Thyroid hormone metabolism in obesity. E Roti1*, R Minelli2 and M Salvi2. 1Istituto di Endocrinologia, Universita degli Studi di Milano, Milano, Italy; and 2Centro ...
International Journal of Obesity (2000) 24, Suppl 2, S113±S115 ß 2000 Macmillan Publishers Ltd All rights reserved 0307±0565/00 $15.00 www.nature.com/ijo
Thyroid hormone metabolism in obesity E Roti1*, R Minelli2 and M Salvi2 1
Istituto di Endocrinologia, Universita degli Studi di Milano, Milano, Italy; and 2Centro per lo Studio, Prevenzione, Diagnosi e Cura delle Tireopatie, UniversitaÁ degli Studi di Parma, Parma, Italy
Serum thyroid hormone concentrations and their metabolic fate are within the normal range limits in obese subjects. Also serum TSH concentrations and its response to TRH are normal, suggesting that tissue availability of thyroid hormones is normally preserved in these subjects. In contrast, during caloric restriction serum T3 concentrations decrease as a consequence of its reduced production rate from peripheral deiodination of T4. Opposite, serum rT3 concentrations markedly increase as a result of its decreased metabolic clearance rate. During caloric overfeeding serum T3 concentration increase whereas serum rT3 concentrations decrease. In this condition the production rate of T3 increases. During caloric restriction and overfeeding serum T4 concentrations and its production and degradation are not modi®ed. International Journal of Obesity (2000) 24, Suppl 2, S113±S115 Keywords: thyroid hormones; metabolism; obesity
Thyroid hormones, thyroxine (T4) and triiodothyronine (T3) are metabolized mainly through the monodeiodination pathway and, less importantly, through non-deiodinative pathways such as sulfo- and glucuronojugation and oxidative degradation. Monodeiodination of T4 is the most important degradative pathway and accounts for up to 80% of total disposal, producing approximately equal amounts of T3 and reverse T3 (rT3). Approximate1y 80% of circulating T3 is derived by extrathyroidal monodeiodination of T4, whereas rT3 is almost totally produced by extrathyroidal T4 monodeiodination.1,2 Monodeiodination of thyroid hormones is exerted by three different types of deiodinase enzymes: type I 50 deiodinase which converts T4 to T3 and is present mainly in liver and kidney; type II 50 deiodinase which also converts T4 to T3 and is distributed in the central nervous system, pituitary and brown adipose tissue; and type III 5 deiodinase which converts T4 to rT3, and is distributed in almost all tissues and, during fetal life, is abundantly present in the placenta and fetal membranes.1,2 In Table 1 serum concentrations and kinetic parameters of T4, T3 and rT3 are reported. As shown, 81 ± 98 mg of T4 are produced in a day, exclusively by the thyroid gland. The production rate (PR) of T3 ranges between 26.3 and 40.2 mg=day. This large variability is due to the different methods employed to calculate kinetic parameters. Approximate1y 80% of T3 production occurs in extrathyroid tissues, predominantly in the liver. Also the PR of rT3 are variable, again as the result of different methods employed. Importantly, the entire production of rT3 is of extrathyroidal origin and by extrahepatic tissue.1 *Correspondence: E Roti, Centro per lo Studio, Prevenzione, Diagnosi e Cura delle Tireopatie, Via Gramsci 14, 43100 Parma, Italy.
Different clinical conditions and drug treatment have been reported to modify the activity of the three deiodinase enzymes (Table 2).1,2 As shown, the activity of type I 50 deiodinase is decreased by a large number of clinical conditions and drugs, whereas the others two deiodinases are differently affected. It is well known that thyroid hormone administration increases thermogenesis.3 This ®nding has led to speculate whether thyroid hormones, acting on energy expenditure, could affect body weight. However, few studies have provided information on the pheripheral metabolism of thyroid hormones. As shown in Table 3, kinetic parameters of peripheral metabolism of T4, T3 and rT3 in obese are similar to those observed in healthy subjects.4,5 As a consequence, serum thyroid hormone concentrations are within the normal range. Donders et al6 have reported that in obese subjects serum T4 and T3 concentrations were 6.9 0.3 mg=dl and 141 8 ng=dl, respectively. Buscemi et al7 reported normal serum total thyroid concentrations in subjects with a body weight of 139.7 24.5 kg. Furthermore, they reported FT4 and FT3 values of 1.30 0.24 ng=dl and 4.18 0.57 pg=ml, similar to those observed in control subjects. Also basal serum thyrotropin (TSH) has been found to be normal in obese subjects.6 However, in some studies the TSH response to TRH has been found to be slightly increased, but normal with respect to control subjects.6 This ®nding does not re¯ect a reduced availability of thyroid hormone at pituitary level, but probably depends on a different hypothalamic neuroendocrine control of TSH secretion. Despite the fact that in obese subjects serum thyroid hormone concentrations and their metabolism are normal, some authors have found that basal metabolic rate (BMR), total energy expenditure (EE) and sleeping energy expenditure (SEE) are positively correlated to the serum total or free T3 concentrations.8 ± 10 In
Thyroid hormone metabolism in obesity E Roti et al
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Table 1 Serum concentrations and kinetic parameters of thyroid hormones in healthy man (range values) Serum concentrations
DS (l)
MCR (l=d)
K (%=day)
PR (mg=day)
6.2 ± 8.0 (mg=dl) 91 ± 172 (ng=dl) 20.2 ± 48 (ng=dl)
9.3 ± 12.4 27.2 ± 54.3 14.4 ± 16.7
1.22 ± 1.32 19.5 ± 28.9 55.5 ± 151
10.7 ± 13.7 60 ± 95 567 ± 722
81 ± 98 26.3 ± 40.2 17.3 ± 60.8
T4 T3 rT3
DS distribution space; MCR metabolic clearance rate; K percentage degradation per day; PR production rate. Hennemann.1 Table 2 Summary of properties of the three iodothyronine deiodinase isoenzymes Property
Type I 5 0 -deiodinase
Type II 5 0 -deiodinase
Type III 5 -deiodinase
Increase Decrease Decrease Decrease
Decrease Increase No change Increase
Increase Decrease No change Increase
Ð ?
Ð
Clinical conditions: Thyrotoxicosis Hypothyroidism Low-T3 syndrome Fetal life Inhibitors: Thiouracils Iopanoic acid Iodoacetate Flavonoids Halogenated aromates Amiodarone 1
2
Hennerman; KoÈhrle.
Table 3 Serum concentrations and kinetic parameters of thyroid hormones in obese subjects
T4 T3 rT3
Age (y)
Weight (kg)
Total concentrations
Free concentrations
MCR (l=day)
PR (mg=day)
32 3 32 3 Ð
120 12 120 12 104 19
7 0.5 (mg=dl) 145 7 (ng=dl) 22.5 2.7 (ng=dl)
1.09 0.07 (ng=dl) 0.23 0.008 (ng=dl) Ð
1.2 0.1 25 4 138 11
82 9 36 5 30.8 2
MCR metabolic clearance rate; PR production rate. Vagenakis et al 5 and Eisenstein et al.5
contrast, body mass index (BMI) is inversely correlated with serum serum rT3 concentrations.7 The above ®ndings indicate that obese subjects do not have a reduced thyroid hormone secretion or diversion of peripheral metabolism of T4 to inactivating pathways. However, it is likely that elevated concentrations of serum T3 concentrations increase EE and, as a consequence, reduce availability of accumulation of energy for conversion to as fat. The latter hypothesis is also supported by the observation that an increase of 1 mU=L of serum TSH concentrations, within the normal range limits, is accompanied
by a reduction of EE of 75 ± 150 kcal=day, corresponding to 8.31 ± 16.6 g of stored fat, equivalent to several kilos over of 5 ± 10 y.11 In order to elucidate the role of thyroid hormones in the process of body weight gain and reduction, peripheral metabolism of thyroid hormones has been studied during caloric restriction, fasting and overfeeding. Vagenakis et al4 reported that during fasting obese subjects showed a marked decrease of serum T3 concentrations from 145 7 to 66 9 ng=dl (P< 0.001), whereas other authors have reported an increase of serum rT3 concentrations from 36.0 15
Table 4 Serum concentrations and kinetics parameters of thyroid hormones before and during fasting Age Mean s.e. P value
32 3
Age Mean s.e. P value
32 3
Weight (kg) Control Fast 120 12 < 0.001
107 11
Weight (kg) Control Fast 120 12 < 0.001
107 11
Weight (kg) Control Fast Mean s.e. P value
104 19 < 0.005
99 18
Serum T4 (mg=dl) Control Fast 7.0 0.5
NS
6.8 0.7
Serum T3 (ng=dl) Control Fast 145 7
< 0.001
66 9
Serum free T4 (ng=dl) Control Fast 1.09 0.07
< 0.05
1.32 0.13
Serum free T3 (ng=dl) Control Fast 0.23 0.08
< 0.001
1.2 0.1
1.1 0.1 n.s.
T3 MCR (day) Control Fast
0.12 0.015
Serum rT3 (ng=dl) Control Fast
25 4
24 3 n.s.
rT3 MCR (day) Control Fast
22.5 35.9 2.7 2.1 < 0.001
138 11 4
MCR metabolic clearance rate; PR production rate. Vagenakis et al and Eisenstein et al. International Journal of Obesity
T4 MCR (day) Control Fast
5
< 0.001
93 9
T4 PR (mg=day) Control Fast 82 9
75 9 n.s.
T3 PR (mg=day) Control Fast 36 5
11 1 < 0.001
rT3 PR (mg=day) Control Fast 30.8 2.2
n.s.
33.7 1.8
Thyroid hormone metabolism in obesity E Roti et al Table 5 Serum thyroid hormone concentrations and kinetic parameters during fasting T4 T3 rT3 (percentage of normal mean values) Total concentrations Free concentrations PR MCR
97 121 102 114
49 64 42 84
169 Ð 119 71
MCR metabolic clearance rate; PR production rate. Vagenakis et al,4 Eisenstein et al,5 Suda et al,12 Pittman et al13 and Bianchi et al.14
to 54 23 ng=dl (P< 0.001).5 In contrast, fasting did not change serum T4 concentrations. The changes in serum total T3 are accompanied by corresponding changes in free T3. Furthermore, during starvation serum FT4 concentrations show a signi®cant increase. As shown in Table 4, PR and MCR of T4 in starving obese subjects did not show any signi®cant change. In contrast the PR of T3 is markedly reduced, whereas its MCR is unchanged. The changes of rT3 are the complete opposite; MCR is markedly decreased whereas PR is unchanged. Thus, during fasting, serum T3 concentrations signi®cantly decrease as a result of a decrease of its production, whereas serum rT3 concentrations increase because its peripheral catabolism is reduced. The pattern of serum concentrations and kinetic parameters of T4, T3 and rT3 during fasting are summarized in Table 5. During overfeeding, serum thyroid hormone concentrations and their metabolic fate are modi®ed. Davidson and Chopra15 have reported that an increase of calorie intake from 2000 to 4000 kcal is accompained by a progressive increment of serum T3 concentrations from 69.3 7 to 108.3 4.6 ng=d1, whereas serum rT3 concentrations decrease from 26.7 2.2 to 20.3 3.6 ng=dl. These changes were not accompained by any signi®cant variations of serum T4 concentrations. Overfeeding with carbohydrate, fat and protein produce similar effects on T3 behavior, whereas overfeeding with fat does not decrease serum rT3 concentrations.16 Overfeeding with only carbohydrate or fat or protein do not have any effect on serum total T4 concentrations. Furthermore, PR, MCR, distribution space (DS) and fractional removal rate (K) of T4 are not modi®ed by the above dietetic variations.16 In contrast, the increase of serum T3 concentrations during carbohydrate, fat and protein overfeeding is the result of marked increase of PR, MCR and DS of the hormone whereas the K value is increased only during protein overfeeding.16 It is of interest that the above changes are not dependent on adipose tissue mass since the deiodinase activity, type II 50 deiodinase activity, is present only in brown adipose tissue which is almost absent in adult human subjects.1,2,17 Only Nauman el al18 reported the presence of type II 50 deiodinase activity in white fat tissue, which was decreased in obese subjects. In conclusion, peripheral metabolism of thyroid hormones even in obese subjects is within the normal range limits and is not affected by adipose tissue mass.
S115
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