Thyroid hormone resistance and increased metabolic rate in the RXR-gamma-deficient mouse.
Vitamin A and retinoids affect pituitary-thyroid function through suppression of serum thyroid-stimulating hormone (TSH) levels and TSH-beta subunit gene expression. We have previously shown that retinoid X receptor-selective (RXR-selective) ligands can suppress serum TSH levels in vivo and TSH-beta promoter activity in vitro. The RXR-gamma isotype has limited tissue distribution that includes the thyrotrope cells of the anterior pituitary gland. In this study, we have performed a detailed analysis of the pituitary-thyroid function of mice lacking the gene for the RXR-gamma isotype. These mice had significantly higher serum T4 levels and TSH levels than did wild-type (WT) controls. Treatment of RXR-gamma-deficient and WT mice with T3 suppressed serum TSH and T4 levels in both groups, but RXR-gamma-deficient mice were relatively resistant to exogenous T3. RXR-gamma-deficient mice had significantly higher metabolic rates than did WT controls, suggesting that these animals have a pattern of central resistance to thyroid hormone. RXR-gamma, which is also expressed in skeletal muscle and the hypothalamus, may have a direct effect on muscle metabolism, regulation of food intake, or thyrotropin-releasing hormone levels in the hypothalamus. In conclusion, the RXR-gamma isotype appears to contribute to the regulation of serum TSH and T4 levels and to affect peripheral metabolism through regulation of the hypothalamic-pituitary-thyroid axis or through direct effects on skeletal muscle.
Brown
N S
NS
Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA.
Smart
A
A
Sharma
V
V
Brinkmeier
M L
ML
Greenlee
L
L
Camper
S A
SA
Jensen
D R
DR
Eckel
R H
RH
Krezel
W
W
Chambon
P
P
Haugen
B R
BR
D000818:Animals; D004734:Energy Metabolism; D005260:Female; D051379:Mice; D010641:Phenotype; D010902:Pituitary Gland / Q000473:pathology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology*; D047488:Retinoid X Receptors; D013961:Thyroid Gland / Q000473:pathology; D018382:Thyroid Hormone Resistance Syndrome / Q000378:metabolism*; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D013972:Thyrotropin; D013974:Thyroxine