Metabolic effects of 3,5-Diiodo-L-Thyronine (original) (raw)
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Metabolic effects of 3,5 Diiodo L Thyronine Giammanco M et al
Journal of Biological Research, 2020
Thyroid hormones have been proposed as anti obesity drugs due to their effects on basal metabolism and the ability to increase energy expenditure. However, their clinical use has been strongly curbed by the concomitant onset of thyrotoxicosis. In this setting, several studies have been undertaken to assess the role of 3,5 diio-do-L-thyronine (T2), an endogenous metabolite of thyroid hormone derived from the enzymatic deiodination of triodothyronine T3. The metabolic effects of T2 are similar to those induced by T3. However, these effects appear to involve different and not well-defined mechanisms that make this molecule clinically useful as potential drug in the treatment of pathological conditions such as obesity and hepatic steatosis. The main pharmacological target of T2 appears to be the mitochondria. Therefore, the administration of T2 to obese subjects might improve the mitochondrial performance, which is generally recognized to be reduced in these subjects who must oxidize greater quantities of substrates. In this context, it can be hypothesized that T2, by acting mainly on mitochondrial function and oxidative stress, might be able to prevent and revert the tissue damages and hepatic steatosis induced by a hyperlipidic diet and a concomitant reduction in the circulating levels LDL and triglyc-erides as well. This review the discuss the mechanisms of action of T2 and the possible, future clinical uses of T2 analogs for the treatment lipid dysmetabolism related to obesity and overweight.
3,5-Diiodo-L-thyronine powerfully reduces adiposity in rats by increasing the burning of fats
Faseb Journal, 2005
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 (T 2 ), 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 T 2 administration to rats receiving a high-fat diet (HFD) reduces both adiposity and body weight gain without inducing thyrotoxicity. Rats receiving HFD + T 2 showed (when compared with rats receiving HFD alone) a 13% lower body weight, a 42% higher liver fatty acid oxidation rate, ~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 T 2 administration. The biochemical mechanism underlying the effects of T 2 on liver metabolism involves the carnitine palmitoyl-transferase system and mitochondrial uncoupling. If the results hold true for humans, pharmacological administration of T 2 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 T 2 on a longer time scale as well as do not show that T 2 acts in the same way in humans.
Endocrinology, 2015
Effective and safe antiobesity drugs are still needed in face of the obesity pandemic worldwide. Recent interventions in rodents revealed 3,5-diiodo-L-thyronine (3,5-T 2) as a metabolically active iodothyronine affecting energy and lipid metabolism without thyromimetic side effects typically associated with T 3 administration. Accordingly, 3,5-T 2 has been proposed as a potential hypolipidemic agent for treatment of obesity and hepatic steatosis. In contrast to other observations, our experiments revealed dose-dependent thyromimetic effects of 3,5-T 2 akin to those of T 3 in dietinduced obese male C57BL/6J mice. 3,5-T 2 treatment exerted a negative feedback regulation on the hypothalamus-pituitary-thyroid axis, similar to T 3. This is demonstrated by decreased expression of genes responsive to thyroid hormones (TH) in pituitary resulting in a suppressed thyroid function with lower T 4 and T 3 concentrations in serum and liver of 3,5-T 2-treated mice. Analyses of hepatic TH target genes involved in lipid metabolism revealed T 3-like changes in gene expression and increased type I-deiodinase activity after application of 3,5-T 2 (2.5 g/g body weight). Reduced hepatic triglyceride and serum cholesterol concentrations reflected enhanced lipid metabolism. Desired increased metabolic rate and reduction of different fat depots were, however, compromised by increased food intake preventing significant body weight loss. Moreover, enlarged heart weights indicate potential cardiac side effects of 3,5-T 2 beyond hepatic thyromimetic actions. Altogether, the observed thyromimetic effects of 3,5-T 2 in several mouse TH target tissues raise concern about indiscriminate administration of 3,5-T 2 as powerful natural hormone for the treatment of hyperlipidemia and pandemic obesity.
Thyroid hormones and mitochondria
Bioscience reports, 2002
Because of their central role in the regulation of energy-transduction, mitochondria, the major site of oxidative processes within the cell, are considered a likely subcellular target for the action that thyroid hormones exert on energy metabolism. However, the mechanism underlying the regulation of basal metabolic rate (BMR) by thyroid hormones still remains unclear. It has been suggested that these hormones might uncouple substrate oxidation from ATP synthesis, but there are no clear-cut data to support this idea. Two iodothyronines have been identified as effectors of the actions of thyroid hormones on energy metabolism: 3',3,5-triiodo-L-thyronine (T3) and 3,5-diiodo-L-thyronine (T2). Both have significant effects on BMR, but their mechanisms of action are not identical. T3 acts on the nucleus to influence the expression of genes involved in the regulation of cellular metabolism and mitochondria function; 3,5-T2, on the other hand, acts by directly influencing the mitochondri...
Action of thyroid hormones at the cellular level: the mitochondrial target
Febs Letters - FEBS LETT, 1999
Thyroid hormones exert profound effects on the energy metabolism. An inspection of the early and more recent literature shows that several targets at the cellular level have been identified. Since their effects on the nuclear signalling pathway have already been well-defined and extensively reviewed, this article focuses on the regulation of mitochondrial activity by thyroid hormones. Mitochondria, by virtue of their biochemical functions, are a natural candidate as a direct target for the calorigenic effects of thyroid hormones. To judge from results coming from various laboratories, it is quite conceivable that mitochondrial activities are regulated both directly and indirectly. Not only triiodo-L-thyronine, but also diiodothyronines are active in regulating the energy metabolism. They influence the resting metabolism in rats with 3,5-diiodo-L-thyronine seeming to show a clearer effect.
FEBS Letters, 2007
We investigated the mechanism by which 3,5-diiodo-L L-thyronine (T2) affects skeletal muscle mitochondrial bioenergetic parameters following its acute administration to hypothyroid rats. One hour after injection, T2 increased both coupled and uncoupled respiration rates by +27% and +42%, respectively. Top-down elasticity analysis revealed that these effects were the result of increases in the substrate oxidation and mitochondrial uncoupling. Discriminating between proton-leak and redox-slip processes, we identified an increased mitochondrial proton conductance as the ''pathway'' underlying the effect of T2 on mitochondrial uncoupling. As a whole, these results may provide a mechanism by which T2 rapidly affects energy metabolism in hypothyroid rats.
3,5-Diiodo-L-Thyronine Activates Brown Adipose Tissue Thermogenesis in Hypothyroid Rats
PLOS ONE, 2015
3,5-diiodo-l-thyronine (T2), a thyroid hormone derivative, is capable of increasing energy expenditure, as well as preventing high fat diet-induced overweight and related metabolic dysfunction. Most studies to date on T2 have been carried out on liver and skeletal muscle. Considering the role of brown adipose tissue (BAT) in energy and metabolic homeostasis, we explored whether T2 could activate BAT thermogenesis. Using euthyroid, hypothyroid, and T2-treated hypothyroid rats (all maintained at thermoneutrality) in morphological and functional studies, we found that hypothyroidism suppresses the maximal oxidative capacity of BAT and thermogenesis, as revealed by reduced mitochondrial content and respiration, enlarged cells and lipid droplets, and increased number of unilocular cells within the tissue. In vivo administration of T2 to hypothyroid rats activated BAT thermogenesis and increased the sympathetic innervation and vascularization of tissue. Likewise, T2 increased BAT oxidative capacity in vitro when added to BAT homogenates from hypothyroid rats. In vivo administration of T2 to hypothyroid rats enhanced mitochondrial respiration. Moreover, UCP1 seems to be a molecular determinant underlying the effect of T2 on mitochondrial thermogenesis. In fact, inhibition of mitochondrial respiration by GDP and its reactivation by fatty acids were greater in mitochondria from T2-treated hypothyroid rats than untreated hypothyroid rats. In vivo administration of T2 led to an increase in PGC-1α protein levels in nuclei (transient) and mitochondria (longer lasting), suggesting a coordinate effect of T2 in these organelles that ultimately promotes net activation of mitochondrial biogenesis and BAT thermogenesis. The effect of T2 on PGC-1α is similar to that elicited by triiodothyronine. As a whole, the data reported here indicate T2 is a thyroid hormone derivative able to activate BAT thermogenesis.
Molecular and Cellular Endocrinology, 2011
Thyronamines T 0 AM and T 1 AM are naturally occurring decarboxylated thyroid hormone derivatives. Their in vivo administration induces effects opposite to those induced by thyroid hormone, including lowering of body temperature. Since the mitochondrial energy-transduction apparatus is known to be a potential target of thyroid hormone and its derivatives, we investigated the in vitro effects of T 0 AM and T 1 AM on the rates of O 2 consumption and H 2 O 2 release by rat liver mitochondria. Hypothyroid animals were used because of the low levels of endogenous thyronamines. We found that both compounds are able to reduce mitochondrial O 2 consumption and increase H 2 O 2 release. The observed changes could be explained by a partial block, operated by thyronamines, at a site located near the site of action of antimycin A. This hypothesis was confirmed by the observation that thyronamines reduced the activity of Complex III where the site of antimycin action is located. Because thyronamines exerted their effects at concentrations comparable to those found in hepatic tissue, it is conceivable that they can affect in vivo mitochondrial O 2 consumption and H 2 O 2 production acting as modulators of thyroid hormone action.