Thyroid hormone resistance and increased metabolic rate in the RXR-gamma-deficient mouse

Vitamin A and retinoids affect pituitary-thyroid function through suppressi on of serum thyroid-stimulating hormone (TSH) levels and TSH-beta subunit g ene 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 distr ibution that includes the thyrotrope cells of the anterior pituitary gland. In this study, we have performed a detailed analysis of the pituitary-thyr oid 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 suppre ssed serum TSH and T4 levels in both groups, but RXR-gamma-deficient mice w ere relatively resistant to exogenous T3. RXR-gamma-deficient mice had sign ificantly higher metabolic rates than did WT controls, suggesting that thes e animals have a pattern of central resistance to thyroid hormone. RXR-gamm a, which is also expressed in skeletal muscle and the hypothalamus, may hav e a direct effect on muscle metabolism, regulation of food intake, or thyro tropin-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 hypoth alamic-pituitary-thyroid axis or through direct effects on skeletal muscle.