Abnormal thyroid function is usually associated with altered cardiac function. Mutations in the thyroid hormone (TH)-binding region of the TH receptor (TR), which eliminate its TH-binding ability, lead to the thyroid hormone resistance syndrome (RTH) in humans. RTH is characterized by high blood TH and thyroid stimulating hormone (TSH) levels, goiter, hyperactivity, and tachycardia. Mutant mice with "knock-in" mutations in the TR or TR receptor that remove their TH-binding ability have been developed. The mouse with the mutated TR receptor (TR^PV/PV) appears to provide a model for RTH, but, unlike the one with the TR mutation (TR1^PV/+), which manifests markedly reduced glucose utilization in brain like that seen in cretinism, its cerebral energy metabolism is little if at all affected. Studies in TR gene knockout mice have indicated that the TR1 receptor may also influence heart rate. Because mutations in both receptor genes appear to have effects on some parameters of cardiac function and because cardiac functional activity and energy metabolism are linked, we have measured heart glucose utilization (HMR_glc) in both the TR^PV/PV and TR1^PV/+ mutant mice. Compared to values in normal wild-type mice local HMR_glc was markedly reduced (-77 to -95%) in the TR1^PV/+ mutants and increased (87 to 340%) in the TR^PV/PV mutants, the degree depending on the region of the heart. Thus the TR1^PV/+ and TR^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.