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TRH-TSH-THYROID |
Dipartimento di Scienze Biologiche ed Ambientali (M.M., E.S., F.G.), Università degli Studi del Sannio, 82100 Benevento, Italy; Dipartimento di Scienze della Vita (A.La.), Seconda Università degli Studi di Napoli, 81100 Caserta, Italy; Dipartimento di Fisiologia Generale ed Ambientale (A.Lo., L.B.), Università di Napoli Federico II, 80134 Napoli, Italy; and Department of Radiology and Nuclear Medicine (G.P.), Benjamin Franklin Medical Center, Free University of Berlin, 12200 Berlin, Germany
Address all correspondence and requests for reprints to: Antonia Lanni, Dipartimento di Scienze della Vita, Seconda Università degli Studi di Napoli, Via Vivaldi 43, 81100 Caserta, Italy. E-mail: antonia.lanni{at}unina2.it
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Introduction |
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The control of energy metabolism requires the participation of a multitude of biochemical and molecular mechanisms and may involve several cellular compartments. The roots of the current hypotheses concerning the cellular mechanism of action of thyroid hormones on energy metabolism can be traced back to early studies of their calorigenic effect by Tata et al. (1, 2, 3) in the 1960s. They showed that the administration of T3 to hypothyroid rats induced an increase in basal metabolic rate, whereas the simultaneous injection of actinomycin D with the T3 completely abolished the stimulatory effect of T3. These results, pointing toward the involvement of de novo transcription, implicated the nucleus as the primary candidate for the location of the cellular signaling pathway involved in mediating the effect of T3 on energy metabolism. However, both the number and the identity of the T3-controlled genes remain unknown, as do their relative contributions.
Mitochondria, on the other hand, are considered to be likely subcellular targets for thyroid hormones because of the central role they play in cellular energy-transduction. They are the major site of oxidative processes in the cell, and extensive changes occur in the mitochondrial compartment in response either to thyroid hormones or to physiological states involving changes in the activity of the thyroid gland (for reviews, see Refs. 4 and 5). In addition, T3 plays an important role in the regulation of mitochondrial function in several metabolically very active tissues, such as skeletal muscle, heart, kidney, and liver (5). The effects on respiratory parameters are often divided into: 1) short-term effects, occurring within minutes or a few hours; and 2) long-term effects, occurring over several hours or days (4, 5). This being so, it is quite conceivable that both nuclear- and extranuclear-mediated pathways are involved in the cellular-level mediation of the effects exerted by T3 on energy metabolism.
On the basis of results purporting to show either the mitochondrion or nucleus as the location of the major signaling pathway, studies concerning the effects of thyroid hormones at the cellular level have been mostly focused on T3; but, in the last decade, evidence has accumulated suggesting that iodothyronines other than T3 may be active in the regulation of energy metabolism. Indeed, studies from several laboratories have suggested that among these other iodothyronines, 3,5-diiodo-L-thyronine (3,5-T2), a putative product of the deiodination pathway involved in T3 metabolism, could be a peripheral mediator of some effects of thyroid hormones on cellular respiration (Refs. 6, 7, 8, 9, 10 ; for review, see Refs. 4 and 11). In our laboratory, we have demonstrated that 3,5-T2, as well as T3, is able to enhance resting metabolic rate (RMR) in hypothyroid rats, although the effects of these iodothyronines differ in terms of both time course and dependency on protein synthesis (12, 13). Thus, injection of T3 enhances RMR via a nuclear-mediated pathway, so its effect takes some days to start and some days to stop, and it is blocked by the simultaneous injection of actinomycin D (13). On the other hand, 3,5-T2 affects RMR more rapidly and in a manner that is independent of new transcription (13). However, the effect of 3,5-T2 on RMR is only evident when it is injected into P+I rats [rats made hypothyroid by combined treatment with propylthiouracil (PTU) and iopanoic acid (IOP)]; these P+I animals show low thyroid-hormone levels and an inhibition of all three of the deiodinase enzymes. Injection of 3,5-T2 into normal euthyroid (N) rats results in a slight or nonexistent change in RMR. Although a convincing explanation for the lack of effect of 3,5-T2 in N rats has previously eluded us, we began to wonder whether, in these animals, injected 3,5-T2 is ineffective at enhancing RMR because it needs to be formed intracellularly from a precursor such as T3. To test this hypothesis, we performed the present study: 1) to compare N rats and P+I rats in terms of the time course of the changes in RMR occurring after a single injection of T3; and 2) to follow the changes in the serum and hepatic levels of 3,5-T2, after such an injection, to see whether their time course is consistent with the effect of T3 on RMR in N rats being, at least partly, attributable to its intracellular conversion into 3,5-T2.
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Materials and Methods |
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Animals
Male Wistar rats (250–300 g), living in a temperature-controlled room at 28 C, were kept one per cage under an artificial lighting regime of 12 h light, 12 h darkness. A commercial mash (Charles River Laboratories, Inc., Lecco, Italy) was available ad libitum, and the animals had free access to water. All experiments were performed in accordance with local and national guidelines covering animal experiments. At the end of the experiment, the rats were anesthetized by ip administration of chloral hydrate (40 mg/100 g body wt) and killed by decapitation. Three different groups of animals were used throughout: normal euthyroid rats (referred to as the N group); rats with both thyroid and deiodinase activities chronically inhibited, as described below, by injection of PTU plus IOP for 3 wk (referred to as the P+I group); and euthyroid rats, in which deiodinase enzymes were inhibited by acute treatment (see below) with PTU plus IOP (referred to as the N+P+I group). Hypothyroidism (P+I group) was chronically produced by an ip administration of PTU (1 mg/100 g body wt), once per day for 3 wk, together with a weekly ip administration of IOP (6 mg/100 g body wt). Acute inhibition of deiodinase enzymes (N+P+I group) was produced in the following way: two administrations of 2 mg of PTU/100 g body wt were given to euthyroid rats (one at 4 h before and one at the time of T3 injection) (16), whereas a single dose of IOP (6 mg/100 g body wt) was injected 30 min after the first PTU injection (17). The inhibition of deiodinase activities allows us to attribute the observed effects to the iodothyronines injected rather than to any of their deiodinated products. Euthyroid controls (N group) were sham-injected with saline.
To enable determination of the time course of the calorigenic effects of iodothyronines, N and P+I animals were acutely injected ip with a single dose of 25 µg/100 g body wt of either T3 or 3,5-T2. As a control for the possible stress effects of the injection itself, saline was injected ip into eu- and hypothyroid control rats. The dose of 25 µg/100 g body wt was chosen because it produces a clear-cut effect on RMR and indeed restores hypothyroid metabolism to the level observed in euthyroid control rats (2, 13).
To enable evaluation of the possible involvement of de novo transcription/translation in the action of the iodothyronines tested, in some groups, actinomycin D (8 µg/100 g body wt) was injected in combination with 25 µg/100 g body wt of either 3,5-T2 or T3. At the extremely low dose used here, actinomycin D only inhibits the synthesis of messenger RNA (18).
The time course of the effect of T3 on RMR was also investigated in another experiment in which deiodinase activities were acutely inhibited (as above). To check deiodinase activities, N+P+I rats were killed at 4, 24, and 48 h after acute administration of PTU plus IOP. In the 24- and 48-h treatment groups, PTU administration was continued until 12 h before the animal was killed.
To assess the rate of conversion of T3 into 3,5-T2 and 3,3'-T2, both N and P+I rats were ip-injected with 25 µg T3/100 g body wt. The rats were killed at 12, 24, 48, or 72 h after the injection; and the trunk blood was collected; and the serum was separated and stored at -20 C for later measurement of the concentrations of iodothyronines. Livers were dissected out, cleaned, immediately weighed (wet weight), and processed for the determination of either 3,5-T2 or 3,3'-T2 content. Samples of brain, brown adipose tissue (BAT), and liver from resting N, P+I, and N+P+I rats were processed for deiodinase-activity assays (see below).
RMR
To acquire time-course data, with respect to oxygen consumption, sequential measurements were taken 1 h before and at various intervals after the start of iodothyronine treatment. The RMR was measured using open-circuit indirect calorimetry. To this end, the rat was placed in a respiration chamber (
32 x 20 x 19 cm), with airflow being measured using an O2-ECO mass flow controller (Columbus Instruments International Corporation, Columbus, OH). Details of this set-up and of the way that measurements are made were given by Lanni et al. (12). Briefly, the experiments done to determine the time course of the calorigenic effects of iodothyronines were run as follows. In each rat, RMR was measured just before the injection of iodothyronines (time 0). In the same rat, RMR was measured at different time-points after the injection, so that time 0 represents the starting value for each rat. The increase in RMR was obtained by comparing the value at time 0 with those at other time points, always in one and the same rat. The measurements for the calculation of RMR (the lowest metabolic rate shown by a resting animal when it is not in a postabsorptive or fasting state and is not sleeping) were taken at 28 C, between 1100 h and 1600 h, when the rat’s energy expenditure is at a lower level than in any other period of the day. The mean values we reported in the figures were obtained by averaging the increases in RMR observed in animals injected with one and the same iodothyronine.
Analytical procedures
Type I deiodinase activity (D1) was determined in the liver microsomal fraction by analysis of the production of radioiodide from [3', 5'-125I]-rT3. To this end, 2 µg microsomal protein was incubated for 30 min at 37 C with 0.1 µM rT3 and approximately 100,000 cpm [3', 5'-125I]-rT3 in 200 µl of 0.2-M phosphate buffer (pH 7.2) with 4 mM EDTA and 5 mM dithiothreitol (DTT), using the method described by Visser et al. (19).
Type II deiodinase activity (D2) was determined in BAT, according to the method of Leonard et al. (20). This involved measuring the release of radioiodide from [3', 5'-125I]-rT3 after the incubation of 20 µg BAT infranatant proteins, for 60 min at 37 C, with 2 nM rT3 and approximately 100,000 cpm [3', 5'-125I]-rT3 in 200 µl 0.1-M phosphate buffer (pH 7.2), 2 mM EDTA, and 20 mM DTT.
In both the type I and type II deiodinase assays, the reactions were stopped by the addition of 100 µl 5% BSA at 0 C. Protein-bound iodothyronines were precipitated by the addition of 500 µl 10% (wt/vol) trichloroacetic acid. After incubation of the mixtures at 0 C for 10 min, they were centrifuged, and the radioactivity in the supernatant was subsequently determined. Enzymatic deiodination was corrected for nonenzymatic 125I production (as determined in blank incubations without enzymes) and multiplied by 2, to account for random labeling and the deiodination of the 3' and 5' positions of [3', 5'-125I]-rT3.
Type III deiodinase activity (D3) was determined in brain microsomes by measuring the formation of 3[3'-125I]-T2 from [3'-125I]-T3 by HPLC analysis, as reported by Schoenmakers et al. (21). A 100-µg sample of brain microsomal protein was incubated for 60 min at 37 C with 1 nM T3 and approximately 100,000 cpm [5'-125I]-T3 in 200 µl of 0.1-M phosphate buffer (pH 7.2) with 4 mM EDTA and 10 mM DTT. The reactions were stopped by the addition of 300 µl methanol on ice. After centrifugation of precipitated proteins, the supernatants were analyzed for 3[3'-125I]T2 formation, by HPLC analysis, after elution with a 45:50 (vol/vol) mixture of methanol and 20 mM ammonium acetate (pH 4.0), at a flow of 0.8 ml/min.
Hormone determinations
T3-, 3,5-T2-, and 3,3'-T2- binding antisera.
Antisera to T3, 3,5-T2, and 3,3'-T2 were produced as previously reported (22). The antisera selected for the experiments were used in a final dilution of 1:100,000, 1:250,000, and 1:150,000 for T3, 3,5-T2, and 3,3'-T2, respectively. The antisera bound about 40% of tracer in an incubation vol of 250 µl.
Preparation of samples.
Among the metabolically active tissues, the liver was chosen for the study of the in vivo conversion of T3 into 3,5-T2 and 3,3'-T2 (T2s) because it is a tissue containing high levels of D1, an enzyme well known to be capable of converting T3 to 3,3'-T2 and potentially (though not yet demonstrated) into 3,5-T2. Accordingly, 3,5-T2 was shown to reach its highest concentrations in the liver, compared with other tissues (12 areas of the brain, pituitary glands, and heart) investigated (Pinna, G., O. Brödel, T. J. Visser, A. Jeitner, H. Grau, M. Eravci, H. Meinhold, and A. Baumgartner, submitted manuscript). By contrast, heart and skeletal muscle are two tissues that derive their intracellular T3 directly from plasma by active transport (23), and no deiodinase activities have been detected in these tissues in the rat (21).
Liver concentrations of T2s were determined after extraction from tissue samples, as reported by Pinna et al. (24). In brief, tissue samples were homogenized in 100% methanol containing 1 mM PTU. The iodothyronines were then purified through AG 1 x 2 resin columns (Bio-Rad Laboratories, Inc., Richmond, CA) and were eluted with 70% acetic acid, evaporated to dryness, and taken up in the experimental buffer (phosphate buffer, 0.04 M, pH 8.0, containing 243 mg/liter merthiolate and 2 g/liter BSA) before RIA measurements. Extracts from 200 µl original serum or tissue were processed individually and assayed together within the same run. Each sample was assayed in triplicate. The results were corrected on the basis of individual recovery data obtained after the addition of tracer (1000 cpm/tube) during the initial extraction process. This amount of tracer did not affect the RIA measurements. The extraction procedure yielded a mean iodothyronine recovery of between 70 and 75%.
RIA procedure for T3, 3,5-T2, and 3,3'-T2.
The RIAs of T3, 3,5-T2, and 3,3'-T2 were carried out as previously reported (24, 25, 26). Briefly, the assay was performed by adding the following in sequence: 1) experimental buffer (0.04 M phosphate buffer, pH 8.0, containing 243 mg/liter Merthiolate and 2 g/liter BSA), to give a final vol of 250 µl/tube; 2) 50 µl of an unknown sample or of a T3, 3,5-T2, or 3,3'-T2 standard at concentrations within the range from 0.3–60 fmol/tube, 0.48–20 fmol/tube, and 0.49–60 fmol/tube for T3, 3,5-T2, and 3,3'-T2, respectively; and 3) 100 µl tracer solution (experimental buffer containing 100 mg/liter L-cysteine) containing approximately 6000 cpm T3, 3-Br-5-[125I]T1, or 3,3'-T2. After a 24-h incubation at room temperature, the antibody-bound iodothyronine portion was precipitated by adding 1 ml stop solution (formed by mixing the experimental buffer, 30% (wt/vol) polyethylene glycol, and 1.3 mg/ml bovine 
-globulin) and centrifuged. The supernatant was discarded, and precipitated bound radioactivity was counted.
The protein concentration was determined by the method of Hartree (27), using BSA as standard.
Statistical analysis
Results are expressed as means ± SEM. The statistical significance of differences between groups was determined by a one-way ANOVA followed by a Student’s-Newman-Keuls test. Comparison between independent means was performed using a t test.
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Results |
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). In addition, RMR was significantly lower in P+I rats than in N controls, thus confirming the hypothyroid status of the animals. Another effect of chronic PTU+IOP treatment (P+I group) was to inhibit the activities of the three deiodinase enzymes (Table 1).
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(upper panel) illustrates the effect, on RMR, of the acute administration of T3, T4, or 3,5-T2 to P+I rats. Injection of T3 caused a maximal increase of about 40% in RMR; the increase started 25–30 h after the injection, peaked at 50–75 h, and lasted 3–5 d. Similarly, injection of 3,5-T2 resulted in a maximal increase of about 40% in RMR; the increase started earlier, between 6 and 12 h after the injection, peaked at about 30 h, and had almost disappeared at 48 h. Injection of T4 evoked a much smaller effect (an increase of about 10%), with latencies to start and peak similar to those seen with T3. A trend similar to that seen with 3,5-T2 was observed after 3,3'-T2 injection (data not shown). In the latter case, the dose needed was at least three times higher than that used for 3,5-T2; but the effect was lower than that elicited by 3,5-T2.
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(lower panel) illustrates the effect of the acute administration of T3, T4, or 3,5-T2 to N rats. Similar to the results reported above for P+I rats, injection of T3 caused a maximal increase of about 40% in RMR; the increase started 16–19 h after the injection, peaked at 24–26 h, and had almost disappeared at 50–75 h. Thus, injection of T3 into N rats evoked a response pattern temporally similar to that evoked by 3,5-T2 in P+I rats, perhaps suggesting that a large part of the early effect of T3 in N animals could be attributed to a deiodinated product of T3, possibly 3,5-T2. Injection of T4 elicited a smaller effect, with the maximal increase in RMR (+20%) being seen at about 50 h. Injection of 3,5-T2 into N rats resulted in little or no change in RMR.
Combined injection of iodothyronines and actinomycin D.
Fig. 2 illustrates the changes in the RMR seen in N and P+I rats after combined administration of actinomycin D and a respective iodothyronine. The effects on RMR produced by T3 in P+I rats were completely prevented by simultaneous injection of actinomycin D, thus indicating an involvement of de novo transcription. The addition of actinomycin D to the injection of 3,5-T2, on the other hand, did not cause any attenuation of the stimulation seen with the 3,5-T2 alone, thus indicating a transcription/translation-independent mechanism of action. The simultaneous injection of actinomycin D with T3 into N rats strongly inhibited the late part of the effect previously seen with T3 (after 24 h), whereas the early effect (between 14 and 24 h) was only slightly affected.
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illustrates the combined effect of T3 and 3,5-T2 on RMR in P+I rats. The increase started between 14 and 25 h and peaked at about 50 h, and the level returned to baseline 3–4 d after the injection. Once again, the simultaneous injection of actinomycin D did not attenuate the presumable 3,5-T2 stimulation observed between 14 and 25 h, but it did inhibit the effect seen after 25 h (presumably T3-induced). The early part of the curve closely resembles that observed in P+I rats after 3,5-T2 injection (Fig. 1, top). These results support the idea that the two iodothyronines exert independent effects on RMR.
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, in N rats, the serum and liver 3,5-T2 and 3,3'-T2 (T2s) concentrations were increased at 12 h after the injection of T3. In the liver, the peak concentration of T2s was reached at 24 h. By contrast, no increase in either serum or liver levels of T2s was evident in P+I rats (data not shown). It could, therefore, be concluded that in vivo deiodination of T3 is responsible for most of the 3,3'-T2 and 3,5-T2 found in the circulation as well as in the liver (because, after an inhibition of the conversion of T3 to T2s, injection of T3 does not lead to any increase in the level of T2s in either serum or liver).
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allows a comparison between the increase in RMR seen in N rats injected with actinomycin D plus T3 and the increase in the liver level of T2s after T3 administration to N rats. The maximal increase in T2s in the liver and the maximal increase in RMR occur at the same time (at about 25 h after the injection). This increase in RMR is actinomycin-D-insensitive (see Figs. 1 and 2), suggesting that T2s derived from T3 mediate this effect in N rats.
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Discussion |
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Support for this idea comes from the data reported here showing: 1) that an acute inhibition of deiodinase activities in euthyroid animals strongly reduced the early effect on RMR induced by T3; and 2) that significant increases in the serum and cellular levels of 3,5-T2 followed the injection of T3 into N animals. The same increases in 3,5-T2 levels were not observed after the injection of T3 into P+I rats. The results reported here, to our knowledge, are the first ones dealing with the 3,5-T2 concentrations in adult euthyroid rats. Future studies, however, ideally need to give confirmatory measurement of the in vivo concentrations providing normal intracellular and serum levels of 3,5-T2 to achieve average concentration values. These results demonstrate that in vivo, N rats have a biochemical pathway transforming T3 into 3,5-T2. No studies have been published, so far, to indicate which deiodinase enzyme might catalyze the conversion of T3 to 3,5-T2, either in vivo or in vitro. The results of early studies in humans all showed that this diiodothyronine is, however, present in the serum and in several areas of the brain (24) and is probably produced by peripheral deiodination from circulating T3, production controlled by the thyroid seeming extremely unlikely (29, 30, 31). Although our efforts to demonstrate a T3-to-3,5-T2 conversion in vitro have been unsuccessful so far, the present data showing an increase in 3,5-T2 levels in N rats after T3 injection demonstrate that it exists in vivo. In addition, studies that focused on the rapid stimulation of mitochondrial respiration by thyroid hormones showed that PTU completely inhibits its rapid stimulation by T3 but does not prevent stimulation by 3,5-T2 (6, 9). The authors suggested that the rapid effect of T3 on mitochondrial respiration may not be attributable directly to T3 itself, but rather to its deiodinated product, 3,5-T2.
Nothing in our data argues against a possible contribution by 3,3'-T2 to the early effect elicited by T3 injection into N rats. Indeed, 3,3'-T2 levels in serum and liver were increased after T3 injection into N rats. Moreover, the existence of a biochemical pathway leading to the formation of 3,3'-T2 from T3 is well established. However, 3,3'-T2 itself is able to increase RMR only if chronically injected into hypothyroid rats, the acute administration of a single dose (even a high one) being ineffective in both N and P+I rats. All of this suggests to us that the early effect on RMR produced by T3 in euthyroid rats may reasonably be attributed to its conversion to 3,5-T2.
The mechanisms by which the two iodothyronines, T3 and 3,5-T2, elicit their effects are different from each other. The effects attributable to T3 are principally the net result of the action of a set of genes whose expression is regulated by T3 through its interaction with nuclear receptors. One of the most important effects of T3 that could be mediated by this pathway is its influence on the expression of uncoupling proteins, with certain consequences on the efficiency of oxidative phosphorylation (for reviews, see Refs. 32 and 33). Recently, in fact, it has been shown that T3 regulates the level of the mRNA for uncoupling protein homologue uncoupling protein 3 (UCP3) (34, 35, 36). These results suggest a hypothetical molecular mechanism by which T3 increases energy expenditure partly by reducing metabolic efficiency. Quite recently, we showed both that the expression of the mRNA for UCP3 in skeletal muscle increased strongly during the transition from hypothyroidism to hyperthyroidism and that skeletal muscle mitochondria from hyperthyroid rats displayed a greater proton-leak than those from their hypothyroid counterparts (34). Very recently, in a study on hypothyroid rats given a single injection of T3, we described a strict correlation, in terms of time course, between the induced increase in UCP3 expression (at mRNA and protein levels) and the decrease in mitochondrial respiratory efficiency, on the one hand, and the increase in RMR, on the other (37). The RMR and the increase in UCP3 protein density both peaked at 65 h after the injection; at the same time-point, gastrocnemius muscle mitochondria showed an increased uncoupling (by comparison with the preinjection level). These results provided the first direct in vivo evidence that UCP3 has the potential to act as a molecular determinant in the regulation of RMR by T3.
Turning now to 3,5-T2, we can say that, in contrast to T3, its effects on RMR seem to be attributable to nuclear-independent mechanisms. Some data support this conclusion. The affinity of 3,5-T2 for nuclear TRs is very low. It has been shown that TRß1 has low affinity for 3,5-T2, with relative affinity constants 0.15% of that for T3 (38). More recently, Ball et al. (28) have shown that TRß2 binds 3,5-T2 more avidly than do the other TRs, this apparent affinity remains substantially (40-fold) less than that for T3. The same authors reported that 3,5-T2 is approximately 1000-fold less potent than T3 in dissociating TRß1 homodimers from a TRE, thus indicating that the relative ability of 3,5-T2 to bind to and produce conformational changes in a TR is consistent with its relatively low binding affinity. Moreover, an extranuclear mechanism of action of 3,5-T2 fits well with our data showing that 3,5-T2 binds to mitochondrial components (39, 40) and with our more recent data ( 41) showing that 3,5-T2 has a very rapid effect on glucose-6-phosphate-dehydrogenase activity that is independent of protein synthesis. In addition, 3,5-T2 is able to stimulate the activity of the cytochrome c oxidase complex (42), and the subunit Va of this complex has been identified as a binding site for 3,5-T2 (43). Recently, Kadenbach and co-workers ( 44) have suggested that 3,5-T2 is able to decrease the efficiency of the cytochrome oxidase complex by inducing a reduction in proton-pumping.
In conclusion, both T3 and 3,5-T2 have the capacity to influence the RMR in rats, but the mechanisms underlying their effects are quite different. Further, on the basis of our results showing that a simultaneous injection of 3,5-T2 and T3 into P+I rats gives rise to an amplified effect on RMR (compared with the effect of either one alone; see filled circles in Fig. 4 and open circles and filled squares in Fig. 1, upper panel), we believe that in N rats, the actions of these two iodothyronines are not mutually exclusive; rather, they cooperate in determining the final metabolic state of the animal. The (as-yet hypothetical) physiological importance of the existence of a double mechanism by which iodothyronines can operate to regulate energy metabolism may be as follows: the short-term mechanism stimulated by 3,5-T2 is useful for a rapid response to sudden physiological variations in energy requirements, whereas the mechanism stimulated by T3 is useful for responding to long-term energy adjustments (i.e. during cold acclimation).
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Footnotes |
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Abbreviations: BAT, Brown adipose tissue; D1 (and D2 and D3), type I (and types II and III, respectively) deiodinase activity; DTT, dithiothreitol; IOP, iopanoic acid; N rats, normal euthyroid rats; RMR, resting metabolic rate; P+I rats, rats made hypothyroid by propylthiouracil and iopanoic acid; PTU, propylthiouracil; 3,5-T2, 3,5-diiodo-L-thyronine; rT3, reverse T3; UCP, uncoupling protein.
Received May 29, 2001.
Accepted for publication October 5, 2001.
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