Stimulation by thyroid hormone of coupled respiration and of respiration apparently not coupled to the synthesis of ATP in rat hepatocytes.
Maximal rates of O2 uptake by hepatocytes from hypothyroid, euthyroid, and hyperthyroid rats, in the absence of uncoupling agents or ionophores, were achieved by simultaneously stimulating ureogenesis and gluconeogenesis. Rates were increased by pretreatment of the donor animals with thyroid hormone. Only a minor part of the increase could be attributed to stimulation of the activity of plasma membrane (Na+ + K+)-ATPase. No synthesis of glycogen occurred, nor was there any evidence of pyruvate cycling under the conditions used, thus ruling out these processes as potential sources of ATP turnover. Calculation of the O2 uptake necessary to satisfy the energy requirements of gluconeogenesis and ureogenesis, based on anticipated ATP demand and an assumed P:O ratio of 3:1, invariably yielded a theoretical quantity that was less than the experimentally measured increase in O2 uptake. The difference between measured and calculated rates of respiration, possibly representing noncoupled respiration, was related to the thyroid status of the animal, being greatest in cells from hyperthyroid rats. In another experimental approach the O2 uptake associated with ATP synthesis was inhibited by the addition of oligomycin to hepatocytes incubated in the presence of substrates, thus abolishing ATP-coupled respiration. The magnitude of the ATP-coupled as well as the residual respiration was increased in response to thyroid hormone. Thyroid hormone increased the turnover of intramitochondrial ATP. These results imply that a considerable portion of the thermogenic effect of thyroid hormone may be mediated by a stimulatory action on metabolism not directly associated with extramitochondrial ATP-dependent synthetic processes.