title: Effects of rexinoids on thyrotrope function and the hypothalamic-pituitary-thyroid axis.
abstract: Retinoid X receptor (RXR)-selective retinoids (rexinoids) can cause central hypothyroidism in humans, and this effect has been confirmed in rodent models. In this report, we characterized the effect of rexinoids on the hypothalamic-pituitary-thyroid axis in mice and TSH regulation in a thyrotrope-derived cell line. The synthetic rexinoid (LG 268) suppressed TSH and T4 levels in mice. Hypothalamic TRH mRNA was unaffected, but steady-state pituitary TSHbeta mRNA levels were significantly lowered, suggesting a direct effect of rexinoids on thyrotropes. LG 268 suppressed TSH protein secretion and TSHbeta mRNA in TalphaT1 thyrotropes as early as 8 h after treatment, whereas the retinoic acid receptor-selective retinoid (TTNPB) had no effect. Type 2 iodothyronine deiodinase (D2) mRNA and activity were suppressed by LG 268 in TalphaT1 cells, whereas only D2 mRNA was suppressed in mouse pituitaries. LG 268 suppressed TSHbeta promoter activity by 42% and the -200 to -149 region accounted for a majority of the LG 268-mediated suppression of promoter activity. The RXRgamma isotype is expressed in thyrotropes. In vitro transfection and in vivo transgenic studies indicate that any RXR isotype can mediate TSH suppression by rexinoids, but the RXRgamma isotype is most efficient at mediating this response. RXRgamma-deficient mice lacked pituitary D2 mRNA suppression by LG 268, but D2 activity remained intact. In summary, RXR-selective retinoids (rexinoids) have multiple effects on the hypothalamic-pituitary-thyroid axis. Rexinoids directly suppress TSH secretion, TSHbeta mRNA levels and promoter activity, and D2 mRNA levels but have no direct effect on hypothalamic TRH levels. Rexinoids also stimulate type 1 iodothyronine deiodinase activity in the liver and pituitary.
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, University of Colorado at Denver and Health Sciences Center, MS 8106, P.O. Box 6511, Aurora, Colorado 80045, USA.
authors.forename: Vibha
authors.initials: V
authors.lastname: Sharma
authors.forename: William R
authors.initials: WR
authors.lastname: Hays
authors.forename: William M
authors.initials: WM
authors.lastname: Wood
authors.forename: Umarani
authors.initials: U
authors.lastname: Pugazhenthi
authors.forename: Donald L
authors.initials: DL
authors.lastname: St Germain
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Bianco
authors.forename: Wojciech
authors.initials: W
authors.lastname: Krezel
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Haugen
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004305:Dose-Response Relationship, Drug; D007031:Hypothalamus / Q000378:metabolism*; D007453:Iodide Peroxidase / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009930:Organic Chemicals / Q000494:pharmacology; D010902:Pituitary Gland / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism*; D012176:Retinoids / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013961:Thyroid Gland / Q000378:metabolism*; D013972:Thyrotropin / Q000378:metabolism; D013974:Thyroxine / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D001565:Benzoates; C423914:LG 268; D009930:Organic Chemicals; D012333:RNA, Messenger; D047488:Retinoid X Receptors; D012176:Retinoids; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid; D013972:Thyrotropin; D007453:Iodide Peroxidase; D013974:Thyroxine