Abnormal thyroid function is usually associated with altered cardiac function. Mutations in the thyroid hormone (TH)-binding region of the TH β-receptor (TRβ) that eliminate its TH-binding ability lead to the thyroid hormone resistance syndrome (RTH) in humans, which is characterized by high blood TH levels, goiter, hyperactivity, and tachycardia. Mice with “knock-in” mutations in the TH α-receptor (TRα) or TRβ that remove their TH-binding ability have been developed, and those with the mutated TRβ (TRβ PV/PV) appear to provide a model for RTH. These two types of mutants show different effects on cerebral energy metabolism, e.g., negligible change in glucose utilization (CMRGlc) in TRβ PV/PV mice and markedly reduced CMRGlc, like that found in cretinous rats, in the mice (TRα PV/+) with the knock-in mutation of the TRα gene. Studies in knockout mice have indicated that the TRα may also influence heart rate. Because mutations in both receptor genes appear to affect some parameters of cardiac function and because cardiac functional activity and energy metabolism are linked, we measured heart glucose utilization (HMRGlc) in both the TRβ PV/PV and TRα PV/+ mutants. Compared with values in normal wild-type mice, HMRGlc was reduced (−77 to −95%) in TRα PV/+ mutants and increased (87 to 340%) in TRβ PV/PV mutants, the degree depending on the region of the heart. Thus the TRα PV/+ and TRβ PV/PV mutations lead, respectively, to opposite effects on energy metabolism in the heart that are consistent with the bradycardia seen in hypothyroidism and the tachycardia associated with hyperthyroidism and RTH.
Hypermetabolism in mice caused by the central action of an unliganded thyroid hormone receptor α1
