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 language | English (US) |
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Pages (from-to) | E326-E331 |
Journal | American Journal of Physiology - Endocrinology and Metabolism |
Volume | 283 |
Issue number | 2 46-2 |
DOIs | |
State | Published - 2002 |
Externally published | Yes |
Keywords
- Hypothyroidism
- Knockout mice
- Nuclear receptors
- Retinoic acid receptors
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Physiology
- Physiology (medical)