RXR receptor agonist suppression of thyroid function: Central effects in the absence of thyroid hormone receptor

Paolo E. Macchia, Ping Jiang, Yan Dar Yuan, Roshantha A.S. Chandarardna, Roy E. Weiss, Olivier Chassande, Jacques Samarut, Samuel Refetoff, Charles F. Burant

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

High-affinity agonists for the retinoic acid X receptors (RXR) have pleotropic effects when administered to humans. These include induction of hypertriglyceridemia and hypothyroidism. We determined the effect of a novel high-affinity RXR agonist with potent antihyperglycemic effects on thyroid function of female Zucker diabetic rats and nondiabetic littermates and in db/db mice. In both nondiabetic and ZFF rats, AGN194204 causes a 70-80% decrease in thyrotropin (TSH), 3,3′,5-triiodothyronine, and thyroxine (T4) concentrations. In the db/db mouse, AGN194204 causes a time-dependent decrease in thyroid hormone levels with the fall in TSH that was significant after 1 day of treatment preceding the fall in T4 levels that was significant at 3 days of treatment. Treatment with AGN194204 caused an initial increase in hepatic 5′-deiodinase mRNA levels which then fell to undetectable levels by 3 days of treatment and continued to be low at 7 days of treatment. After treatment for 5 days with AGN194204, both wild-type and thyroid hormone receptor β (TRβ-/-)-deficient mice demonstrated a nearly 50% decrease in serum TSH and T4 concentrations. The results suggest that a high-affinity RXR agonist with antihyperglycemic activity can cause central hypothyroidism independently of TRβ, the main mediator of hormone-induced TSH suppression.

Original languageEnglish (US)
Pages (from-to)E326-E331
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume283
Issue number2 46-2
DOIs
StatePublished - 2002

Keywords

  • Hypothyroidism
  • Knockout mice
  • Nuclear receptors
  • Retinoic acid receptors

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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    Macchia, P. E., Jiang, P., Yuan, Y. D., Chandarardna, R. A. S., Weiss, R. E., Chassande, O., Samarut, J., Refetoff, S., & Burant, C. F. (2002). RXR receptor agonist suppression of thyroid function: Central effects in the absence of thyroid hormone receptor. American Journal of Physiology - Endocrinology and Metabolism, 283(2 46-2), E326-E331. https://doi.org/10.1152/ajpendo.00313.2001