title: The selective loss of the type 2 iodothyronine deiodinase in mouse thyrotrophs increases basal TSH but blunts the thyrotropin response to hypothyroidism.
abstract: 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 β-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.
authors.affiliation: Thyroid Section, Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine (C.L., C.M., A.M., J.W.H., A.M.Z., P.R.L.), Brigham and Women's Hospital and Harvard Medical School, and Division of Endocrinology, Diabetes, and Metabolism (K.V.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115; Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Studio di Diagnostica Nucleare "SDN" (R.A.), 80142 Naples, Italy; and Department of Clinical Medicine and Surgery (M.D., D.S.), University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Luongo
authors.forename: Cecilia
authors.initials: C
authors.lastname: Martin
authors.forename: Kristen
authors.initials: K
authors.lastname: Vella
authors.forename: Alessandro
authors.initials: A
authors.lastname: Marsili
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ambrosio
authors.forename: Monica
authors.initials: M
authors.lastname: Dentice
authors.forename: John W
authors.initials: JW
authors.lastname: Harney
authors.forename: Domenico
authors.initials: D
authors.lastname: Salvatore
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Zavacki
authors.forename: P Reed
authors.initials: PR
authors.lastname: Larsen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000201:enzymology; D005260:Female; D020868:Gene Silencing; D007037:Hypothyroidism / Q000097:blood*; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D013963:Thyroid Hormones; D052684:Thyrotrophs / Q000201:enzymology*; D013972:Thyrotropin / Q000097:blood*; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D013963:Thyroid Hormones; D013972:Thyrotropin; D000097564:Iodothyronine Deiodinase Type II