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

Abstract

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...

Tissue thyroid hormone metabolism is differentially regulated during illness in mice

“…Deiodinase type 1 and type 3 activity was measured as previously described (Kwakkel et al 2010, van Zeijl et al 2014. Tissue was homogenised on ice in PED50 buffer (0.1 M sodium phosphate, 2 mM EDTA pH 7.2, 50 mM dithiothreitol (DTT)) using a Polytron (Kinematica, Luzern, Switzerland).…”

The effect of growth hormone replacement on the thyroid axis in patients with hypopituitarism: in vivo and ex vivo studies

“…DIO3 activity was measured as described previously by van Zeijl et al . In brief, adipose tissue (approximately 40 mg) was homogenized on ice in 500 μl PE buffer (0·1 m sodium phosphate, 2 m m EDTA, pH 7·2) containing 50 m m dithiothreitol (DTT) using a Polytron (Kinematica, Luzern, Switzerland).…”

The role of thyrostimulin and its potential clinical significance

“…Th e potential role of GPB5 in acute illness could be the suppression of TSHR in the hypothalamus and pituitary, as this is not observed in GPB5KO mice (GPB5-/-), unlike their WT counterparts (van Zeijl et al 2011). By contrast, GPB5 most likely has no eff ect in the liver or adipose tissue during acute illness, as LPS administration in mice is unremarkable in terms of GPB5 mRNA expression in these areas (van Zeijl et al 2014). Th ese fi ndings necessitate further research into the actions of thyrostimulin's individual subunits, an area which is currently poorly understood but clearly possesses potential.…”