Mice bearing the genomic mutation D337T on the thyroid hormone receptor b (TRb) gene present the classical signs of resistance to thyroid hormone (TH), with high serum TH and TSH. This mutant TR is unable to bind TH, remains constitutively bound to co-repressors, and has a dominant negative effect on normal TRs. In this study, we show that homozygous (TRbD337T) mice for this mutation have reduced body weight, length, and body fat content, despite augmented relative food intake and relative increase in serum leptin. TRbD337T mice exhibited normal glycemia and were more tolerant to an ip glucose load accompanied by reduced insulin secretion. Higher insulin sensitivity was observed after single insulin injection, when the TRbD337T mice developed a profound hypoglycemia. Impaired hepatic glucose production was confirmed by the reduction in glucose generation after pyruvate administration.

In addition, hepatic glycogen content was lower in homozygous TRbD337T mice than in wild type. Collectively, the data suggest that TRbD337T mice have deficient hepatic glucose production, by reduced gluconeogenesis and lower glycogen deposits. Analysis of liver gluconeogenic gene expression showed a reduction in the mRNA of phosphoenolpyruvate carboxykinase, a rate-limiting enzyme, and of peroxisome proliferator-activated receptor-g coactivator 1a, a key transcriptional factor essential to gluconeogenesis. Reduction in both gene expressions is consistent with resistance to TH action via TRb, reproducing a hypothyroid phenotype. In conclusion, mice carrying the D337T-dominant negative mutation on the TRb are leaner, exhibit impaired hepatic glucose production, and are more sensitive to hypoglycemic effects of insulin.