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Plasma T3 levels can be \u201csensed\u201d directly by the anterior pituitary and medial basal hypothalamus; plasma T4 levels require local conversion of T4 to T3, which is mediated by the type 2 deiodinase (D2). To study D2-mediated T4 to T3 conversion and T3 production in the anterior pituitary gland, we used mouse pituitary explants incubated with 125I-T4 for 48 hours to measure T3 production at different concentrations of free T4. The results were compared with cultures of D1- or D2-expressing cells, as well as freshly isolated mouse tissue. These studies revealed a unique regulation of the D2 pathway in the anterior pituitary gland, distinct from that observed in nonpituitary tissues. In the anterior pituitary, increasing T4 levels reduced D2 activity slightly but caused a direct increase in T3 production. However, the same changes in T4 levels decreased T3 production in human HSkM cells and murine C2C12 cells (both skeletal muscle) and mouse bone marrow tissue, which reached zero at 50 pM free T4. In contrast, the increase in T4 levels caused the pig kidney LLC-PK1 cells and kidney fragments to proportionally increase T3 production. These findings have important implications for both physiology and clinical practice because they clarify the mechanism by which fluctuations in plasma T4 levels are transduced in the anterior pituitary gland to mediate the TSH feedback mechanism.<\/jats:p>","DOI":"10.1210\/endocr\/bqad155","type":"journal-article","created":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T20:28:37Z","timestamp":1697747317000},"source":"Crossref","is-referenced-by-count":19,"title":["Sustained Pituitary T3 Production Explains the T4-mediated TSH Feedback Mechanism"],"prefix":"10.1210","volume":"164","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2815-7504","authenticated-orcid":false,"given":"Alice","family":"Batistuzzo","sequence":"first","affiliation":[{"name":"Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, University of Chicago , Chicago, IL 60637 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4141-5790","authenticated-orcid":false,"given":"Federico","family":"Salas-Lucia","sequence":"additional","affiliation":[{"name":"Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, University of Chicago , Chicago, IL 60637 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bal\u00e1zs","family":"Gereben","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Cell Metabolism, Institute of Experimental Medicine , Budapest, H-1083 , Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam O","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Developmental Disorders Program, Center for Biological Sciences and Health, Mackenzie Presbyterian University , Sao Paulo, SP, 01302-907 , Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7737-6813","authenticated-orcid":false,"given":"Antonio C","family":"Bianco","sequence":"additional","affiliation":[{"name":"Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, University of Chicago , Chicago, IL 60637 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2023,10,21]]},"reference":[{"issue":"4","key":"2023112004520780000_bqad155-B1","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1210\/er.2018-00275","article-title":"Paradigms of dynamic control of thyroid hormone signaling","volume":"40","author":"Bianco","year":"2019","journal-title":"Endocr Rev"},{"issue":"1","key":"2023112004520780000_bqad155-B2","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1210\/edrv.23.1.0455","article-title":"Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases","volume":"23","author":"Bianco","year":"2002","journal-title":"Endocr Rev"},{"issue":"2","key":"2023112004520780000_bqad155-B3","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1210\/endo-119-2-840","article-title":"Hormonal control of a low Km (type II) iodothyronine 5\u2032-deiodinase in cultured NB41A3 mouse neuroblastoma cells","volume":"119","author":"St. Germain","year":"1986","journal-title":"Endocrinology"},{"issue":"11","key":"2023112004520780000_bqad155-B4","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1210\/mend.14.11.0558","article-title":"Selective proteolysis of human type 2 deiodinase: a novel ubiquitin-proteasomal mediated mechanism for regulation of hormone activation","volume":"14","author":"Gereben","year":"2000","journal-title":"Mol Endocrinol"},{"issue":"2","key":"2023112004520780000_bqad155-B5","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/S0021-9258(19)40140-3","article-title":"Regulation of type II iodothyronine 5\u2032-deiodinase by thyroid hormone. 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