Mice expressing the mutant thyroid hormone receptor TRalpha1R384C, which has a 
10-fold reduced affinity to the ligand T(3), 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 T(3) treatment. In contrast, 
mice expressing a mutant TRalpha1L400R specifically in the liver did not show a 
dysregulation of these genes; however, when the TRalpha1L400R was expressed 
ubiquitously, the hepatic phenotype differed from TRalpha1R384C 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 TRalpha1R384C 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.