OR10-3 Contributions of the Hypothalamus and Pituitary in Expressing the Thyroid Phenotype of SBP2 Deficiency: Other Regulatory Tiers in Addition to the Thyroid Gland

Background: Selenocysteine insertion sequence binding protein 2 (SBP2) is essential for selenoprotein synthesis, including the selenoenzymes deiodinases. Selenoprotein deficiency in individuals with SBP2 deficiency results in a multi-organ syndrome with characteristic thyroid function tests (TFTs) abnormalities of high serum T4, rT3, TSH and low T3. Sbp2 deficient mice (Sbp2 iCKO) replicate most of the TFTs except for normal T3. Previously, we reported the thyroid gland contribution in expressing the thyroid phenotype in Sbp2 iCKO mice with increased thyroid hormone (TH) content and increased synthesis capacity. The decreased expression and activity of selenoenzyme glutathione peroxidase and accumulation of hydrogen peroxide was implicated to promote iodine organification and TH synthesis. Methods: In this study, we evaluated the role of hypothalamus and pituitary in expressing the thyroid phenotype. TH content and gene expression were measured in cerebrum. mRNA expression, TSH content and TRH stimulation test were assessed in pituitary. Results: In the brain, Sbp2 iCKO mice had similar T4 levels compared to WT mice, 9.9 vs 8.4 pg/mg prot, while T3 content was decreased, 12 vs 17 pg/mg prot, discrepant to the respective serum levels. An indicator of local TH status, the expression of TH responsive gene Hr was decreased, 66% of that in WT mice, also indicative of local hypothyroidism. In addition, the expression of TH transporters Mct8 and Oatp1c1 was decreased in cerebrum, 78% and 71% vs WT mice, respectively. While the direct mechanisms for this finding remain elusive, this together with the low deiodinase 2 activity, likely contribute to the low cerebral T3 level. In contrast, at the level of pituitary, which is outside the blood brain barrier, Sbp2 iCKO mice had normal expression of Hr and Tshb gene, indicating adequate local T3. However, pituitary Trhr1 gene expression was increased in Sbp2 iCKO mice, 139% of that in WT, indicative of hypothyroidism at the level of hypothalamus, in line with the aforementioned findings in cerebrum. Although Sbp2 iCKO mice had higher baseline serum TSH, the peak TSH 15 minutes after TRH stimulation was significantly lower, 70% of that in WT mice. This is in part due to the decreased baseline pituitary TSH content by RIA, 71 vs 147 mU/mg prot in Sbp2 iCKO vs WT mice, indicating lower availability of preformed TSH in the pituitary gland. Thus, the observed different T3 availability between brain/hypothalamus and pituitary in Sbp2 deficiency contribute to the characteristic thyroid phenotype through complex regulation of thyrotroph function, dependent on both local and hypothalamic TH status and signaling. Conclusions: In the expression of thyroid phenotype of Sbp2 deficiency, there are contributions not only from the impaired TH metabolism due to deficiency of the deiodinases, but also from each level of the hypothalamic-pituitary-thyroid axis.