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Goglia, Moreno
Biological effects of 3,5-diiodothyronine (T(2)).Goglia F. Biochemistry (Mosc). 2005 Feb;70(2):164-72. Review.
"This article is principally intended to describe the facts concerning the actions of 3,5-diiodothyronine (T(2)). Until recent years, T(2), because of its very low affinity for thyroid hormone receptors (THR), was considered an inactive metabolite of thyroid hormones (TH) (thyroxine (T(4)) and triiodo-L-thyronine (T(3))). Several observations, however, led to a reconsideration of this idea. Early studies dealing with the biological activities of this iodothyronine revealed its ability to stimulate cellular/mitochondrial respiration by a nuclear-independent pathway. Mitochondria and bioenergetic mechanisms seem to be major targets of T(2), although outside the mitochondria T(2) also has effects on carriers, ion-exchangers, and enzymes. Recent studies suggest that T(2) may also affect the transcription of some genes, but again the underlying mechanisms seem to be different from those actuated by T(3). The accumulated evidence permits the conclusion that the actions of T(2) do not simply mimic those of T(3) but instead are specific actions exerted through mechanisms that are independent of those actuated by T(3) and do not involve THR."
Thyroid hormones as molecular determinants of thermogenesis.Silvestri E, Schiavo L, Lombardi A, Goglia F. Acta Physiol Scand. 2005 Aug;184(4):265-83. Review [abstract only]
"Thyroid hormones (TH) are major modulators of energy metabolism and thermogenesis. It is generally believed that 3,5,3'-triiodo-l-thyronine (T3) is the only active form of TH, and that most of its effects are mediated by nuclear T3 receptors, which chiefly affect the transcription of target genes. Some of these genes encode for the proteins involved in energy metabolism. However, a growing volume of evidence now indicates that other iodothyronines may be biologically active. Several mechanisms have been proposed to explain the calorigenic effect of TH, but none has received universal acceptance. Cold acclimation/exposure and altered nutritional status are physiological conditions in which a modulation of energy expenditure is particularly important. TH seem to be deeply involved in this modulation, and this article will review some aspects of their possible influence in these conditions."
3,5-diiodo-L-thyronine powerfully reduces adiposity in rats by increasing the burning of fats.Lanni A, Moreno M, Lombardi A, de Lange P, Silvestri E, Ragni M, Farina P, Baccari GC, Fallahi P, Antonelli A, Goglia F. FASEB J. 2005 Sep;19(11):1552-4. Epub 2005 Jul
12. "The effect of thyroid hormones on metabolism has long supported their potential as drugs to stimulate fat reduction, but the concomitant induction of a thyrotoxic state has greatly limited their use. Recent evidence suggests that 3,5-diiodo-L-thyronine (T2), a naturally occurring iodothyronine, stimulates metabolic rate via mechanisms involving the mitochondrial apparatus. We examined whether this effect would result in reduced energy storage. Here, we show that T2 administration to rats receiving a high-fat diet (HFD) reduces both adiposity and body weight gain without inducing thyrotoxicity. Rats receiving HFD + T2 showed (when compared with rats receiving HFD alone) a 13% lower body weight, a 42% higher liver fatty acid oxidation rate, appoximately 50% less fat mass, a complete disappearance of fat from the liver, and significant reductions in the serum triglyceride and cholesterol levels (-52% and -18%, respectively). Thyroid hormones and thyroid-stimulating hormone (TSH) serum levels were not influenced by T2 administration. The biochemical mechanism underlying the effects of T2 on liver metabolism involves the carnitine palmitoyl-transferase system and mitochondrial uncoupling. If the results hold true for humans, pharmacological administration of T2 might serve to counteract the problems associated with overweight, such as accumulation of lipids in liver and serum, without inducing thyrotoxicity. However, the results reported here do not exclude deleterious effects of T2 on a longer time scale as well as do not show that T2 acts in the same way in humans."
Non-nuclear actions of thyroid hormones: The case for T2Goglia F, De Lange P Hot Thyroidology, June, No 1, 2003
"Thyroid hormones (THs) exert a multiplicity of
effects. Among these are crucial effects on development,
differentiation and metabolism. The first two are particularly
relevant in the early stages of development, and a deficit in THs in
the neonatal period has serious consequences, such as mental
retardation and growth disturbance. However, notwithstanding the
knowledge of this wide spectrum of activity, the publication of an
enormous number of reports and a long list of hypotheses, the
mechanism by which THs exert their diverse actions has not finally
been established. In particular, with regard to the stimulatory
effects of THs on metabolism we can distinguish three historical
periods during which some major hypotheses regarding their mechanisms
of action have been developed and have attracted the attention of
investigators in the field. The first period was from the early 1950s
to the middle 1960s. At this time, the most intriguing hypothesis put
forward was "the uncoupling hypothesis", which suggested that THs
stimulated metabolic rate by acting at the mitochondrial level by
uncoupling the electron transport chain from ATP synthesis (1,2).
Mainly because of the large doses employed and also because of the
non-reproducibility of the observations "in vivo", this hypothesis was
subsequently discarded on the grounds that it was not physiologically
relevant.
Are the effects of T3 on resting metabolic rate in euthyroid rats entirely caused by T3 itself?Moreno M, Lombardi A, Beneduce L, Silvestri E, Pinna G, Goglia F, Lanni A. Endocrinology. 2002 Feb;143(2):504-10.
"Because we previously
reported that T3 and 3,5-diiodo-L-thyronine (3,5-T2) both increase
resting metabolic rate (RMR), 3,5-T2 could be another thyroidal
regulator of energy metabolism. This effect of 3,5-T2 is evident in
rats made hypothyroid by propylthiouracil and iopanoic acid, not in
normal euthyroid (N) rats. Possibly, under euthyroid conditions,
active 3,5-T2 may need to be formed intracellularly from a precursor
such as T3. We tested this hypothesis by giving a single injection of
T3 to N rats and comparing the time course of the variations in RMR
with those of the changes in the serum and hepatic levels of 3,5-T2.
Acute injection had an evident effect on RMR, 25 h earlier, in N rats
than in rats made hypothyroid by propylthiouracil and iopanoic acid,
maximal values (+40%) being reached in the former at 24-26 h. In N
rats, the simultaneous injection of actinomycin D with the T3
inhibited the late part of the effect (after 24 h) more strongly than
the early part (14-24 h). In serum and liver, 3,5-T2 levels were
increased significantly at 12-24 h after T3 injection into N rats, a
time at which RMR was rising rapidly to peak. These results seem to
indicate that when T3 is injected into N animals, not all the effects
on RMR are attributable to T3 itself, the early effect presumably
being largely because of its in vivo deiodination to 3,5-T2. Because
the effects of T3 and 3,5-T2 are additive, in N rats, the two
iodothyronines probably cooperate in vivo to determine the total
metabolic rate."
3,5-diiodo-L-thyronine regulates glucose-6-phosphate dehydrogenase activity in the rat.Lombardi A, Beneduce L, Moreno M, Diano S, Colantuoni V, Ursini MV, Lanni A, Goglia F. Endocrinology. 2000 May;141(5):1729-34. "Thyroid hormones influence the activity of lipogenic enzymes such as malic enzyme (ME) and glucose-6-phosphate dehydrogenase (G6PD). The effect of T3 on ME is exerted at the transcriptional level, but it is unclear if its effect on G6PD is also nuclear mediated. Furthermore, other iodothyronines that have been shown to possess biological activity (such as diiodothyronines) could contribute to this enzyme's regulation. In this study the effects of 3,5-diiodothyronine (T2) on the aforementioned enzymes were examined and compared with those of T3. Rats made hypothyroid by propylthiouracil and iopanoic acid treatment were used throughout. Enzyme activities were determined spectrophotometrically, and G6PD messenger RNA (mRNA) expression was analyzed by Northern blotting using a human G6PD complementary DNA probe. Injections of T2 to hypothyroid animals significantly enhanced the activity of both enzymes. The effect of T2 on ME was nuclear mediated and mimicked the effect of T3. The effects of T2 and T3 on G6PD differed. Injection of T3 into hypothyroid rats induced an increase in both enzyme activity and G6PD mRNA expression, indicating a nuclear-mediated effect. The effect of T2 on G6PD activity, on the other hand, was not nuclear mediated. The injection of T2 into hypothyroid animals did not change G6PD mRNA expression, and the strong increase in the enzyme's activity (from +70% to +300%) was unaffected by simultaneous injection of protein synthesis inhibitors. As the lowest dose of 1 microg T2/100 g BW affects G6PD activity 3-5 times more than the same dose of T3, these data provide the first evidence that T2 is a factor capable of regulating G6PD activity."
Effect of 3,5-diiodo-L-thyronine on thyroid stimulating hormone and growth hormone serum levels in hypothyroid rats.Moreno M, Lombardi A, Lombardi P, Goglia F, Lanni A. Life Sci. 1998;62(26):2369-77. [abstract only]
"We have investigated the
biological effects of physiological doses of 3,5-diiodo-L-thyronine
(3,5-T2) and 3,3'-diiodo-L-thyronine (3,3'-T2) (at doses from 2.5 to
10 microg/100 g BW) on serum TSH and GH levels in rats made
hypothyroid by propylthiouracil and iopanoic acid administration. In
such animals deiodinase activities were inhibited and thyroid hormones
serum levels strongly reduced. The effects of T2s were compared with
those elicited by 3,5,3'-triiodo-L-thyronine (T3) (2.5 microg/100 g
BW).The serum TSH level was much greater in hypothyroid rats than in
euthyroid ones. T3 administration suppressed TSH by 88% compared to
control (i.e, the level in hypothyroid rats); it thus reached a value
not significantly different from that seen in the euthyroid rats.
3,5-T2 produced a similar effect, suppressing the TSH level by about
75% compared to control; it thus reached values not significantly
different from those of the euthyroid and T3-treated rats. By
contrast, 3,3'-T2 had no effect on TSH, whatever the dose. The serum
GH level was much lower in hypothyroid rats than in euthyroid ones. T3
administration increased the GH level by about 5-fold, restoring it to
the value seen in euthyroid rats. 3,5-T2-treated hypothyroid rats, at
all the doses used (from 2.5 to 10 microg/100 g BW), showed increased
serum GH levels: at a dose of 10 microg/100 g BW the level reached a
value about 5-fold higher than that in hypothyroid rats. This value
was not significantly different from those of euthyroid and T3-treated
rats. 3,3'-T2 did not affect GH levels whatever the dose. Thus, 3,5-T2
(but not 3,3'-T2) seems to mimic the effects of T3 on serum TSH and GH
levels in rats."
3,5-Diiodo-L-thyronine and 3,5,3'-triiodo-L-thyronine both improve the cold tolerance of hypothyroid rats, but possibly via different mechanisms.Lanni A, Moreno M, Lombardi A, Goglia F. Pflugers Arch. 1998 Aug;436(3):407-14. [abstract only]
"The effects of 3,5-diiodo-L-thyronine (3,5-T2, 2.5-10 microg/100 g BW) on cold tolerance, energy expenditure and oxidative capacity of four metabolically very active tissues (brown adipose tissue, skeletal muscle, liver and heart) were determined in hypothyroid, cold-exposed rats. Hypothyroid rats survived cold for only 3-4 days. 3,5-T2 improved survival dose dependently; with 10 microg/100 g BW the rats survived 3 weeks (limit of observation). This effect was paralleled by an increased energy expenditure of the whole animal for the entire 3 weeks. Similar effects were observed in hypothyroid rats treated with 3,3',5-triiodo-L-thyronine (T3). 3,5-T2 stimulated the specific oxidative capacity (expressed as cytochrome oxidase activity per milligram protein) of all four tissues dose dependently. When the oxidative capacity was expressed as total activity (cytochrome oxidase activity times organ weight), the percentage increases were of the same order. T3 exerted similar effects, but the changes in total activity were much greater than in specific activity, indicating an effect on the tissue trophism. The effect of 3,5-T2 on cold tolerance thus mimics the effect of T3, but via different cellular mechanisms. T3 seems to act primarily on the trophism of the tissues, while 3,5-T2 may act directly on mitochondria without an effect on tissue trophism."
How the thyroid controls metabolism in the rat: different roles for triiodothyronine and diiodothyronines.Moreno M, Lanni A, Lombardi A, Goglia F. J Physiol. 1997 Dec 1;505 ( Pt 2):529-38. "1. Although the first evidence of a relationship between the thyroid and metabolism was reported in 1895, the mechanism by which thyroid hormones influence resting metabolic rate in whole animals is still poorly understood. This paper reports an attempt to test whether diiodothyronines (T2s) and triiodothyronine (T3) have different roles in the control of resting metabolism (RM).
2. Changes in resting metabolic rate were measured in hypothyroid rats treated acutely (25 micrograms (100 g body weight)-1) either with one of the T2s or with T3. Injection of T3 induced an increase of about 35% in RM that started 25-30 h after the injection and lasted until 5-6 days after the injection, the maximal value being observed at 50-75 h. The injection of T2s evoked a temporally different pattern of response. The increases in RM started 6-12 h after the injection, had almost disappeared after 48 h, and the maximal stimulation was observed at 28-30 h.
3. When actinomycin D (an inhibitor of protein synthesis) and T3 were given together, the stimulation of RM was almost completely abolished. The simultaneous injection of actinomycin D and either of the T2s, on the other hand, did not cause any attenuation of the stimulation seen with the T2s alone.
4. Following chronic treatment (3 weeks) with either T3 or T2s there was a stimulation of organ growth only after the administration of T3.
5. Chronic administration of either T2s or T3 to hypothyroid rats significantly enhanced the oxidative capacity of each of the tissues considered. In the case of T2s the stimulation was almost the same whether it was expressed as an increase in specific activity or total tissue activity. In the case of T3 the increases were, in the main, secondary to the hypertrophic or hyperplastic effect.
6. These results indicate that T2s and T3 exert different effects on RM. The effects of T2s are rapid and possibly mediated by their direct interaction with mitochondria. Those of T3 are slower and more prolonged, and at least partly attributable to a modulation of the cellularity of tissues that are metabolically very active."
Calorigenic effect of diiodothyronines in the rat.Lanni A, Moreno M, Lombardi A, Goglia F. J Physiol. 1996 Aug 1;494 ( Pt 3):831-7. "1. In hypothyroid rats, we determined the effects of administration of different doses of 3,3',5-triiodo-L-thyronine (T3), 3,3'-diiodo-L-thyronine (3,3'-T2) and 3,5-diiodo-L-thyronine (3,5-T2) ("T2 isomers' refers specifically to these latter two isomers throughout this paper) on resting metabolism (RM) and on the oxidative capacity (measured as cytochrome oxidase activity) of tissues that are metabolically very active.
2. The T2 isomers induced a dose-dependent calorigenic effect when injected I.P. into hypothyroid rats. The increase in RM was already evident at a dose of 2.5 micrograms (100 g body wt)(-1), and the greatest effect was observed at the highest dose, 10 micrograms (100 g body wt)(-1), when RM reached a value not significantly different from that of the euthyroid controls (1.92 +/- 0.08 and 1.93 +/- 0.13 (1 O2) kg(-1) h(-1) for 3,5'-T2, respectively, vs. 2.1 +/- 0.12 (1 O2) kg(-1) h(-1) for euthyroid controls). T3 administration restored RM to normal euthyroid values, even at a dose of 2.5 micrograms (100 g body wt)(-1).
3. The effect of T2 isomers on RM was paralleled by an increase in the oxidative capacity of tissues that are metabolically very active (liver, skeletal muscle, brown adipose tissue (BAT) and heart). The increases were between 33% (liver + 3,3'-T2) and 63% (muscle + 3,3'-T2). By contrast, T3 induced its greatest effect on the liver, with a smaller effect on skeletal muscle, but no significant stimulation in heart and BAT, whatever the dose.
4. These results suggest that T2 isomers might be mediators of the direct thyroid hormone regulation of energy metabolism."
Rapid stimulation in vitro of rat liver cytochrome oxidase activity by 3,5-diiodo-L-thyronine and by 3,3'-diiodo-L-thyronine.Lanni A, Moreno M, Lombardi A, Goglia F. Mol Cell Endocrinol. 1994 Feb;99(1):89-94. [abstract only]
"The effect of the
iodothyronines (thyroxine (T4), 3,5,3'-triiodo-L-thyronine (L-T3),
3,5-diiodo-L-thyronine (3,5-T2), 3,3'-diiodo-L-thyronine (3,3'-T2),
3',5'-diiodo-L-thyronine (3',5'-T2), 3'-monoiodo-L-thyronine (3'-T1),
3-monoiodo-L-thyronine (3-T1) and thyronine (T0)) on rat liver
cytochrome oxidase (COX) activity after their addition to rat liver
homogenate and isolated mitochondria from normal and hypothyroid rats
has been investigated. The addition of 3,3'-T2 and 3,5-T2 (T2s) to the
liver homogenate from hypothyroid rats, but not from normal rats,
significantly enhanced COX activity. The addition of T3 had a
remarkably lower effect that was almost completely abolished when the
propylthiouracil (PTU), an inhibitor of the type I deiodinase
activity, was also added to the incubation mixture. After the addition
of T2s the maximum effect was obtained at a concentration of about
10(-6) M for both 3,3'-T2 and 3,5-T2, while a 50% increase was
obtained at a concentration of about 10(-9) M in both cases. The
effects of T2s were rapid and already evident after 5 min of
incubation (+40-50%). The maximal effect was reached after only 30 min
of incubation. The above effects were not observed after the addition
of T2s to the isolated mitochondria. The results clearly demonstrate
that both 3,3'-T2 and 3,5-T2 directly stimulate mitochondrial COX
activity which is possibly achieved through a cytoplasmic factor. The
addition of the other iodothyronines (T4, 3',5'-T2, 3'-T1, 3-T1 and
T0)."
Effect of 3,3'-di-iodothyronine and 3,5-di-iodothyronine on rat liver mitochondria.Lanni A, Moreno M, Cioffi M, Goglia F. J Endocrinol. 1993 Jan;136(1):59-64. [abstract only]
"In the present study we report that 3,3',5-tri-iodothyronine (T3) as well as two iodothyronines (3,5-di-iodothyronine (3,5-T2) and 3,3'-di-iodothyronine (3,3'-T2)) significantly influence rat liver mitochondrial activity. Liver oxidative capacity (measured as cytochrome oxidase activity/g wet tissue) in hypothyroid compared with normal rats was significantly reduced (21%, P > 0.01) and the administration of T3 and both iodothyronines restored normal values. At the mitochondrial level, treatment with T3 stimulated respiratory activity (state 4 and state 3) and did not influence cytochrome oxidase activity. On the other hand, both the mitochondrial respiratory rate and specific cytochrome oxidase activity significantly increased in hypothyroid animals after treatment with 3,3'-T2 or 3,5-T2 (about 50 and 40% respectively). The actions of both iodothyronines were rapid and evident by 1 h after the injection. The hepatic mitochondrial protein content which decreased in hypothyroid rats (9.6 mg/g liver compared with 14.1 in normal controls, P < 0.05) was restored by T3 injection, while neither T2 was able to restore it. Our results suggest that T3 and both iodothyronines have different mechanisms of action. T3 acts on both mitochondrial mass and activity; the action on mitochondrial activity was not exerted at the cytochrome oxidase complex level. The action of the iodothyronines, on the other hand, is exerted directly on the cytochrome oxidase complex without any noticeable action on the mitochondrial mass"
Effect of 3,3'-diiodothyronine and 3,5-diiodothyronine on rat liver oxidative capacity.Lanni A, Moreno M, Cioffi M, Goglia F. Mol Cell Endocrinol. 1992 Aug;86(3):143-8. [abstract only]
"We report that 3,5,3'-triiodothyronine (T3) as well as two other iodothyronines (3,3'-diiodothyronine and 3,5-diiodothyronine (T2s)) stimulate rat liver oxidative capacity (measured as cytochrome oxidase activity (COX)). In hypothyroid rats COX activity and mitochondrial protein content are significantly lower than in normal control animals. The administration of both T3 and T2s to hypothyroid rats significantly enhances hepatic COX activity with T3 having the greatest effect (+60%); moreover, T3 restores the mitochondrial protein content whereas the T2s are ineffective. Administration of T2s results in a faster stimulation (already significant 1 h after the injection) of hepatic COX activity than T3 injection. Our results suggest that T3 acts on the protein synthesis mechanism involved in the regulation of the mitochondrial mass while T2s would act directly at the mitochondrial level."
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