RXR receptor agonist suppression of thyroid function: central effects in the absence of thyroid hormone receptor.
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 (T(4)) 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 T(4) 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 beta (TR beta(-/-))-deficient mice demonstrated a nearly 50% decrease in serum TSH and T(4) concentrations. The results suggest that a high-affinity RXR agonist with antihyperglycemic activity can cause central hypothyroidism independently of TR beta, the main mediator of hormone-induced TSH suppression.
Department of Medicine, Committee on Genetics and the J. P. Kennedy Jr. Mental Retardation Research Center, The University of Chicago, Chicago, Illinois 60637-1470, USA.
Paolo E
PE
Macchia
Ping
P
Jiang
Yan-Dar
YD
Yuan
Roshantha A S
RA
Chandarardna
Roy E
RE
Weiss
Olivier
O
Chassande
Jacques
J
Samarut
Samuel
S
Refetoff
Charles F
CF
Burant
D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics / Q000503:physiopathology*; D015536:Down-Regulation; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005260:Female; D007037:Hypothyroidism / Q000139:chemically induced; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D020033:Protein Isoforms / Q000172:deficiency; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D011988:Receptors, Thyroid Hormone / Q000172:deficiency*; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013961:Thyroid Gland / Q000187:drug effects* / Q000503:physiopathology*; D013972:Thyrotropin / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D013974:Thyroxine / Q000037:antagonists & inhibitors / Q000097:blood; D014157:Transcription Factors / Q000819:agonists*
C430898:AGN 194204; D005231:Fatty Acids, Unsaturated; D008024:Ligands; D020033:Protein Isoforms; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; D013972:Thyrotropin; D013974:Thyroxine