Use of top-down elasticity analysis to identify sites of thyroid hormone-induced thermogenesis

Top-down elasticity analysis is a novel extension of top-down metabolic control analysis. It has provided researchers with a theoretical and practical platform upon which quantitative analyses of the sites of action of hormones and drugs can be based. This approach is easy to apply and involves dividing up the metabolic system in question into two or three blocks of enzyme reactions around an intermediate between the blocks of reactions. The kinetic response of each block to the intermediate is measured in the steady state in situ by determining the flux through the block at different measured intermediate concentrations. The intermediate can be manipulated by titrating the other blocks with suitable inhibitors or activators. Then, to determine which blocks of reactions are quantitatively the most important in terms of any change in the flux rate of the system, a quantitative comparison of the titration curves from the experimental preparations is made with those of the control preparations. In this minireview we will examine, as an example, the use of top-down elasticity analysis for the quantitative identification of the important sites of action of thyroid hormones on oxidative phosphorylation in hepatocytes. The experimental results show that approximately 50% of the change in resting oxygen consumption in hepatocytes from hypothyroid and hyperthyroid rats (compared with euthyroid controls) is attributable to changes in the rate of the mitochondrial proton leak; the remaining 50% is accounted for by changes in nonmitochondrial- and ATP turnover-dependent oxygen consumption in hypothyroid and hyperthyroid hepatocytes, respectively.