Vitamin A and retinoids affect pituitary-thyroid function through suppression of serum thyroid-stimulating hormone (TSH) levels and TSH-β subunit gene expression. We have previously shown that retinoid X receptor–selective (RXR-selective) ligands can suppress serum TSH levels in vivo and TSH-β promoter activity in vitro. The RXR-γ 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-γ isotype. These mice had significantly higher serum T4 levels and TSH levels than did wild-type (WT) controls. Treatment of RXR-γ–deficient and WT mice with T3 suppressed serum TSH and T4 levels in both groups, but RXR-γ–deficient mice were relatively resistant to exogenous T3. RXR-γ–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-γ, 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-γ 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.
Nicole S. Brown, Alexandra Smart, Vibha Sharma, Michelle L. Brinkmeier, Lauren Greenlee, Sally A. Camper, Dalan R. Jensen, Robert H. Eckel, Wojciech Krezel, Pierre Chambon, Bryan R. Haugen