletal muscle is a key energy-regulating organ, skilled in rapidly boosting the rate of energy production and substrate consumption following increased workload demand. The alteration of skeletal muscle metabolism is directly associated with numerous pathologies and disorders. Thyroid hormones (THs) and their receptors (TRs, namely, TRα and TRβ) exert pleiotropic functions in almost all cells and tissues. Skeletal muscle is a major THs-target tissue and alterations of THs levels have multiple influences on the latter. However, the biological role of THs and TRs in orchestrating metabolic pathways in skeletal muscle has only recently started to be addressed. The purpose of this paper is to investigate the muscle metabolic response to TRs abrogation, by using two different mouse models of global TRα- and TRβKO. In line with the clinical features of resistance to THs syndromes in humans, characterized by THRs gene mutations, both animal models of TRs deficiency exhibit developmental delay and mitochondrial dysfunctions. Moreover, using transcriptomic and metabolomic approaches, we found that the TRs–THs complex regulates the Fatty Acids (FAs)-binding protein GOT2, affecting FAs oxidation and transport in skeletal muscle. In conclusion, these results underline a new metabolic role of THs in governing muscle lipids distribution and metabolism. Full article

(This article belongs to the Special Issue Metabolic Effects of the Intracellular Regulation of Thyroid Hormone)

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10 pages, 530 KiB

Open AccessArticle

Type 2 Deiodinase Thr92Ala Polymorphism Is Not Associated with Cognitive Impairment in Older Adults: A Cross-Sectional Study

by Wallace Klein Schwengber, Vitor Bock Silveira, Guilherme Moreira Hetzel, Amanda Robaina, Lucieli Ceolin, Marli Teresinha Camelier, Iuri Goemann, Roberta Rigo Dalla Corte, Rafael Selbach Scheffel, Renato Gorga Bandeira de Mello, Ana Luiza Maia and José Miguel Dora

Metabolites 2022, 12(5), 375; https://doi.org/10.3390/metabo12050375 - 21 Apr 2022

Cited by 1 | Viewed by 2009

Abstract

Background: Type 2 Deiodinase (DIO2) converts thyroxine (T4) into the active hormone triiodothyronine (T3). Thr92Ala DIO2 polymorphism has been associated with reduced conversion of T4 into T3 and central nervous system hypothyroidism. However, how Thr92Ala DIO2 polymorphism affects cognitive function is still unclear. Objective: To assess the association between Thr92Ala DIO2 polymorphism and cognitive performance in older adults. Design: Cross-sectional study. Setting: University-based tertiary hospital in Brazil. Patients: > 65-year-old with no limiting clinical disease. Interventions: All participants answered a standard questionnaire before undergoing thyroid function laboratory evaluation and genotyping of the Thr92Ala DIO2 polymorphism. Main Outcomes: Cognitive impairment measured by the Word List Memory task from the Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Battery (CERAD-NB) and the Brief Cognitive Screening Battery (BCSB). Results: A hundred individuals were included. Clinical and laboratory characteristics were similar among DIO2 genotypes (all p > 0.05). No differences were found in the Word List Memory, recall, or recognition tests of the CERAD-NB assuming a recessive model for the Ala/Ala vs. Thr/Ala-Thr/Thr genotypes. Results of Clock Drawing Test, Animal Fluency Test, Mini-Mental State Exam, and Figure Memory Test of the BCSB were similar between groups. Conclusions: These findings suggest that Thr92Ala DIO2 polymorphism is not associated with relevant cognitive impairment in older adults. Full article

(This article belongs to the Special Issue Metabolic Effects of the Intracellular Regulation of Thyroid Hormone)

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19 pages, 2568 KiB

Open AccessArticle

Effects of Anticancer Agent P-bi-TAT on Gene Expression Link the Integrin Thyroid Hormone Receptor to Expression of Stemness and Energy Metabolism Genes in Cancer Cells

by Gennadi V. Glinsky, Kavitha Godugu, Thangirala Sudha, Mehdi Rajabi, Sridar V. Chittur, Aleck A. Hercbergs, Shaker A. Mousa and Paul J. Davis

Metabolites 2022, 12(4), 325; https://doi.org/10.3390/metabo12040325 - 4 Apr 2022

Cited by 2 | Viewed by 2190

Abstract

Chemically modified forms of tetraiodothyroacetic acid (tetrac), an L-thyroxine derivative, have been shown to exert their anticancer activity at plasma membrane integrin αvβ3 of tumor cells. Via a specific hormone receptor on the integrin, tetrac-based therapeutic agents modulate expression of genes relevant to cancer cell proliferation, survival and energy metabolism. P-bi-TAT, a novel bivalent tetrac-containing synthetic compound has anticancer activity in vitro and in vivo against glioblastoma multiforme (GBM) and other types of human cancers. In the current study, microarray analysis was carried out on a primary culture of human GBM cells exposed to P-bi-TAT (10⁻⁶ tetrac equivalent) for 24 h. P-bi-TAT significantly affected expression of a large panel of genes implicated in cancer cell stemness, growth, survival and angiogenesis. Recent interest elsewhere in ATP synthase as a target in GBM cells caused us to focus attention on expression of genes involved in energy metabolism. Significantly downregulated transcripts included multiple energy-metabolism-related genes: electron transport chain genes ATP5A1 (ATP synthase 1), ATP51, ATP5G2, COX6B1 (cytochrome c oxidase subunit 6B1), NDUFA8 (NADH dehydrogenase (ubiquinone) FA8), NDUFV2I and other NDUF genes. The NDUF and ATP genes are also relevant to control of oxidative phosphorylation and transcription. Qualitatively similar actions of P-bi-TAT on expression of subsets of energy-metabolism-linked genes were also detected in established human GBM and pancreatic cancer cell lines. In conclusion, acting at αvβ3 integrin, P-bi-TAT caused downregulation in human cancer cells of expression of a large number of genes involved in electron transport and oxidative phosphorylation. These observations suggest that cell surface thyroid hormone receptors on αvβ3 regulate expression of genes relevant to tumor cell stemness and energy metabolism. Full article

(This article belongs to the Special Issue Metabolic Effects of the Intracellular Regulation of Thyroid Hormone)

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Review

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15 pages, 2203 KiB

Open AccessReview

Cardiovascular and Neuronal Consequences of Thyroid Hormones Alterations in the Ischemic Stroke

by Melania Murolo, Olivia Di Vincenzo, Annunziata Gaetana Cicatiello, Luca Scalfi and Monica Dentice

Metabolites 2023, 13(1), 22; https://doi.org/10.3390/metabo13010022 - 23 Dec 2022

Cited by 4 | Viewed by 3455

Abstract

Ischemic stroke is one of the leading global causes of neurological morbidity and decease. Its etiology depends on multiple events such as cardiac embolism, brain capillaries occlusion and atherosclerosis, which ultimately culminate in blood flow interruption, incurring hypoxia and nutrient deprivation. Thyroid hormones (THs) are pleiotropic modulators of several metabolic pathways, and critically influence different aspects of tissues development. The brain is a key TH target tissue and both hypo- and hyperthyroidism, during embryonic and adult life, are associated with deranged neuronal formation and cognitive functions. Accordingly, increasing pieces of evidence are drawing attention on the consistent relationship between the THs status and the acute cerebral and cardiac diseases. However, the concrete contribution of THs systemic or local alteration to the pathology outcome still needs to be fully addressed. In this review, we aim to summarize the multiple influences that THs exert on the brain and heart patho-physiology, to deepen the reasons for the harmful effects of hypo- and hyperthyroidism on these organs and to provide insights on the intricate relationship between the THs variations and the pathological alterations that take place after the ischemic injury. Full article

(This article belongs to the Special Issue Metabolic Effects of the Intracellular Regulation of Thyroid Hormone)

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20 pages, 2118 KiB

Open AccessReview

3,5-T2-an Endogenous Thyroid Hormone Metabolite as Promising Lead Substance in Anti-Steatotic Drug Development?

by Rajas Sane, Eva K. Wirth and Josef Köhrle

Metabolites 2022, 12(7), 582; https://doi.org/10.3390/metabo12070582 - 23 Jun 2022

Cited by 4 | Viewed by 2589

Abstract

Thyroid hormones, their metabolites, and synthetic analogues are potential anti-steatotic drug candidates considering that subclinical and manifest hypothyroidism is associated with hepatic lipid accumulation, non-alcoholic fatty liver disease, and its pandemic sequelae. Thyromimetically active compounds stimulate hepatic lipogenesis, fatty acid beta-oxidation, cholesterol metabolism, and metabolic pathways of glucose homeostasis. Many of these effects are mediated by T3 receptor β1-dependent modulation of transcription. However, rapid non-canonical mitochondrial effects have also been reported, especially for the metabolite 3,5-diiodothyronine (3,5-T2), which does not elicit the full spectrum of “thyromimetic” actions inherent to T3. Most preclinical studies in rodent models of obesity and first human clinical trials are promising with respect to the antisteatotic hepatic effects, but potent agents exhibit unwanted thyromimetic effects on the heart and/or suppress feedback regulation of the hypothalamus-pituitary-thyroid-periphery axis and the fine-tuned thyroid hormone system. This narrative review focuses on 3,5-T2 effects on hepatic lipid and glucose metabolism and (non-)canonical mechanisms of action including its mitochondrial targets. Various high fat diet animal models with distinct thyroid hormone status indicate species- and dose-dependent efficiency of 3,5-T2 and its synthetic analogue TRC150094. No convincing evidence has been presented for their clinical use in the prevention or treatment of obesity and related metabolic conditions. Full article

(This article belongs to the Special Issue Metabolic Effects of the Intracellular Regulation of Thyroid Hormone)

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Other

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17 pages, 896 KiB

Open AccessSystematic Review

Influence of Altered Thyroid Hormone Mechanisms in the Progression of Metabolic Dysfunction Associated with Fatty Liver Disease (MAFLD): A Systematic Review

by Rafael Aguiar Marschner, Fernanda Arenhardt, Rafael Teixeira Ribeiro and Simone Magagnin Wajner

Metabolites 2022, 12(8), 675; https://doi.org/10.3390/metabo12080675 - 22 Jul 2022

Cited by 6 | Viewed by 1922

Abstract

We performed a systematic review of the mechanisms of thyroid hormones (THs) associated with metabolic dysfunction associated with fatty liver disease (MAFLD). This systematic review was registered under PROSPERO (CRD42022323766). We searched the MEDLINE (via PubMed) and Embase databases from their inception to March 2022. We included studies that assessed thyroid function by measuring the serum level of THs and those involved in MAFLD. We excluded reviews, case reports, editorials, letters, duplicate studies and designed controls. Forty-three studies included MAFLD, eleven analyzed THs, and thirty-two evaluated the mechanisms of THs in MAFLD. Thyroid hormones are essential for healthy growth, development and tissue maintenance. In the liver, THs directly influence the regulation of lipid and carbohydrate metabolism, restoring the homeostatic state of the body. The selected studies showed an association of reduced levels of THs with the development and progression of MAFLD. In parallel, reduced levels of T3 have a negative impact on the activation of co-regulators in the liver, reducing the transcription of genes important in hepatic metabolism. Overall, this is the first review that systematically synthesizes studies focused on the mechanism of THs in the development and progression of MAFLD. The data generated in this systematic review strengthen knowledge of the impact of TH changes on the liver and direct new studies focusing on therapies that use these mechanisms. Full article

(This article belongs to the Special Issue Metabolic Effects of the Intracellular Regulation of Thyroid Hormone)

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