Thyroid Hormone Regulation of Metabolism

Mullur, Rashmi S.; Liu, Yanyun; Brent, Gregory A.

doi:10.1152/physrev.00030.2013

Cited by 1,732 publications

(1,442 citation statements)

References 267 publications

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“…T3 is known to signal within the hypothalamus and is essential as a mediator for environmental regulators of growth and energy balance (Mullur et al, 2014). However, the genes on which T3 directly acts upon to bring about these changes in the hypothalamus are poorly understood.…”

Section: Resultsmentioning

confidence: 99%

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

Stoney

Helfer

Rodrigues

et al. 2015

Glia

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Thyroid hormone (TH) is essential for adult brain function and its actions include several key roles in the hypothalamus. Although TH controls gene expression via specific TH receptors of the nuclear receptor class, surprisingly few genes have been demonstrated to be directly regulated by TH in the hypothalamus, or the adult brain as a whole. This study explored the rapid induction by TH of retinaldehyde dehydrogenase 1 (Raldh1), encoding a retinoic acid (RA)‐synthesizing enzyme, as a gene specifically expressed in hypothalamic tanycytes, cells that mediate a number of actions of TH in the hypothalamus. The resulting increase in RA may then regulate gene expression via the RA receptors, also of the nuclear receptor class. In vivo exposure of the rat to TH led to a significant and rapid increase in hypothalamic Raldh1 within 4 hours. That this may lead to an in vivo increase in RA is suggested by the later induction by TH of the RA‐responsive gene Cyp26b1. To explore the actions of RA in the hypothalamus as a potential mediator of TH control of gene regulation, an ex vivo hypothalamic rat slice culture method was developed in which the Raldh1‐expressing tanycytes were maintained. These slice cultures confirmed that TH did not act on genes regulating energy balance but could induce Raldh1. RA has the potential to upregulate expression of genes involved in growth and appetite, Ghrh and Agrp. This regulation is acutely sensitive to epigenetic changes, as has been shown for TH action in vivo. These results indicate that sequential triggering of two nuclear receptor signalling systems has the capability to mediate some of the functions of TH in the hypothalamus. GLIA 2016;64:425–439

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Section: Resultsmentioning

confidence: 99%

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

Stoney

Helfer

Rodrigues

et al. 2015

Glia

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“…TRα1 and TRβ1 are the two main thyroid hormone-binding isoforms and regulate transcription either by direct binding to thyroid hormone response elements (TREs) in target genes or by modulating the activity of other transcription factors and signaling pathways (21,22). TRβ mediates the majority of the actions of T3 in the liver (23), playing an important role in regulating metabolism (24,25), regeneration (26), senescence (27), and carcinogenesis (28). Recent findings suggest that nonalcoholic fatty liver disease, which can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma, is associated with impaired thyroid action in the liver (29)(30)(31)(32).…”

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confidence: 99%

Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses

Alonso-Merino

Orozco

Ruíz-Llorente

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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TGF-β, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to antagonize transcriptional activation by TGF-β/SMAD. This antagonism involves reduced phosphorylation of SMADs and a direct interaction of the receptors with SMAD3 and SMAD4 that is independent of T3-mediated transcriptional activity but requires residues in the receptor DNA binding domain. T3 reduces occupancy of SMADbinding elements in response to TGF-β, reducing histone acetylation and inhibiting transcription. In agreement with this transcriptional cross-talk, T3 is able to antagonize fibrotic processes in vivo. Liver fibrosis induced by carbon tetrachloride is attenuated by thyroid hormone administration to mice, whereas aged TR knockout mice spontaneously accumulate collagen. Furthermore, skin fibrosis induced by bleomycin administration is also reduced by the thyroid hormones. These findings define an important function of the thyroid hormone receptors and suggest TR ligands could have beneficial effects to block the progression of fibrotic diseases.This work was supported by Grants BFU2011-28058 and BFU2014-53610P from Ministerio de Economía y Competitividad; S2011/BMD-2328 TIRONET from the Comunidad de Madrid; and RD12/0036/0030 from the Instituto de Salud Carlos III. The cost of this publication has been paid in part by FEDER fund

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“…TH has important roles in regulating hepatic fatty acid, cholesterol, and carbohydrate homeostasis (6,7). Indeed, recent metabolomics analyses showed that acute TH treatment increased acylcarnitines in the mouse liver (8).…”

Section: Introductionmentioning

confidence: 99%

Changes in Hepatic TRβ Protein Expression, Lipogenic Gene Expression, and Long-Chain Acylcarnitine Levels During Chronic Hyperthyroidism and Triiodothyronine Withdrawal in a Mouse Model

Ohba

Sinha

Singh

et al. 2017

Thyroid

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Background: Thyroid hormone (TH) has important roles in regulating hepatic metabolism. It was previously reported that most hepatic genes activated by a single triiodothyronine (T3) injection became desensitized after multiple injections, and that approximately 10% of target genes did not return to basal expression levels after T3 withdrawal, despite normalization of serum TH and thyrotropin (TSH) levels. To determine the possible mechanism(s) for desensitization and incomplete recovery of hepatic target gene transcription and their effects on metabolism, mRNA and/or protein expression levels of key regulators of TH action were measured, as well as metabolomic changes after chronic T3 treatment and withdrawal. Methods: Adult male mice were treated with daily injections of T3 (20 lg/100 g body weight) for 14 days followed by the cessation of T3 for 10 days. Livers were harvested at 6 hours, 24 hours, and 14 days after the first T3 injection, and at 10 days after withdrawal, and then analyzed by quantitative reverse transcription polymerase chain reaction, Western blotting, and metabolomics. Results: Although TH receptor (TRa and TRb) mRNAs decreased slightly after chronic T3 treatment, only TRb protein decreased before returning to basal expression level after withdrawal. The expression of other regulators of TH action was unchanged. TRb protein expression was also decreased in adult male monocarboxylate transporter-8 (Mct8)-knockout mice, an in vivo model of chronic intrahepatic hyperthyroidism. Previously, increased hepatic long-chain acylcarnitine levels were found after acute TH treatment. However, in this study, long-chain acylcarnitine levels were unchanged after chronic T3, and paradoxically increased after T3 withdrawal. Pathway analyses of the previous microarray results showed upregulation of lipogenic genes after acute T3 treatment and withdrawal. Phosphorylation of acetyl-CoA carboxylase also decreased after T3 withdrawal. Conclusions: Decreased hepatic TRb protein expression occurred after chronic T3 exposure in adult male wild-type and Mct8-knockout mice. Gene array pathway and metabolomics analyses showed abnormalities in hepatic lipogenic gene expression and acylcarnitine levels, respectively, after withdrawal, despite normalization of serum TSH and TH levels. These findings may help explain the variable clinical presentations of some patients during hyperthyroidism and recovery, since TRb protein, target gene expression, and metabolic adaptive changes can occur in individual tissues without necessarily being reflected by circulating TH and TSH concentrations.

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Thyroid Hormone Regulation of Metabolism

Cited by 1,732 publications

References 267 publications

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses

Changes in Hepatic TRβ Protein Expression, Lipogenic Gene Expression, and Long-Chain Acylcarnitine Levels During Chronic Hyperthyroidism and Triiodothyronine Withdrawal in a Mouse Model

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