Mice expressing the mutant thyroid hormone receptor TRα1R384C, which has a 10-fold reduced affinity to the ligand T₃, exhibit hypermetabolism due to an overactivation of the sympathetic nervous system. To define the consequences in the liver, we analyzed hepatic metabolism and the regulation of liver genes in the mutant mice. Our results showed that hepatic phosphoenolpyruvate-carboxykinase was up-regulated and pyruvate kinase mRNA down-regulated, contrary to what observed after T₃ treatment. In contrast, mice expressing a mutant TRα1L400R specifically in the liver did not show a dysregulation of these genes; however, when the TRα1L400R was expressed ubiquitously, the hepatic phenotype differed from TRα1R384C animals, suggesting that the localization of the mutation plays an important role for its consequences on glucose metabolism. Furthermore, we observed that glycogen stores were completely depleted in TRα1R384C animals, despite increased gluconeogenesis and decreased glycolysis. Exposure of the mutant mice to high maternal levels of thyroid hormone during fetal development leads to a normal liver phenotype in the adult. Our results show how genetic and maternal factors interact to determine the metabolic setpoint of the offspring and indicate an important role for maternal thyroid hormone in the susceptibility to metabolic disorders in adulthood.