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Endocrinology ; 156(2): 745-54, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25456070


The type 2 iodothyronine deiodinase (D2) is essential for feedback regulation of TSH by T4. We genetically inactivated in vivo D2 in thyrotrophs using a mouse model of Cga-driven cre recombinase. Pituitary D2 activity was reduced 90% in the Cga-cre D2 knockout (KO) mice compared with control Dio2(fl/fl) mice. There was no growth or reproductive phenotype. Basal TSH levels were increased 1.5- to 1.8-fold, but serum T4 and T3 were not different from the controls in adult mice. In hypothyroid adult mice, suppression of TSH by T4, but not T3, was impaired. Despite mild basal TSH elevation, the TSH increase in response to hypothyroidism was 4-fold reduced in the Cga-cre D2KO compared with control mice despite an identical level of pituitary TSH α- and ß-subunit mRNAs. In neonatal Cga-cre D2KO mice, TSH was also 2-fold higher than in the controls, but serum T4 was elevated. Despite a constant TSH, serum T4 increased 2-3-fold between postnatal day (P) 5 and P15 in both genotypes. The pituitary, but not cerebrocortical, D2 activity was markedly elevated in P5 mice decreasing towards adult levels by P17. In conclusion, a congenital severe reduction of thyrotroph D2 causes a major impairment of the TSH response to hypothyroidism. This would be deleterious to the compensatory adaptation of the thyroid gland to iodine deficiency.

Hipotireoidismo/sangue , Iodeto Peroxidase/metabolismo , Tireotrofos/enzimologia , Tireotropina/sangue , Animais , Animais Recém-Nascidos , Córtex Cerebral/enzimologia , Feminino , Inativação Gênica , Iodeto Peroxidase/genética , Masculino , Camundongos Knockout , Hormônios Tireóideos
J Clin Invest ; 123(4): 1492-500, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23524969


Type II deiodinase (D2) activates thyroid hormone by converting thyroxine (T4) to 3,5,3'-triiodothyronine (T3). This allows plasma T4 to signal a negative feedback loop that inhibits production of thyrotropin-releasing hormone (TRH) in the mediobasal hypothalamus (MBH) and thyroid-stimulating hormone (TSH) in the pituitary. To determine the relative contributions of these D2 pathways in the feedback loop, we developed 2 mouse strains with pituitary- and astrocyte-specific D2 knockdown (pit-D2 KO and astro-D2 KO mice, respectively). The pit-D2 KO mice had normal serum T3 and were systemically euthyroid, but exhibited an approximately 3-fold elevation in serum TSH levels and a 40% reduction in biological activity. This was the result of elevated serum T4 that increased D2-mediated T3 production in the MBH, thus decreasing Trh mRNA. That tanycytes, not astrocytes, are the cells within the MBH that mediate T4-to-T3 conversion was defined by studies using the astro-D2 KO mice. Despite near-complete loss of brain D2, tanycyte D2 was preserved in astro-D2 KO mice at levels that were sufficient to maintain both the T4-dependent negative feedback loop and thyroid economy. Taken together, these data demonstrated that the hypothalamic-thyroid axis is wired to maintain normal plasma T3 levels, which is achieved through coordination of T4-to-T3 conversion between thyrotrophs and tanycytes.

Regulação da Expressão Gênica , Hipotálamo/enzimologia , Iodeto Peroxidase/metabolismo , Hipófise/enzimologia , Tireotropina/genética , Tri-Iodotironina/sangue , Animais , Astrócitos/enzimologia , Composição Corporal , Córtex Cerebral/metabolismo , Ativação Enzimática , Retroalimentação Fisiológica , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Hipotálamo/citologia , Hipotálamo/metabolismo , Iodeto Peroxidase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Especificidade de Órgãos , Hipófise/citologia , Glândula Tireoide/metabolismo , Glândula Tireoide/fisiologia , Tireotrofos/enzimologia , Tireotropina/sangue , Hormônio Liberador de Tireotropina , Tiroxina/sangue , Tiroxina/fisiologia , Tri-Iodotironina/fisiologia