Design and Characterization of a Thyroid Hormone Receptor α (TRα)-Specific Agonist

Ocasio, Cory A.; Scanlan, Thomas S.

doi:10.1021/cb600311v

Cited by 44 publications

(21 citation statements)

References 29 publications

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“…TRα1 and TRα2 are located mainly in bones, digestive tract, cardiac and skeletal muscle and central nervous system 2. Three subtypes of TRβ are mainly expressed in the liver, kidney, hypothalamus and pituitary, where they regulate the release of thyroliberin or thyrotropin, subject to the current concentration of THs in blood serum and in the thyroid gland 3 4…”

Section: Introductionmentioning

confidence: 99%

Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor α gene (THRA)

et al. 2015

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Section: Introductionmentioning

confidence: 99%

Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor α gene (THRA)

et al. 2015

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“…1998, Ocasio & Scanlan 2006). Activation of TRβ with a selective thyroid hormone analog (GC-1 compound) in rats results in the induction of UCP1 gene, while only minimally mediating synergism between thyroid hormone and the sympathetic nervous system (Ribeiro et al .…”

Section: Introductionmentioning

confidence: 99%

A TRβ-selective agonist confers resistance to diet-induced obesity

Amorim

Ueta

Freitas

et al. 2009

Journal of Endocrinology

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Thyroid hormone receptor b (TRb also listed as THRB on the MGI Database)-selective agonists activate brown adipose tissue (BAT) thermogenesis, while only minimally affecting cardiac activity or lean body mass. Here, we tested the hypothesis that daily administration of the TRb agonist GC-24 prevents the metabolic alterations associated with a hypercaloric diet. Rats were placed on a high-fat diet and after a month exhibited increased body weight (BW) and adiposity, fasting hyperglycemia and glucose intolerance, increased plasma levels of triglycerides, cholesterol, nonesterified fatty acids and interleukin-6. While GC-24 administration to these animals did not affect food ingestion or modified the progression of BW gain, it did increase energy expenditure, eliminating the increase in adiposity without causing cardiac hypertrophy. Fasting hyperglycemia remained unchanged, but treatment with GC-24 improved glucose tolerance by increasing insulin sensitivity, and also normalized plasma triglyceride levels. Plasma cholesterol levels were only partially normalized and liver cholesterol content remained high in the GC-24-treated animals. Gene expression in liver, skeletal muscle, and white adipose tissue was only minimally affected by treatment with GC-24, with the main target being BAT. In conclusion, during high-fat feeding treatment with the TRb-selective agonist, GC-24 only partially improves metabolic control probably as a result of accelerating the resting metabolic rate.

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“…The synthetic TRa selective ligand, CO-23, was also tested. Although CO-23 binds with a similar affinity to both TR isoforms, it exhibits fivefold greater activation for TRa than for native TRb (Ocasio & Scanlan 2006). In our single-dose assays, CO-23 showed significant binding to only the native TRb LBD and the R243W mutant.…”

Section: Agonist Assaymentioning

confidence: 69%

Analysis of the roles of mutations in thyroid hormone receptor-β by a bacterial biosensor system

Shi¹,

Meng²,

Wood³

2013

Journal of Molecular Endocrinology

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Mutations in thyroid hormone receptors (TRs) often lead to metabolic and developmental disorders, but patients with these mutations are difficult to treat with existing thyromimetic drugs. In this study, we analyzed six clinically observed mutations in the ligand-binding domain of the human TRb using an engineered bacterial hormone biosensor. Six agonist compounds, including triiodothyronine (T 3 ), thyroxine (T 4 ), 3,5,3 0 -triiodothyroacetic acid (Triac), GC-1, KB-141, and CO-23, and the antagonist NH-3 were examined for their ability to bind to each of the TRb mutants. The results indicate that some mutations lead to the loss of ability to bind to native ligands, ranging from several fold to several hundred fold, while other mutations completely abolish the ability to bind to any ligand. Notably, the effect of each ligand on each TRb mutant in this bacterial system is highly dependent on both the mutation and the ligand; some ligands were bound well by a wide variety of mutants, while other ligands lost their affinity for all but the WT receptor. This study demonstrates the ability of our bacterial system to differentiate agonist compounds from antagonist compounds and shows that one of the TRb mutations leads to an unexpected increase in antagonist ability relative to other mutations. These results indicate that this bacterial sensor can be used to rapidly determine ligand-binding ability and character for clinically relevant TRb mutants. Key Words" thyroid hormone receptor " ligand-binding assay " hormone receptor mutations " engineered biosensor

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Design and Characterization of a Thyroid Hormone Receptor α (TRα)-Specific Agonist

Cited by 44 publications

References 29 publications

Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor α gene (THRA)

Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor α gene (THRA)

A TRβ-selective agonist confers resistance to diet-induced obesity

Analysis of the roles of mutations in thyroid hormone receptor-β by a bacterial biosensor system

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