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The impact of varying caloric intake on peripheral monodeiodination and plasma disposal of T3, rT3, and the three diiodothyronines (T2) was studied in five normal subjects while they were consuming a low calorie diet (1200 Cal/day) and again while receiving a high calorie diet (3600 Cal/day). Toward the end of each diet period 240 nmol 3,3'-T2 (126 micrograms) and 80 nmol 3',5'-T2 (42 micrograms) were infused for 7 h, and a bolus injection of 137 nmol 3,5-T2 (72 micrograms) was followed by a 12-h infusion of 69 nmol 3,5-T2 (36 micrograms) and 111 nmol rT3 (72 micrograms) on another day. [125I]T3 (30 muCi) was injected on the third day. The T2 and rT3 concentrations were measured by RIA during the 2 days of infusion, and the serum disappearance of [125I]T3 was studied by immunoprecipitation and trichloroacetic acid precipitation of the labeled T3. Four to 5% of the plasma disposal of T3 was accounted for by 3'-monodeiodination, and 36-39% by 5-monodeiodination. Increasing caloric intake resulted in a higher overall plasma disposal rate of T3, but no change in the percentage of T3 metabolized by monodeiodination pathways. In contrast, 5'-monodeiodination accounted for 21% of the total plasma disposal of rT3 during the low calorie diet and 45% during the high calorie intake. This increase in 5'-monodeiodination of rT3 was at the expense of alternative pathways of disposal. A marked increase in the plasma clearance rate of 3,5-T2 was also found during the high calorie diet, indicating that the level of caloric intake affects pathways of metabolism other than outer ring monodeiodination. These studies emphasize the important role played by diet in the regulation of peripheral thyroid hormone metabolism through modulating outer ring monodeiodination, and that overnutrition changes other pathways of iodothyronine metabolism as well.

We have investigated the effect of FFA on the RIA of rT3 because of our previous findings of a correlation between serum rT3 values and increased FFA concentrations during prolonged exercise and reports of interference by FFA in other thyroid hormone assays. Apparent rT3 values increased by 19% and 34% in in vivo studies of acute lipolysis in subjects 5 min post exercise or 10 min post heparin, respectively, while T3 and T4 concentrations were unchanged. Varying concentrations of palmitic acid were added in vitro to four normal sera, and the increase in FFA concentration correlated significantly with the increase in apparent rT3 values. The mean +/- SE of the regression slope was 9.3 +/- 1.8 ng/dl rT3/mM FFA (r = 0.96 +/- 0.02). The addition of linoleic acid produced a similar effect. T3 and T4 concentrations were unchanged. The interaction of FFA in the rT3 RIA was unrelated to the procedure used to separate the assay, to the concentration of 8-anilino-1-napthalene-sulfonic acid in the assay buffer, to FFA binding directly to the antisera or to use of a particular antisera. The magnitude of the effect was similar in charcoal-treated sera, and the addition of 2 mM palmitic acid to the assay standard curve decreased the y intercept but did not alter the slope, suggesting an interaction of rT3 with FFA, rather than change in affinity of the antisera.

The effects of hyper- and hypothyroidism on sympathetic nervous system activity and energy expenditure are well recognized. The impact of altered sympathetic nervous system activity on energy expenditure and thyroid hormone metabolism has not been well studied. We investigated the effects of orally administered terbutaline sulfate, a beta 2-receptor agonist (5 mg, three times per day for 2 weeks), on the activity of the sympathetic nervous system, energy expenditure, and thyroid hormone metabolism in six normal men, aged 21-36 yr. The cardiovascular, metabolic, and thermogenic responses to an infusion of the beta-adrenergic agonist isoproterenol were clearly blunted after 2 weeks of treatment with terbutaline sulfate, indicating down-regulation of beta-receptors and/or development of reduced sensitivity. There were no significant changes in the cardiovascular, metabolic, or thermogenic responses to an infusion of the alpha-adrenergic agonist phenylephrine. Basal metabolic rate was significantly increased by the chronic administration of terbutaline sulfate [5.040 +/- 0.167 (+/- SE) vs. 5.421 +/- 0.234 kJ/min; P less than 0.05]. There was a highly significant change in the serum T3 to T4 ratio (19.4 +/- 1.0 vs. 24.4 +/- 1.0; P less than 0.001). This was a result of increased serum T3 concentrations (136 +/- 9 vs. 160 +/- 14 ng/dl; P less than 0.05) and decreased serum T4 concentrations (7.2 +/- 0.8 vs. 6.7 +/- 0.8 micrograms/dl; P = NS). Chronic beta-receptor stimulation with terbutaline sulfate increases the basal metabolic rate and T3 concentrations. These changes occurred despite down-regulation of beta-receptors and/or decreased sensitivity in response to chronic terbutaline administration.

The effect of moderate bicycle exercise (3.5 h) on peripheral thyroid hormone metabolism was studied under two conditions (with and without glucose infusion) in four normal males. Serum T3, rT3, total protein, plasma glucose, and FFA were determined. Exercise induced an increase in rT3 from 29 to 40 ng/dl (P less than 0.01), a decrease in T3 from 154 to 147 ng/dl (P less than 0.01), and an increase in T4 from 7.1 to 7.5 micrograms/dl (P less than 0.05). When glucose was infused during exercise, the changes in rT3 were blunted (P less than 0.01) and the changes in T3 and T4 were diminished. During exercise, rT3 correlated with FFA (r = 0.95) and plasma glucose (r = -0.87). When glucose was infused during exercise, these correlations decreased (r = 0.81 and -0.56, respectively). Since moderate, prolonged exercise induces a state of early or acute starvation it is concluded that the changes in peripheral thyroid hormone metabolism reported here are similar to those found in starvation. The temporal changes of rT3, FFA, and plasma glucose during exercise suggest a relationship between thyroid hormone metabolism and the uptake and utilization of FFA and glucose or the mixture of these body fuels.