Induction of Type 2 Iodothyronine Deiodinase After Status Epilepticus Modifies Hippocampal Gene Expression in Male Mice

Nascimento, Bruna Pascarelli Pedrico do; Bocco, Bárbara M L C; Fernandes, Gustavo W.; Fonseca, Tatiana L.; McAninch, Elizabeth A.; Cardoso, Cristiane de Almeida Baldini; Bondan, Eduardo Fernandes; Nassif, Renata J; Cysneiros, Roberta Monterazzo; Bianco, Antonio C.; Ribeiro, Miriam O.

doi:10.1210/en.2018-00146

Cited by 6 publications

(5 citation statements)

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“…Currently, some studies have evidenced opposite changes in DIO2 and DIO3 in other pathologies. An increase in DIO2 and a decrease in DIO3 mRNA expression in the hippocampus, amygdala, and prefrontal cortex have been evidenced in mice with epilepsy [ 34 ]. On the other hand, in papillary thyroid tumors, it has been shown that the expression of DIO2 was reduced and DIO3 was increased, by the ERK signaling pathway [ 35 ].…”

Section: Resultsmentioning

confidence: 99%

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High levels of maternal total tri-iodothyronine, and low levels of fetal free L-thyroxine and total tri-iodothyronine, are associated with altered deiodinase expression and activity in placenta with gestational diabetes mellitus

et al. 2020

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Gestational Diabetes Mellitus (GDM) is characterized by abnormal maternal D-glucose metabolism and altered insulin signaling. Dysregulation of thyroid hormones (TH) tri-iodethyronine (T3) and L-thyroxine (T4) Hormones had been associated with GDM, but the physiopathological meaning of these alterations is still unclear. Maternal TH cross the placenta through TH Transporters and their Deiodinases metabolize them to regulate fetal TH levels. Currently, the metabolism of TH in placentas with GDM is unknown, and there are no other studies that evaluate the fetal TH from pregnancies with GDM. Therefore, we evaluated the levels of maternal TH during pregnancy, and fetal TH at delivery, and the expression and activity of placental deiodinases from GDM pregnancies. Pregnant women were followed through pregnancy until delivery. We collected blood samples during 10–14, 24–28, and 36–40 weeks of gestation for measure Thyroid-stimulating hormone (TSH), Free T4 (FT4), Total T4 (TT4), and Total T3 (TT3) concentrations from Normal Glucose Tolerance (NGT) and GDM mothers. Moreover, we measure fetal TSH, FT4, TT4, and TT3 in total blood cord at the delivery. Also, we measured the placental expression of Deiodinases by RT-PCR, western-blotting, and immunohistochemistry. The activity of Deiodinases was estimated quantified rT3 and T3 using T4 as a substrate. Mothers with GDM showed higher levels of TT3 during all pregnancy, and an increased in TSH during second and third trimester, while lower concentrations of neonatal TT4, FT4, and TT3; and an increased TSH level in umbilical cord blood from GDM. Placentae from GDM mothers have a higher expression and activity of Deiodinase 3, but lower Deiodinase 2, than NGT mothers. In conclusion, GDM favors high levels of TT3 during all gestation in the mother, low levels in TT4, FT4 and TT3 at the delivery in neonates, and increases deiodinase 3, but reduce deiodinase 2 expression and activity in the placenta.

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Section: Resultsmentioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

High levels of maternal total tri-iodothyronine, and low levels of fetal free L-thyroxine and total tri-iodothyronine, are associated with altered deiodinase expression and activity in placenta with gestational diabetes mellitus

et al. 2020

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“…Studies have also shown that Dio2 expression is upregulated in a variety of neurological disorders. In mice that experienced 3 hours of status epilepticus (SE) caused by pilocarpine, the mRNA expression of Dio2 increased rapidly in the hippocampus, amygdala, and prefrontal cortex; however, the targeted disruption of Dio2 in astrocytes of mice had effects on highly induced genes in the hippocampus associated with inflammation, apoptosis, and cell death, suggesting that Dio2 induction caused by SE accelerated the production of T3 in different areas of the CNS and modified the hippocampal gene expression profile, affecting the balance between adaptive and maladaptive mechanisms [ 64 ]. Moreover, Dio2 mRNA expression significantly increased in the frontal cortex of two mandibular extension-treated rats compared with sham-operated rats, indicating the major involvement of Dio2 in an attempt to restore more physiological conditions and correct T3 levels, associated with normotensive status in the brain [ 65 ].…”

Section: Physiological Functions Of Dio2mentioning

confidence: 99%

The Physiological Functions and Polymorphisms of Type II Deiodinase

Deng¹,

Han²,

Gao³

et al. 2023

Endocrinol Metab

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Type II deiodinase (DIO2) is thought to provide triiodothyronine (T3) to the nucleus to meet intracellular needs by deiodinating the prohormone thyroxine. DIO2 is expressed widely in many tissues and plays an important role in a variety of physiological processes, such as controlling T3 content in developing tissues (e.g., bone, muscles, and skin) and the adult brain, and regulating adaptive thermogenesis in brown adipose tissue (BAT). However, the identification and cloning of DIO2 have been challenging. In recent years, several clinical investigations have focused on the Thr92Ala polymorphism, which is closely correlated with clinical syndromes such as type 2 diabetes, obesity, hypertension, and osteoarthritis. Thr92Ala-DIO2 was also found to be related to bone and neurodegenerative diseases and tumors. However, relatively few reviews have synthesized research on individual deiodinases, especially DIO2, in the past 5 years. This review summarizes current knowledge regarding the physiological functions of DIO2 in thyroid hormone signaling and adaptive thermogenesis in BAT and the brain, as well as the associations between Thr92Ala-DIO2 and bone and neurodegenerative diseases and tumors. This discussion is expected to provide insights into the physiological functions of DIO2 and the clinical syndromes associated with Thr92Ala-DIO2.

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“…In order to verify the D3 expression, immunohistochemistry with a specific affinity-purified polyclonal rabbit antibody ( catalog no. NB110-96414, Novus Biologicals, Centennial, CO, USA) was performed, as previously described ( 6 ).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Consumptive hypothyroidism in a patient with malignant rhabdoid tumor of the kidney: case report on a newly found association

Fiore

Rosa

Uccella

et al. 2022

European Thyroid Journal

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Introduction: Consumptive hypothyroidism is a rare paraneoplastic condition most commonly associated with infantile hemangiomas. It is caused by overexpression of deiodinase type 3 (D3), which leads to preferential conversion of thyroxine to the metabolically inactive reverse triiodothyronine (rT3), paralleled by a decrease of the biologically active T3. Case presentation: A 46-year-old male patient with previously normal thyroid function was diagnosed with a renal carcinoma with rhabdoid differentiation. He was treated with sunitinib, followed by the immune checkpoint inhibitors ipilimumab and nivolumab, and he developed primary hypothyroidism secondary to thyroiditis. Substitution with unusually high doses of levothyroxine as high as 4.3 µg/kg/day did not normalize his thyroid function. Poor compliance was refuted because there was no improvement after observed administration. He had no malabsorption. Although tyrosine kinase inhibitors can increase the expression of D3, this effect tends to be modest. Therefore, the suspicion of tumor-related consumptive hypothyroidism was raised and supported by low free T3 and elevated rT3 levels. The therapy could not be further modified because the patient opted for palliative care and passed twelve days later. Immunohistochemistry of the tumor from a sample obtained prior to systemic therapy documented abundant expression of D3 corroborating the diagnosis of consumptive hypothyroidism. Conclusions: This observation extends the spectrum of malignancies overexpressing D3. Although rare, increased awareness for this paraneoplastic syndrome is key, if persistent hypothyroidism cannot be explained by compliance issues or malabsorption. Substitution with high doses of levothyroxine, and combination therapy with liothyronine, can correct hypothyroidism in these patients.

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Induction of Type 2 Iodothyronine Deiodinase After Status Epilepticus Modifies Hippocampal Gene Expression in Male Mice

Cited by 6 publications

References 50 publications

High levels of maternal total tri-iodothyronine, and low levels of fetal free L-thyroxine and total tri-iodothyronine, are associated with altered deiodinase expression and activity in placenta with gestational diabetes mellitus

High levels of maternal total tri-iodothyronine, and low levels of fetal free L-thyroxine and total tri-iodothyronine, are associated with altered deiodinase expression and activity in placenta with gestational diabetes mellitus

The Physiological Functions and Polymorphisms of Type II Deiodinase

Consumptive hypothyroidism in a patient with malignant rhabdoid tumor of the kidney: case report on a newly found association

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