title: Thyroxine-induced expression of pyroglutamyl peptidase II and inhibition of TSH release precedes suppression of TRH mRNA and requires type 2 deiodinase.
abstract: Suppression of TSH release from the hypothyroid thyrotrophs is one of the most rapid effects of 3,3',5'-triiodothyronine (T(3)) or thyroxine (T(4)). It is initiated within an hour, precedes the decrease in TSHβ mRNA inhibition and is blocked by inhibitors of mRNA or protein synthesis. TSH elevation in primary hypothyroidism requires both the loss of feedback inhibition by thyroid hormone in the thyrotrophs and the positive effects of TRH. Another event in this feedback regulation may be the thyroid hormone-mediated induction of the TRH-inactivating pyroglutamyl peptidase II (PPII) in the hypothalamic tanycytes. This study compared the chronology of the acute effects of T(3) or T(4) on TSH suppression, TRH mRNA in the hypothalamic paraventricular nucleus (PVN), and the induction of tanycyte PPII. In wild-type mice, T(3) or T(4) caused a 50% decrease in serum TSH in hypothyroid mice by 5  h. There was no change in TRH mRNA in PVN over this interval, but there was a significant increase in PPII mRNA in the tanycytes. In mice with genetic inactivation of the type 2 iodothyronine deiodinase, T(3) decreased serum TSH and increased PPII mRNA levels, while T(4)-treatment was ineffective. We conclude that the rapid suppression of TSH in the hypothyroid mouse by T(3) occurs prior to a decrease in TRH mRNA though TRH inactivation may be occurring in the median eminence through the rapid induction of tanycyte PPII. The effect of T(4), but not T(3), requires the type 2 iodothyronine deiodinase.
authors.affiliation: Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Marsili
authors.forename: Edith
authors.initials: E
authors.lastname: Sanchez
authors.forename: Praful
authors.initials: P
authors.lastname: Singru
authors.forename: John W
authors.initials: JW
authors.lastname: Harney
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Zavacki
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Lechan
authors.forename: P R
authors.initials: PR
authors.lastname: Larsen
mesh_terms: D000626:Aminopeptidases / Q000378:metabolism*; D000818:Animals; D013956:Antithyroid Agents / Q000009:adverse effects; D004195:Disease Models, Animal; D007037:Hypothyroidism / Q000139:chemically induced / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism / Q000473:pathology; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013972:Thyrotropin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013974:Thyroxine / Q000008:administration & dosage / Q000494:pharmacology*; D014284:Triiodothyronine / Q000008:administration & dosage / Q000494:pharmacology; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D000626:Aminopeptidases; D013956:Antithyroid Agents; D007453:Iodide Peroxidase; D011761:Pyrrolidonecarboxylic Acid; D012333:RNA, Messenger; D013972:Thyrotropin; D013973:Thyrotropin-Releasing Hormone; D013974:Thyroxine; D014284:Triiodothyronine; D000097564:Iodothyronine Deiodinase Type II; C023166:pyroglutamyl-peptidase II