Altered triiodothyronine metabolism in Zucker fatty rats

Genetically obese Zucker fatty rats require two autosomal recessive genes (fa/fa) to express the obese phenotype. The obese Zucker rat (fa/fa) has decreased total and free serum T3 concentrations, but normal serum T4 concentrations, compared to those in their lean littermates. To elucidate the mechanism of these differences, we measured the MCR and production rate (PR) of T4 and T3 in the three genotypes of 4-month-old male Zucker rats (Fa/Fa, Fa/fa, and fa/fa). In addition, 5'-deiodinase activity in liver, kidney, and brown adipose tissue homogenates was determined. T4 MCRs were equivalent in all three genotypes, but a decreased T3 MCR was seen in Fa/fa and fa/fa rats. An additive effect of the fa gene was noted with respect to the decrease in T3 MCR (Fa/Fa, 42.0 +/- 1.5; Fa/fa, 38.7 +/- 2.4; fa/fa, 34.7 +/- 3.4 ml/h; P less than 0.05). Whole body T4 PRs were equal in all three genotypes, but the T3 PR was decreased in the fa/fa rat by 25% compared to that in the homozygous lean rats (15.7 +/- 2.1 vs. 21.2 +/- 2.4 ng/h; P less than 0.005). Liver and kidney 5'-deiodinase activities were decreased in the fa/fa rat by 34% (P less than 0.005) and 20% (P less than 0.01), respectively. Brown adipose tissue and pituitary 5'-deiodinase activity were similar in all three genotypes. These results show a reduction in T3, but not T4, MCR in obese Zucker rats. Whole body T3 production and type I 5'-deiodinase activity were decreased in the obese (fa/fa) rats. These results suggest that decreased T4 to T3 conversion is responsible for the decreased T3 production rate in the fatty rat and may contribute to its obesity.