Isolation and Characterization of Mouse Complementary DNAs Encoding α and β Thyroid Hormone Receptors from Thyrotrope Cells: The Mouse Pituitary-Specific β2 Isoform Differs at the Amino Terminus from the Corresponding Species fromRat Pituitary Tumor Cells

Wm, Wood; Kw, Ocran; Df, Gordon; Ec, Ridgway

doi:10.1210/mend-5-8-1049

Cited by 70 publications

(31 citation statements)

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“…Most of TH actions occur through the nuclear TH receptors (TRs), which are ligand-dependent and ligand-independent transcription factors (Yen 2001). TRs are encoded by two distinct genes, Thra and Thrb, located on mouse chromosomes 11 and 14 (Thompson et al 1987, Wood et al 1991. The use of alternative splicing or transcription initiation sites generates at least three TH-binding isoforms TRa1, TRb1, and TRb2.…”

Section: Introductionmentioning

confidence: 99%

The Δ337T mutation on the TRβ causes alterations in growth, adiposity, and hepatic glucose homeostasis in mice

Santiago¹,

Santiago²,

Faustino³

et al. 2011

Journal of Endocrinology

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Mice bearing the genomic mutation D337T on the thyroid hormone receptor b (TRb) gene present the classical signs of resistance to thyroid hormone (TH), with high serum TH and TSH. This mutant TR is unable to bind TH, remains constitutively bound to co-repressors, and has a dominant negative effect on normal TRs. In this study, we show that homozygous (TRbD337T) mice for this mutation have reduced body weight, length, and body fat content, despite augmented relative food intake and relative increase in serum leptin. TRbD337T mice exhibited normal glycemia and were more tolerant to an i.p. glucose load accompanied by reduced insulin secretion. Higher insulin sensitivity was observed after single insulin injection, when the TRbD337T mice developed a profound hypoglycemia. Impaired hepatic glucose production was confirmed by the reduction in glucose generation after pyruvate administration.In addition, hepatic glycogen content was lower in homozygous TRbD337T mice than in wild type. Collectively, the data suggest that TRbD337T mice have deficient hepatic glucose production, by reduced gluconeogenesis and lower glycogen deposits. Analysis of liver gluconeogenic gene expression showed a reduction in the mRNA of phosphoenolpyruvate carboxykinase, a rate-limiting enzyme, and of peroxisome proliferator-activated receptor-g coactivator 1a, a key transcriptional factor essential to gluconeogenesis. Reduction in both gene expressions is consistent with resistance to TH action via TRb, reproducing a hypothyroid phenotype. In conclusion, mice carrying the D337T-dominant negative mutation on the TRb are leaner, exhibit impaired hepatic glucose production, and are more sensitive to hypoglycemic effects of insulin.

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Section: Introductionmentioning

confidence: 99%

The Δ337T mutation on the TRβ causes alterations in growth, adiposity, and hepatic glucose homeostasis in mice

Santiago¹,

Santiago²,

Faustino³

et al. 2011

Journal of Endocrinology

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“…Initial attempts to determine the role of each of the TR proteins indicated the wide distribution of TR 1, TR 2, and TR 1 mRNAs among target tissues, whereas TR 2 mRNA is limited to the anterior pituitary or to a certain region of the central nervous system (Thompson et al 1987, Wood et al 1991. Schwartz et al (1992) compared the concentration of TR and TR mRNA to nuclear T 3 binding capacity in rat tissues by using specific antibodies against each TR type.…”

Section: Introductionmentioning

confidence: 99%

Expression of thyroid hormone receptor alpha in 3T3-L1 adipocytes; triiodothyronine increases the expression of lipogenic enzyme and triglyceride accumulation

Jiang

Miyamoto

Kakizawa³

et al. 2004

Journal of Endocrinology

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Thyroid hormone receptors (TR) are members of the nuclear receptor superfamily. There are at least two TR isoforms, TR and TR , which act as mediators of thyroid hormone in tissues. However, the relative expression of each TR isoform in target tissues is still elusive. Herein, we have developed an RT-PCR and restriction enzyme digestion method to determine the expression of TR 1 and TR 1. We analyzed the expression of TR isoforms in 3T3-L1 preadipocytes induced to differentiate by an adipogenic cocktail in the presence or absence of 100 nM triiodothyronine (T 3 ). The TR 1 isoform was predominantly expressed in 3T3-L1 adipocytes, and its expression was increased at the stage of development concomitant with the emergence of lipid droplets. Little, if any, TR 1 mRNA was detected in adipocytes. Administration of T 3 to the differentiating 3T3-L1 cells enhanced the accumulation of triglyceride. The expression profile of TR 1 in T 3 -treated adipocytes was similar to that in non-treated cells. The transcripts of adipogenic factors, CCAAT/ enhancer binding protein (C/EBP ) and peroxisome proliferator activated receptor (PPAR ), were not altered by T 3 . Lipid binding protein, aP2, that is downstream of these transcription factors was also unaffected by T 3 . In contrast, the lipogenic enzyme, glyceraldehyde-3-phosphate dehydrogenase mRNA was significantly increased in the presence of T 3 . Therefore, T 3 appears to be a hormone capable of modulating the expression of lipogenic enzyme and augments the accumulation of lipid droplets. We conclude that the TR isoform might play an important role in the generation and maintenance of the mature adipocyte phenotype, regulating the expression of lipogenic enzymes.

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“…Three tri-iodothyronine (T 3 ) binding isoforms of the thyroid hormone exist: TR-α1, TR-β1, and TR-β2 (7). These isoforms are all expressed within the thyrotroph (8) and the TRH neurons of the paraventricular hypothalamus (9). However, TR-β2 is the most abundant isoform in the thyrotroph (10) and potentially in the TRH neurons of the paraventricular hypothalamus (9).…”

Section: Introductionmentioning

confidence: 99%

Critical role for thyroid hormone receptor β2 in the regulation of paraventricular thyrotropin-releasing hormone neurons

Ahima¹,

Boers²,

Elmquist³

et al. 2001

J. Clin. Invest.

178

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IntroductionThyroid hormone concentrations in vivo are maintained in a narrow range by the ability of thyroid hormone to limit its own production by feedback inhibition of the synthesis of thyrotropin (TSH) by pituitary thyrotrophs (1). TSH synthesis and bioactivity is also regulated by thyrotropin-releasing hormone (TRH) originating from hypothalamic paraventricular TRH neurons (2, 3). Thyroid hormone mediates the negative regulation of the TSH subunit and TRH genes by binding to thyroid hormone receptors (TRs) that interact with thyroid hormone-responsive elements on the promoters of these genes (4-6). Three tri-iodothyronine (T 3 ) binding isoforms of the thyroid hormone exist: TR-α1, TR-β1, and TR-β2 (7). These isoforms are all expressed within the thyrotroph (8) and the TRH neurons of the paraventricular hypothalamus (9). However, TR-β2 is the most abundant isoform in the thyrotroph (10) and potentially in the TRH neurons of the paraventricular hypothalamus (9). Indeed, the restricted expression of TR-β2 (thyrotroph, TRH neurons of the paraventricular hypothalamus, developing ear, and developing retina) contrasts with the ubiquitous expression of TR-α1 and TR-β1 isoforms (7). Thus, the expression pattern of TR-β2 suggests that this isoform may be the important mediator of negative regulation of TSH and TRH production by T 3 .Transgenic and knockout animals have shed important insight into the relative roles of TR isoforms in the regulation by thyroid hormone of the hypothalamicpituitary-thyroid (HPT) axis. Mice with targeted ablation of the TR-α locus (11) or the TR-α1 gene (12) develop minor abnormalities in thyroxine (T 4 ) and TSH concentrations. Mice that lack both TR-β isoforms (TR-β null) develop elevated concentrations of T 4 and TSH and exhibit partial suppression of TSH production after Thyroid hormone thyroxine (T 4 ) and tri-iodothyronine (T 3 ) production is regulated by feedback inhibition of thyrotropin (TSH) and thyrotropin-releasing hormone (TRH) synthesis in the pituitary and hypothalamus when T 3 binds to thyroid hormone receptors (TRs) interacting with the promoters of the genes for the TSH subunit and TRH. All of the TR isoforms likely participate in the negative regulation of TSH production in vivo, but the identity of the specific TR isoforms that negatively regulate TRH production are less clear. To clarify the role of the TR-β2 isoform in the regulation of TRH gene expression in the hypothalamic paraventricular nucleus, we examined preprothyrotropin-releasing hormone (prepro-TRH) expression in mice lacking the TR-β2 isoform under basal conditions, after the induction of hypothyroidism with propylthiouracil, and in response to T 3 administration. Prepro-TRH expression was increased in hypothyroid wild-type mice and markedly suppressed after T 3 administration. In contrast, basal TRH expression was increased in TR-β2-null mice to levels seen in hypothyroid wild-type mice and did not change significantly in response to induction of hypothyroidism or T 3 treatment. However, the suppressi...

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Isolation and Characterization of Mouse Complementary DNAs Encoding α and β Thyroid Hormone Receptors from Thyrotrope Cells: The Mouse Pituitary-Specific β2 Isoform Differs at the Amino Terminus from the Corresponding Species fromRat Pituitary Tumor Cells

Cited by 70 publications

References 0 publications

The Δ337T mutation on the TRβ causes alterations in growth, adiposity, and hepatic glucose homeostasis in mice

The Δ337T mutation on the TRβ causes alterations in growth, adiposity, and hepatic glucose homeostasis in mice

Expression of thyroid hormone receptor alpha in 3T3-L1 adipocytes; triiodothyronine increases the expression of lipogenic enzyme and triglyceride accumulation

Critical role for thyroid hormone receptor β2 in the regulation of paraventricular thyrotropin-releasing hormone neurons

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