Vol. 283, Issue 2, E326-E331, August 2002
RXR receptor agonist suppression of thyroid function: central
effects in the absence of thyroid hormone receptor
Paolo E.
Macchia1,
Ping
Jiang2,
Yan-Dar
Yuan3,
Roshantha A. S.
Chandarardna3,4,
Roy
E.
Weiss1,
Olivier
Chassande5,
Jacques
Samarut5,
Samuel
Refetoff1,2, and
Charles F.
Burant6
1 Departments of Medicine and Pediatrics, Committee
on Genetics and the J. P. Kennedy Jr. Mental Retardation
Research Center, The University of Chicago, Chicago, Illinois
60637-1470; Retinoid Research, Departments of 3 Biology
and 4 Chemistry, Allergan, Irvine, California 92612;
5 Ecole Normale Superieure, 69364 Lyon, France;
2 Department of Molecular Sciences, Pfizer Global
Research and Development-Ann Arbor Laboratories, Ann Arbor 48105;
and 6 Division of Endocrinology and Metabolism,
Department of Internal Medicine, University of Michigan, Ann Arbor,
Michigan 48109-0354
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 
(TR
/)-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 TR, the main mediator of hormone-induced TSH suppression.
nuclear receptors; retinoic acid receptors; hypothyroidism; knockout mice
