Distinct ligand-dependent and independent modes of thyroid hormone receptor (TR)/PGC-1α interaction

Yuan, Chaoshen; Nguyen, Phuong; Baxter, John D.; Webb, Paul

doi:10.1016/j.jsbmb.2012.09.001

Cited by 8 publications

(15 citation statements)

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“…Mammalian expression vectors for human TRβ1 and PGC-1α and the bacterial expression vector for TRβ1 (GST-TRβ1) were described previously [9]. SIRT1 were cloned by PCR from a cDNA library of HepG2 cells in frame at BamHI and XbaI sites of pCDNA3Flag vector.…”

Section: Methodsmentioning

confidence: 99%

“…TR coregulators could also play a role. For example, peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) is induced in different tissues in response to a variety of different environmental signals and strongly potentiates TR activity [9]–[15]. In liver, PGC-1α is induced under fasting conditions and is required for optimal T 3 activation of genes involved in fatty acid β-oxidation, mitochondrial activity and other metabolic pathways [13]–[15].…”

Section: Introductionmentioning

confidence: 99%

“…Since TR binds PGC-1α [9], we tested the possibility that SIRT1 may enhance activity of TRβ1, the predominant TR subtype in liver, via effects upon PGC-1α activity. We confirm that SIRT1 synergizes with PGC-1α to potentiate T 3 response, in accordance with recent findings of another group [24], but also find that SIRT1 enhances TRβ1 activity independently of PGC-1α.…”

Section: Introductionmentioning

confidence: 99%

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SIRT1 is a Direct Coactivator of Thyroid Hormone Receptor β1 with Gene-Specific Actions

et al. 2013

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Sirtuin 1 (SIRT1) NAD+-dependent deacetylase regulates energy metabolism by modulating expression of genes involved in gluconeogenesis and other liver fasting responses. While many effects of SIRT1 on gene expression are mediated by deacetylation and activation of peroxisome proliferator activated receptor coactivator α (PGC-1α), SIRT1 also binds directly to DNA bound transcription factors, including nuclear receptors (NRs), to modulate their activity. Since thyroid hormone receptor β1 (TRβ1) regulates several SIRT1 target genes in liver and interacts with PGC-1α, we hypothesized that SIRT1 may influence TRβ1. Here, we confirm that SIRT1 cooperates with PGC-1α to enhance response to triiodothyronine, T3. We also find, however, that SIRT1 stimulates TRβ1 activity in a manner that is independent of PGC-1α but requires SIRT1 deacetylase activity. SIRT1 interacts with TRβ1 in vitro, promotes TRβ1 deacetylation in the presence of T3 and enhances ubiquitin-dependent TRβ1 turnover; a common response of NRs to activating ligands. More surprisingly, SIRT1 knockdown only strongly inhibits T3 response of a subset of TRβ1 target genes, including glucose 6 phosphatase (G-6-Pc), and this is associated with blockade of TRβ1 binding to the G-6-Pc promoter. Drugs that target the SIRT1 pathway, resveratrol and nicotinamide, modulate T3 response at dual TRβ1/SIRT1 target genes. We propose that SIRT1 is a gene-specific TRβ1 co-regulator and TRβ1/SIRT1 interactions could play important roles in regulation of liver metabolic response. Our results open possibilities for modulation of subsets of TR target genes with drugs that influence the SIRT1 pathway.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SIRT1 is a Direct Coactivator of Thyroid Hormone Receptor β1 with Gene-Specific Actions

et al. 2013

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“…Thyroid receptors induce expression of metabolically important genes and thereby modulate mitochondrial capacity and metabolic flux (López et al, 2010). Thyroid receptors interact with the metabolic co-activator PGC-1α and its target transcription factors to alter gene expression, including that of PGC-1α itself (Knutti and Kralli, 2001;Yuan et al, 2013). As a result, in response to cold there is an increase in the expression of mitochondrial proteins involved in energy metabolism.…”

Section: Commentarymentioning

confidence: 99%

“…alter gene expression, including that of PGC-1α itself (Knutti and Kralli, 2001;Yuan et al, 2013). As a result, in response to cold there is an increase in the expression of mitochondrial proteins involved in energy metabolism.…”

Section: Thyroid Hormone Regulates Thermal Responses In An Ectothermimentioning

confidence: 99%

The evolution of endothermy is explained by thyroid hormone-mediated responses to cold in early vertebrates

Little

Seebacher

2014

Journal of Experimental Biology

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The evolution of endothermy is one of the most intriguing and consistently debated topics in vertebrate biology, but the proximate mechanisms that mediated its evolution are unknown. Here, we suggest that the function of thyroid hormone in regulating physiological processes in response to cold is key to understanding the evolution of endothermy. We argue that the capacity of early chordates to produce thyroid hormone internally was the first step in this evolutionary process. Selection could then act on the capacity of thyroid hormone to regulate metabolism, muscle force production and cardiac performance to maintain their function against the negative thermodynamic effects of decreasing temperature. Thyroid-mediated cold acclimation would have been the principal selective advantage. The actions of thyroid hormone during cold acclimation in zebrafish are very similar to its role during endothermic thermogenesis. The thyroid-mediated increases in metabolism and locomotor performance in ectotherms eventually resulted in sufficient heat production to affect body temperature. From this point onwards, increased body temperature per se could be of selective advantage and reinforce thyroid-induced increases in physiological rates. Selection for increased body temperature would promote those mechanisms that maximise heat production, such as increased Na + /K + -ATPase activity, futile cycling by SERCA, and mitochondrial uncoupling, all of which are regulated by thyroid hormone. The specific end point of this broader evolutionary process would be endothermic thermoregulation. However, considering the evolution of endothermy in isolation is misleading because the selective advantages that drove the evolutionary process were independent from endothermy. In other words, without the selective advantages of thyroid-mediated cold acclimation in fish, there would be no endotherms. KEY WORDS: Thermoregulation, Locomotion, Metabolism, Heat production, Aerobic capacity IntroductionThe advantages that have led to the evolution of an endothermic physiology are still under debate. A widely accepted model is that directional selection for incremental increases in aerobic capacity and sustained activity led to the evolution of endothermy (the 'aerobic capacity' model) (Bennett and Ruben, 1979;Nespolo et al., 2011). The greater scope for physical activity means that endotherms tire less quickly and are therefore better able to forage, escape predators and migrate (Clarke and Pörtner, 2010). Increased physical activity requires a greater capacity for energy (ATP) production, and oxidative metabolic capacities of endotherms are consequently an order of magnitude greater than those of ectotherms COMMENTARY School of Biological Sciences A08, University of Sydney, NSW 2006, Australia.*Author for correspondence (frank.seebacher@sydney.edu.au) (Bennett and Ruben, 1979). In contrast, the 'parental care' model suggests that increased non-shivering thermogenesis permitted parents to control incubation temperatures and thereby provided the...

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Brown adipocytes local response to thyroid hormone is required for adaptive thermogenesis in adult male mice

Zekri

Guyot

Suñer

et al. 2022

Preprint

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Thyroid hormone (T3) and its nuclear receptors (TR) are important regulators of energy expenditure and adaptive thermogenesis, notably through their action in the brown adipose tissue (BAT). However, T3 acts in many other peripheral and central tissues which are also involved in energy expenditure. The general picture of how T3 regulates BAT thermogenesis is currently not fully established, notably due to the absence of extensive omics analyses and the lack of specific mice model. Here, we first used transcriptome and cistrome analyses to establish the list of T3/TR direct target genes in brown adipocytes. We then developed a novel model of transgenic mice, in which T3-signaling is specifically suppressed in brown adipocytes at adult stage. We addressed the capacity of these mice to mount a thermogenic response when challenged by either a cold exposure or a high-fat diet, and analyzed the associated changes in BAT transcriptome. We conclude that T3 plays a crucial role in the thermogenic response of the BAT, controlling the expression of genes involved in lipid and glucose metabolism and regulating BAT proliferation. The resulting picture provides an unprecedented view on the pathways by which T3 activates energy expenditure through an efficient adaptive thermogenesis in the BAT.

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Distinct ligand-dependent and independent modes of thyroid hormone receptor (TR)/PGC-1α interaction

Cited by 8 publications

References 39 publications

SIRT1 is a Direct Coactivator of Thyroid Hormone Receptor β1 with Gene-Specific Actions

SIRT1 is a Direct Coactivator of Thyroid Hormone Receptor β1 with Gene-Specific Actions

The evolution of endothermy is explained by thyroid hormone-mediated responses to cold in early vertebrates

Brown adipocytes local response to thyroid hormone is required for adaptive thermogenesis in adult male mice

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