Distinct Expression Patterns of Glycoprotein Hormone-α2 and -β5 in a Basal Chordate Suggest Independent Developmental Functions

Santos, Sandra Dos; Bardet, Claire; Bertrand, Stéphanie; Escrivà, Héctor; Habert, Damien; Quérat, Bruno

doi:10.1210/en.2008-1743

Cited by 83 publications

(66 citation statements)

References 39 publications

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“…Currently, it is uncertain whether thyrostimulin acts as a functional glycoprotein hormone in vivo, as the GPA2 and GPB5 subunits are unlikely to form a stable heterodimer in the circulation (5,14). However, local coexpression of GPA2 and GPB5 suggests that thyrostimulin may have a paracrine function in peripheral tissues (14 -16, 19).…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…Th e number of oligosaccharide chains in other species is variable. Some of amphioxus, insect, and nematode GPA2 lack the oligosaccharides, which is also true for mosquito and fl y GPB5 (Dos Santos et al 2009). Nevertheless, the oligosaccharide chains possess considerable importance for thyrostimulin's expression and receptor activation.…”

Section: Th E Unique Structure Of Thyrostimulinmentioning

confidence: 99%

“…Th us, there is no seat belt formation in thyrostimulin. Th erefore, it is questionable whether it can, indeed, heterodimerize in the circulation (Dos Santos et al 2009). Th yrostimulin heterodimerizes only aft er treatment with a bifunctional reagent and it is likely that it may be less stable than other glycoprotein hormones (Shupnik et al 1989;Nakabayashi et al 2002).…”

Section: Th E Unique Structure Of Thyrostimulinmentioning

confidence: 99%

The role of thyrostimulin and its potential clinical significance

Karponis

Ananth

2017

Endocrine Regulations

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Th yrostimulin is a glycoprotein heterodimer of GPA2 and GPB5, fi rst described in 2002. It is involved in the physiological function of several tissues. Moreover, evidence points towards the ability of thyrostimulin's individual monomers to induce a biological eff ect, which could denote the circulatory/systemic eff ects of the molecule when found in higher concentrations. From the evolutionary point of view, thyrostimulin shares a binding epitope with the thyroid-stimulating hormone for the thyroid stimulating hormone receptor, whilst possessing affi nity for another unique binding site on the same receptor. Although thyrostimulin can be involved in the hypothalamicpituitary-thyroid axis, its presence in various tissues in an eclectic array of diff erent species renders it multifunctional. From weight loss via increasing metabolic rate to progression of cancer in human ovaries, it is certainly not a signaling molecule to overlook. Furthermore, thyrostimulin has been implicated in bone metabolism, acute illness, and reproductive function. In summary, to our knowledge, this is the fi rst review dealing with the physiological role of thyrostimulin and its potential applications in the clinical practice.

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“…With the discovery of GPA2 and glycoprotein β-subunit 5 (GPB5, thyrostimulin beta) homologs not only in other vertebrates but invertebrates including fly, nematode, and sea urchin (40,41), it is proposed that ancestral glycoprotein existed before the divergence of vertebrates/invertebrates, and that later gene duplication events in vertebrates produced the thyrostimulin (GPA2 and GPB5) and GTH/TSH [GPHα and GPHβ (LHβ/FSHβ/TSHβ)] (40) (Figure 1). The basal lineage of chordates such as tunicates and amphioxus contains GPA2 and GPA5 in their genome but not GPHα or GPHβ (2,(42)(43)(44)(45). Lamprey also has GPA2 and GPB5 genes in addition to the canonical GTHβ (1,33,34,42).…”

Section: Glycoprotein Hormone Familymentioning

confidence: 99%

“…The basal lineage of chordates such as tunicates and amphioxus contains GPA2 and GPA5 in their genome but not GPHα or GPHβ (2,(42)(43)(44)(45). Lamprey also has GPA2 and GPB5 genes in addition to the canonical GTHβ (1,33,34,42). At present, no information is available as to the presence of GPA2/GPB5 in the hagfish.…”

Section: Glycoprotein Hormone Familymentioning

confidence: 99%

The hagfish heart

Davison¹

2015

Hagfish Biology

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The hypothalamic-pituitary system is considered to be a seminal event that emerged prior to or during the differentiation of the ancestral agnathans (jawless vertebrates). Hagfishes as one of the only two extant members of the class of agnathans are considered the most primitive vertebrates known, living or extinct. Accordingly, studies on their reproduction are important for understanding the evolution and phylogenetic aspects of the vertebrate reproductive endocrine system. In gnathostomes (jawed vertebrates), the hormones of the hypothalamus and pituitary have been extensively studied and shown to have well-defined roles in the control of reproduction. In hagfish, it was thought that they did not have the same neuroendocrine control of reproduction as gnathostomes, since it was not clear whether the hagfish pituitary gland contained tropic hormones of any kind. This review highlights the recent findings of the hypothalamic-pituitary-gonadal endocrine system in the hagfish. In contrast to gnathostomes that have two gonadotropins (GTH: luteinizing hormone and follicle-stimulating hormone), only one pituitary GTH has been identified in the hagfish. Immunohistochemical and functional studies confirmed that this hagfish GTH was significantly correlated with the developmental stages of the gonads and showed the presence of a steroid (estradiol) feedback system at the hypothalamic-pituitary levels. Moreover, while the identity of hypothalamic gonadotropin-releasing hormone (GnRH) has not been determined, immunoreactive (ir) GnRH has been shown in the hagfish brain including seasonal changes of ir-GnRH corresponding to gonadal reproductive stages. In addition, a hagfish PQRFamide peptide was identified and shown to stimulate the expression of hagfish GTHβ mRNA in the hagfish pituitary. These findings provide evidence that there are neuroendocrine-pituitary hormones that share common structure and functional features compared to later evolved vertebrates.

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Distinct Expression Patterns of Glycoprotein Hormone-α2 and -β5 in a Basal Chordate Suggest Independent Developmental Functions

Cited by 83 publications

References 39 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

The role of thyrostimulin and its potential clinical significance

The hagfish heart

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