Impaired peripheral thyroid hormone metabolism in genetic obesity

The obese Zucker rat has alterations in thyroid hormone metabolism resulting in a lower serum T3 concentration and T3 plasma appearance rate compared to its lean littermates. This study was undertaken to measure the contribution of specific nonthyroidal tissues to the total production of T3 in vivo in the Zucker fatty rat. Simultaneous pulse kinetic studies of T4 and T3 were performed in lean and obese Zucker littermates and analyzed according to a three-pool model of distribution and metabolism. The serum concentration and plasma appearance rate of T3 were both decreased in the obese vs. lean Zucker phenotype (P < 0.05) despite an elevated serum concentration and plasma appearance rate for T4. The quantity of T4 within the fast pool (i.e. liver and kidney) available for deiodination was equal for both phenotypes; however, generation of T3 within the fast pool was impaired for the obese compared to the lean group (-25%; P < 0.05). The tissue content of radiolabeled T3 generated within the liver 24 h post injection of T4 for the obese group was 48% lower (P < 0.02) vs. the lean group. A separate group of lean and obese littermates were surgically thyroid-ectomized and replaced with T4 to maintain a euthyroid state. The obese Zucker group had lower serum T3 concentrations and T3 plasma appearance rates compared to similarly treated lean Zucker animals despite similar T4 serum concentrations. Treatment with propylthiouracil produced a decline in serum T3 plasma appearance rate T3 PAR (-55%; P < 0.02) in the T4-replaced lean rat but no alteration in T3 metabolism in the fatty Zucker rat. We conclude that the obese Zucker rat has impaired T3 synthesis in tissues containing Type I 5-deiodinase despite adequate T4 availability as substrate for deiodination to T3.