Thyroid hormone receptor beta (THRB) dependent regulation of diurnal hepatic lipid metabolism in adult male mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE254467 | GEO | 2024/08/13
REPOSITORIES: GEO
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Project description:Thyroid hormones (THs) play a critical role in development and throughout adulthood. THs act through the thyroid receptor (TR), which binds to the TH response element (TRE) to regulate the expression of target genes. Although TH action has been studied for decades, surprisingly few TREs have been well validated and characterized. In this study we used chromatin immunoprecipitation followed by microarray analysis (ChIP-chip) to identify TR-binding sites in juvenile (postnatal day 15) mice liver. Microarray analysis revealed twelve TR-binding sites consistent between all analyzed samples. In silico analysis was carried out to search for moderately conserved classic TRE sequences within these novel binding regions, which led to the identification of six candidate TREs within three binding regions. Luciferase reporter assays confirmed the presence of a TRE in the promoter region of DEAD (Asp-Glu-Ala-Asp) box polypeptide 54 (Ddx54) and thyroid hormone responsive SPOT14 (Thrsp). The TR/retinoid X receptor (RXR) heterodimer and RXR homodiner were shown to bind the promoter region of Ddx54 and drive gene expression in the presence of 9-cis-retinoic acid (9cRA). The promoter region of Thrsp was shown to allow binding of the TR/RXR heterodimer, and both T3 and 9cRA were able to significantly increase luciferase activity. The RXR homodimer was also able to bind the response element in the promoter region of Thrsp and increase luciferase activity. Overall, ChIP-chip analysis revealed a relatively limited number of TR-binding sites in juvenile mouse liver despite previous studies showing that numerous genes can be affected by TH disruption at that developmental stage, suggesting that TH action may also be mediated through other intermediates. Collectively the results provide an important step towards characterizing TR-binding sites and identifying the underlying drivers of TR-gene regulation. Three samples were analyzed (total input and immunoprecipitated for each samples).
2013-11-16 | E-GEOD-52417 | biostudies-arrayexpress
Project description:Thyroid hormone (TH) signaling plays an important role in the regulation of long-wavelength vision in vertebrates. In the retina, thyroid hormone receptor β (thrb) is required for expression of long-wavelength-sensitive opsin (lws) in red cone photoreceptors; whereas in retinal pigment epithelium (RPE), TH regulates expression of a cytochrome P450 enzyme, Cyp27c1, that converts vitamin A1 into vitamin A2 to produce a red-shifted chromophore. To better understand how TH controls these processes, we analyzed the phenotype of zebrafish with mutations in the three known TH nuclear receptor transcription factors (thraa, thrab, and thrb). We found that no single TH nuclear receptor is required for TH-mediated induction of cyp27c1 but that deletion of all three (thraa-/-;thrab-/-;thrb-/-) completely abrogates its induction and the resulting conversion of A1- to A2-based retinaldehydes. In the retina, loss of thrb resulted in an absence of red cones at both larval and adult stages without disruption of the underlying cone mosaic. RNA-seq analysis revealed significant downregulation of only five genes in adult thrb-/- retina, of which three (lws1, lws2, and miR-726) occur in a single syntenic cluster. In the larval thrb-/- retina, retinal progenitors destined to become red cones were transfated to ultraviolet (UV) cone opsin (sws1)-expressing cells and cells resembling horizontal cells. Taken together, our findings demonstrate cooperative regulation of cyp27c1 by TH receptors and a requirement for thrb in red cone fate determination. Thus, TH signaling coordinately regulates both spectral sensitivity and sensory plasticity.
2020-05-06 | GSE143312 | GEO
Project description:Thyroid hormone receptor beta (THRB) is post-translationally modified by small ubiquitin-like modifier (SUMO). To investigate the biological role of THRB sumoylation, we generated a mouse model with a mutation that disrupts sumoylation at lysine 146 (K146Q). The THRB K146Q mutant mice had normal serum thyroxine (T4), markedly elevated serum thyrotropin (TSH) (81-fold above control), and enlargement of both the pituitary and the thyroid gland. The marked elevation in TSH, despite a normal serum T4 concentration, indicated blunted feedback regulation of TSH. TH profuction was 10-fold lower (per mg of thyroid tissue) in mutant mice compared to Wt mice.
2021-02-20 | GSE167105 | GEO
Project description:Thyroid hormones (THs) play a critical role in development and throughout adulthood. THs act through the thyroid receptor (TR), which binds to the TH response element (TRE) to regulate the expression of target genes. Although TH action has been studied for decades, surprisingly few TREs have been well validated and characterized. In this study we used chromatin immunoprecipitation followed by microarray analysis (ChIP-chip) to identify TR-binding sites in juvenile (postnatal day 15) mice liver. Microarray analysis revealed twelve TR-binding sites consistent between all analyzed samples. In silico analysis was carried out to search for moderately conserved classic TRE sequences within these novel binding regions, which led to the identification of six candidate TREs within three binding regions. Luciferase reporter assays confirmed the presence of a TRE in the promoter region of DEAD (Asp-Glu-Ala-Asp) box polypeptide 54 (Ddx54) and thyroid hormone responsive SPOT14 (Thrsp). The TR/retinoid X receptor (RXR) heterodimer and RXR homodiner were shown to bind the promoter region of Ddx54 and drive gene expression in the presence of 9-cis-retinoic acid (9cRA). The promoter region of Thrsp was shown to allow binding of the TR/RXR heterodimer, and both T3 and 9cRA were able to significantly increase luciferase activity. The RXR homodimer was also able to bind the response element in the promoter region of Thrsp and increase luciferase activity. Overall, ChIP-chip analysis revealed a relatively limited number of TR-binding sites in juvenile mouse liver despite previous studies showing that numerous genes can be affected by TH disruption at that developmental stage, suggesting that TH action may also be mediated through other intermediates. Collectively the results provide an important step towards characterizing TR-binding sites and identifying the underlying drivers of TR-gene regulation.
2013-11-16 | GSE52417 | GEO
Project description:Thyroid hormones (THs) influence adipose tissue development and metabolism. They regulate both adipocyte proliferation and differentiation and, as they increase the metabolic rate, may be helpful for obesity treatment. However, due to their cardiotoxic effects, like tachycardia and arrhythmia, their use is limited to hypothyroid obese patients. Interestingly, some TH metabolites have been recently shown to possess the same beneficial metabolic effects as THs without any negative effect. The biogenic amine 3-Iodothyronamine (T1AM), for example, affects carbohydrate and lipid metabolism without undesirable side effects. In mice T1AM exhibits cardiac effects opposite to those associated with thyroid hormones, like bradycardia, and, in isolated working rat hearts, produces a rapid, reversible, dose-dependent decrease in cardiac output, aortic pressure and coronary flow. Intraperitoneal injections of T1AM, moreover, induce reduction of RQ from 0.9 to 0.7, both in mice and Djungarian hamsters, indicating that carbohydrate utilisation is reduced and energy requirements are covered by lipid consumption. Ketone bodies in the urine and the significant loss of body fat mass confirm that lipids are predominantly used to cover the energy requirements in response to T1AM administration. The molecular mechanisms by which T1AM favors the lipid rather than glucose catabolism are not known, but it is possible to envisage changes in gene expression, given the delayed and long-lasting phenotypic effects. The complete RQ shift, for example, is reached 4.5 h after the T1AM injection and persists at least for 24 h. In this paper we analyzed the gene expression profiles in subcutaneous adipose tissue and in liver of eight rats chronically treated with T1AM as compared with eight untreated rats. Many genes linked to lipid metabolism, adipogenesis and angiogenesis appeared modulated by T1AM, thus contributing to explain the T1AM phenotypic effects observed in rodents. Furthermore, T1AM influenced the expression of several genes relating to lipoprotein metabolism that provide new insights on T1AM mechanism of action, like, for example, the regulation of cholesterol homeostasis.
2014-09-08 | E-MTAB-2178 | biostudies-arrayexpress
Project description:Thyroid hormones (THs) influence adipose tissue development and metabolism. They regulate both adipocyte proliferation and differentiation and, as they increase the metabolic rate, may be helpful for obesity treatment. However, due to their cardiotoxic effects, like tachycardia and arrhythmia, their use is limited to hypothyroid obese patients. Interestingly, some TH metabolites have been recently shown to possess the same beneficial metabolic effects as THs without any negative effect. The biogenic amine 3-Iodothyronamine (T1AM), for example, affects carbohydrate and lipid metabolism without undesirable side effects. In mice T1AM exhibits cardiac effects opposite to those associated with thyroid hormones, like bradycardia, and, in isolated working rat hearts, produces a rapid, reversible, dose-dependent decrease in cardiac output, aortic pressure and coronary flow. Intraperitoneal injections of T1AM, moreover, induce reduction of RQ from 0.9 to 0.7, both in mice and Djungarian hamsters, indicating that carbohydrate utilisation is reduced and energy requirements are covered by lipid consumption. Ketone bodies in the urine and the significant loss of body fat mass confirm that lipids are predominantly used to cover the energy requirements in response to T1AM administration. The molecular mechanisms by which T1AM favors the lipid rather than glucose catabolism are not known, but it is possible to envisage changes in gene expression, given the delayed and long-lasting phenotypic effects. The complete RQ shift, for example, is reached 4.5 h after the T1AM injection and persists at least for 24 h. In this paper we analyzed the gene expression profiles in subcutaneous adipose tissue and in liver of eight rats chronically treated with T1AM as compared with eight untreated rats. Many genes linked to lipid metabolism, adipogenesis and angiogenesis appeared modulated by T1AM, thus contributing to explain the T1AM phenotypic effects observed in rodents. Furthermore, T1AM influenced the expression of several genes relating to lipoprotein metabolism that provide new insights on T1AM mechanism of action, like, for example, the regulation of cholesterol homeostasis.
2014-09-08 | E-MTAB-2177 | biostudies-arrayexpress
Project description:NCoR1 (Nuclear receptor Co-Repressor) and SMRT (Silencing Mediator of Retinoid and Thyroid hormone receptor) are well-recognized coregulators of nuclear receptor (NR) action. However, their unique roles in the regulation of thyroid hormone (TH) signaling in specific cell types have not been determined. To accomplish this we generated a mouse model that lacked function of either NCoR1 or SMRT or both in the liver only. Despite both corepressors being present in the liver, SMRT had no ability to regulate TH signaling when deleted in either euthyroid or hypothyroid animals. In contrast, disruption of NCoR1 action confirmed that it is the principal mediator of TH sensitivity in vivo. While SMRT played little role in TH signaling alone, when disrupted in combination with NCoR1 it greatly accentuated the activation of hepatic lipogenesis regulated by NCoR1. Thus, corepressor specificity exists in vivo and NCoR1 is the principal regulator of TH action in the liver. However, both NCoR1 and SMRT collaborate to control hepatic lipogenesis and lipid storage, which likely reflects their cooperative activity in regulating the action of multiple NRs including the thyroid hormone receptor (TR). RNA was extracted from livers from 3 individual mice for each group (Double-floxed, Liver specific-SMRT knock out, and Liver specific-double knock out); all were euthyroid, female mice
2014-11-21 | E-GEOD-54192 | biostudies-arrayexpress
Project description:Diurnal (i.e., 24-hour) physiological rhythms depend on transcriptional programs controlled by a set of circadian clock genes/proteins. Systemic factors like humoral and neuronal signals, oscillations in body temperature, and food intake align physiological circadian rhythms with external time. Thyroid hormones (THs) are major regulators of circadian clock target processes such as energy metabolism, but little is known about how fluctuations in TH levels affect the circadian coordination of tissue physiology. In this study, a high triiodothyronine (T3) state was induced in mice by supplementing T3 in the drinking water, which affected body temperature, and oxygen consumption in a time-of-day dependent manner. 24-hour transcriptome profiling of liver tissue identified 37 robustly and time independently T3 associated transcripts as potential TH state markers in the liver. Such genes participated in xenobiotic transport, lipid and xenobiotic metabolism. We also identified 10 – 15 % of the liver transcriptome as rhythmic in control and T3 groups, but only 4 % of the liver transcriptome (1,033 genes) were rhythmic across both conditions – amongst these several core clock genes. In-depth rhythm analyses showed that most changes in transcript rhythms were related to mesor (50%), followed by amplitude (10%), and phase (10%). Gene set enrichment analysis revealed TH state dependent reorganization of metabolic processes such as lipid and glucose metabolism. At high T3 levels, we observed weakening or loss of rhythmicity for transcripts associated with glucose and fatty acid metabolism, suggesting increased hepatic energy turnover. In sum, we provide evidence that tonic changes in T3 levels restructure the diurnal liver metabolic transcriptome independent of local molecular circadian clocks.
2022-07-26 | GSE199998 | GEO
Project description:Perfluorooctanesulfonic acid (PFOS) is a persistent anthropogenic chemical that can affect the thyroid hormone system in humans. In experimental animals, PFOS exposure decreases thyroxine (T4) and triiodothyronine (T3) levels, without a compensatory upregulation of thyroid stimulating hormone (TSH). In adults, THs are regulated by the hypothalamus-pituitary-thyroid (HPT) axis, but also organs such as the liver and potentially the gut microbiota. PFOS and other xenobiotics can therefore potentially disrupt the TH system through various entry points of disruption. To start addressing this issue, we performed a PFOS exposure study to identify effects in multiple organs and pathways simultaneously.
2022-05-04 | GSE196133 | GEO
Project description:Per- and polyfluoroalkyl substances (PFAS) are surfactants utilized in an array of commercial products including nonstick cookware, stain resistant textiles, personal care products, and firefighting foam. Despite their widespread use, concerns regarding the safety of these compounds have been raised. One of the most reproducible effects of some PFAS is their ability to reduce serum thyroid hormones (THs) such as thyroxine (T4) and triiodothyronine (T3) in animal models. As THs are required for normal brain development, PFAS may also be developmental neurotoxicants. Here, we examine the endocrine and neurodevelopmental consequences of perfluorohexane sulfonate (PFHxS) exposure in pregnant, lactating, and developing rats, and compare its effects to the goitrogen propylthiouracil (PTU). We show that PFHxS dramatically reduces maternal serum T4, nearly equivalently to PTU (-55 and -51%, respectively). However, only PTU increases thyroid stimulating hormone (TSH). The lactational transfer of PFHxS is significant and reduces pup serum T4 across the postnatal period. However, only PTU drastically reduces brain THs. Evaluation of brain TH action by phenotyping, RNA-Sequencing, and quantification of radial glia cell morphology supports that PTU interrupts brain TH signaling while PFHxS has limited to no effect. Overall, these data show that PFHxS induces abnormal serum TH profiles in dams and pups; however, there were no indications of hypothyroidism in the postnatal brain. We suggest the stark differences between the neurodevelopmental effects of PFHxS and a typical goitrogen may be due, in part, to the ability of PFHxS to interact with thyroid hormone distributing proteins like transthyretin.
2025-02-12 | GSE262750 | GEO