TSH receptor activation and body composition

Lloyd, Anna de; Bursell, James; Gregory, John W.; Rees, Dafydd Aled; Ludgate, Marian

doi:10.1677/joe-09-0262

Cited by 46 publications

(34 citation statements)

References 86 publications

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“…We studied D2, D3, and TSHR expression in muscle tissue and observed no prominent differences between GPB5 Ϫ/Ϫ and WT mice. Previous studies had suggested that muscle TSHR mRNA expression resulted from expression in fibroblasts rather than myocytes (10). We stimulated a skeletal muscle cell line with TSH, thyrostimulin, or GPB5.…”

Section: Discussionmentioning

confidence: 96%

“…In addition to the thyroid gland, TSHR expression has been reported in a number of peripheral tissues including WAT, BAT, muscle, kidney, skin, and bone (10). Activation of the TSHR is known to regulate deiodinase expression and activity in several tissues (6, 11-13, 23, 28).…”

Section: Discussionmentioning

confidence: 99%

“…As the TSHR is expressed in several peripheral extrathyroidal tissues (10), and activation of the TSHR is known to regulate the expression and activity of deiodinating enzymes, which are involved in thyroid hormone metabolism (6,11), we hypothesized that altered thyrostimulin expression in peripheral tissues could also account for changes in thyroid hormone metabolism seen in NTIS. To this end, we investigated a possible role for GPB5 in peripheral thyroid hormone metabolism during acute inflammation, induced by LPS administration using GPB5 Ϫ/Ϫ and WT mice.…”

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confidence: 99%

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Thyrostimulin deficiency does not alter peripheral responses to acute inflammation-induced nonthyroidal illness

Zeijl

Surovtseva

Kwakkel

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Thyrostimulin, a putative glycoprotein hormone, comprises the subunits GPA2 and GPB5 and activates the TSH receptor (TSHR). The observation that proinflammatory cytokines stimulate GPB5 transcription suggested a role for thyrostimulin in the pathogenesis of nonthyroidal illness syndrome (NTIS). In the present study, we induced acute inflammation by LPS administration to GPB5Ϫ/Ϫ and WT mice to evaluate the role of thyrostimulin in peripheral thyroid hormone metabolism during NTIS. In addition to serum thyroid hormone concentrations, we studied mRNA expression and activity of deiodinase types I, II, and III (D1, D2, and D3) in peripheral T 3 target tissues, including liver, muscle, and white and brown adipose tissue (WAT and BAT), of which the latter three express the TSHR. LPS decreased serum free (f)T 4 and fT3 indexes to a similar extent in GPB5 Ϫ/Ϫ and WT mice. Serum reverse (r)T 3 did not change following LPS administration. LPS also induced significant alterations in tissue D1, D2, and D3 mRNA and activity levels, but only the LPS-induced increase in WAT D2 mRNA expression differed between GPB5 Ϫ/Ϫ and WT mice. In conclusion, lacking GPB5 during acute illness does not affect the LPS-induced decrease of serum thyroid hormones while resulting in subtle changes in tissue D2 expression that are unlikely to be mediated via the TSHR. thyrostimulin; type II deiodinase; inflammation; thyroid hormone THE PUTATIVE GLYCOPROTEIN HORMONE thyrostimulin, comprising ␣2-(GPA2) and ␤5-(GPB5) subunits, has been reported to activate the thyroid-stimulating hormone (TSH) receptor (TSHR). Thyrostimulin does not play a major role in the classical feedback regulation of the hypothalamo-pituitarythyroid (HPT) axis, as GPB5 knockout (GPB5 Ϫ/Ϫ ) mice do not have an abnormal thyroid phenotype and transcription of GPB5 is not regulated by thyroid hormone or thyrotropin-releasing hormone (TRH) (14,20). Furthermore, we recently showed that deletion of Gpb5 in mice does not result in abnormal regulation of the HPT axis during hypothyroidism and thyrotoxicosis (24).The nonthyroidal illness syndrome (NTIS) is a state of altered thyroid hormone metabolism occurring during illness, characterized by decreased serum triiodothyronine (T 3 ) and thyroxine (T 4 ) levels without an increase in pituitary TSH or hypothalamic TRH expression (3). The recent finding that proinflammatory cytokines upregulate the transcription of GPB5 in vitro suggests that thyrostimulin may have a role in the pathogenesis of NTIS (21). Accordingly, we demonstrated a marked increase in GPB5 mRNA expression in the pituitary and, to a lesser extent, in the hypothalamus of mice after administration of lipopolysaccharide (LPS) (25), which is a well-established mouse model of NTIS.In addition to central alterations of the HPT axis, NTIS results in altered peripheral thyroid hormone metabolism and plasma thyroid hormone binding capacity (26). As the TSHR is expressed in several peripheral extrathyroidal tissues (10), and activation of the TSHR is known to regulate the expression...

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Thyrostimulin deficiency does not alter peripheral responses to acute inflammation-induced nonthyroidal illness

Zeijl

Surovtseva

Kwakkel

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Thus, T4 is a pro-hormone of the biologically active T3 (19,20). A recent study on human osteoblast cell line showed increased expression of deiodinase 2 (which converts T4 to T3) by administration of TSH, suggesting that TSH may indirectly promote bone turnover by increasing local T3 availability (21). Furthermore, the HPT axis set-point in an individual is at least in part genetically determined and may influence fracture risk (22,23).…”

Section: Discussionmentioning

confidence: 99%

TSH-receptor antibodies may prevent bone loss in pre- and postmenopausal women with Graves' disease and Graves' orbitopathy

Siderova¹,

Hristozov²,

Tsukeva³

2018

Archives of Endocrinology and Metabolism

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Objective: Thyrotoxicosis is established risk factor for osteoporosis due to increased bone turnover. Glucocorticoids often administered for Graves' orbitopathy (GO) have additional negative effect on bone mineral density (BMD). Our aim was to examine the influence of thyroid hormones, TSH, TSH-receptor antibodies (TRAb) and glucocorticoid treatment on bone in women with Graves' thyrotoxicosis and Graves' orbitopathy (GO). Subjects and methods: Forty seven women with Graves' disease, mean age 55.6 ± 12.8 (23 women with thyrotoxicosis and 24 hyperthyroid with concomitant GO and glucocorticoid therapy) and 40 age-matched healthy female controls were enrolled in the study. We analyzed clinical features, TSH, FT4, FT3, TRAb, TPO antibodies. BMD of lumbar spine and hip was measured by DEXA and 10-year fracture risk was calculated with FRAX tool. Results: The study showed significantly lower spine and femoral BMD (g/cm 2 ) in patients with and without GO compared to controls, as well as significantly higher fracture risk. Comparison between hyperthyroid patients without and with orbitopathy found out significantly lower spine BMD in the first group (p = 0.0049). Negative correlations between FT3 and femoral neck BMD (p = 0.0001), between FT4 and BMD (p = 0.049) and positive between TSH and BMD (p = 0.0001), TRAb and BMD (p = 0.026) were observed. Fracture risk for major fractures and TRAb were negatively associated (p = 0.05). We found negative correlation of BMD to duration of thyrotoxicosis and cumulative steroid dose. Conclusions: Our results confirm the negative effect of hyperthyroid status on BMD. TRAb, often in high titers in patients with GO, may have protective role for the bone, but further research is needed. Arch Endocrinol Metab. 2018;62(2):221-6

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“…These two conditions have been associated with opposing effects on human BMD. Specifically, while hyperthyroidism is traditionally associated with low BMD, TSHR gain-of-function has been associated with high BMD (de Lloyd et al, 2010); it was unknown whether opallus exhibited an axial skeletal phenotype. In a first cohort where we performed an initial screen of n = 2 fish ( Figure 9A), we observed a clear increase in TMD in opallus that was not present in standard length matched AB controls, or in another mutant derived in a forward genetic screen that exhibits pigmentation defects, pissarro (Quigley et al, 2004) (SL of AB: 23.7 ± 1.1 mm, SL of opallus: 24.3 ± 1.4 mm, SL of pissarro: 23.7 ± 0.1 mm, mean ± SD).…”

Section: Identification Of Opallus As a Novel Axial Skeletal Mutantmentioning

confidence: 99%

MicroCT-Based Phenomics in the Zebrafish Skeleton Reveals Virtues of Deep Phenotyping in a Distributed Organ System

et al. 2018

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Phenomics, which ideally involves in-depth phenotyping at the whole-organism scale, may enhance our functional understanding of genetic variation. Here, we demonstrate methods to profile hundreds of phenotypic measures comprised of morphological and densitometric traits at a large number of sites within the axial skeleton of adult zebrafish. We show the potential for vertebral patterns to confer heightened sensitivity, with similar specificity, in discriminating mutant populations compared to analyzing individual vertebrae in isolation. We identify phenotypes associated with human brittle bone disease and thyroid stimulating hormone receptor hyperactivity. Finally, we develop allometric models and show their potential to aid in the discrimination of mutant phenotypes masked by alterations in growth. Our studies demonstrate virtues of deep phenotyping in a spatially distributed organ system. Analyzing phenotypic patterns may increase productivity in genetic screens, and facilitate the study of genetic variants associated with smaller effect sizes, such as those that underlie complex diseases.

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TSH receptor activation and body composition

Cited by 46 publications

References 86 publications

Thyrostimulin deficiency does not alter peripheral responses to acute inflammation-induced nonthyroidal illness

Thyrostimulin deficiency does not alter peripheral responses to acute inflammation-induced nonthyroidal illness

TSH-receptor antibodies may prevent bone loss in pre- and postmenopausal women with Graves' disease and Graves' orbitopathy

MicroCT-Based Phenomics in the Zebrafish Skeleton Reveals Virtues of Deep Phenotyping in a Distributed Organ System

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