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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 diiodo- 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 welldefined 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 triglycerides 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.

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 diiodo-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 welldefined 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 triglycerides 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. [ABSTRACT FROM AUTHOR]

Hepatic de novo lipogenesis (DNL), the process by which carbohydrates are converted into lipids, is strictly controlled by nutritional and hormonal status. 3,5‐Diiodo‐L‐thyronine (T2), a product of the 3,5,3′‐triiodo‐L‐thyronine (T3) peripheral metabolism, has been shown to mimic some T3 effects on lipid metabolism by a short‐term mechanism independent of protein synthesis. Here, we report that T2, administered for 1 week to hypothyroid rats, increases total fatty acid synthesis from acetate in isolated hepatocytes. Studies carried out on liver subcellular fractions demonstrated that T2 not only increases the activity and the expression of acetyl‐CoA carboxylase and fatty acid synthase but also of other proteins linked to DNL such as the mitochondrial citrate carrier and the cytosolic ATP citrate lyase. Parallelly, T2 stimulates the activities of enzymes supplying cytosolic NADPH needed for the reductive steps of DNL. With respect to both euthyroid and hypothyroid rats, T2 administration decreases the hepatic mRNA level of SREBP‐1, a transcription factor which represents a master regulator of DNL. However, when compared to hypothyroid rats T2 significantly increases, without bringing to the euthyroid value, the content of both mature (nSREBP‐1), and precursor (pSREBP‐1) forms of the SREBP‐1 protein as well as their ratio. Moreover, T2 administration strongly augmented the nuclear content of ChREBP, another crucial transcription factor involved in the regulation of lipogenic genes. Based on these results, we can conclude that in the liver of hypothyroid rats the transcriptional activation by T2 of DNL genes could depend, at least in part, on SREBP‐1‐ and ChREBP‐dependent mechanisms. © 2019 IUBMB Life, 2019 [ABSTRACT FROM AUTHOR]

Using differentiated rat L6 cells, we studied the direct effect of 3,5,3'-triiodo-l-thyronine (T3) and 3,5-diiodo-l-thyronine (T2) on the response to insulin in presence of fatty acids with a varying degree of saturation. We found that T3 and T2 both invert the response to insulin by modulating Akt Ser473 phosphorylation in the presence of palmitate and oleate. Both hormones prevented palmitate-induced insulin resistance, whereas increased insulin sensitivity in the presence of oleate was reduced, with normalization to (or, in the case of T3, even below) control levels. Both hormones effectively reduced intracellular acylcarnitine concentrations. Interestingly, insulin sensitization was lowered by incubation of the myotubes with relevant concentrations of palmitoylcarnitines (C16) and increased by oleylcarnitines and linoleylcarnitines (C18:1 and C18:2, respectively). The efficiency of mitochondrial respiration decreased in the order palmitate-oleate-linoleate; in the presence of palmitate, only T3 increased ATP synthesis-independent cellular respiration and mitochondrial respiratory complex activities. Both hormones modulated gene expression and enzyme activities related to insulin sensitivity, glucose metabolism, and lipid handling. Although T2 and T3 differentially regulated the expression of relevant genes involved in glucose metabolism, they equally stimulated related metabolic activities. T2 and T3 differentially modulated mitochondrial fatty acid uptake and oxidation in the presence of each fatty acid. The results show that T2 and T3 both invert the fatty acid-induced response to insulin but through different mechanisms, and that the outcome depends on the degree of saturation of the fatty acids and their derived acylcarnitines. [ABSTRACT FROM AUTHOR]

The 3,5-diiodo-L-thyronine (3,5-T2) is an endogenous metabolite of thyroid hormones, whose administration to rodents fed high-fat diet (HFD) prevents body weight increase and reverts the expression pattern of pro-inflammatory factors associated to HFD. The diet-induced obese (D.I.O.) zebrafish (Danio rerio) has been recently used as an experimental model to investigate fundamental processes underlying central and peripheral obesity-driven inflammation. Herein, we aim to understand the role of 3,5-T2 in regulating central and peripheral inflammation in D.I.O. model of zebrafish. 3,5-T2 (10 nM and 100 nM) was administered with the obesity-inducing diet (D.I.O. with 3,5-T2) or after 4 weeks of obesity-inducing diet (D.I.O. flw 3,5-T2). 3,5-T2 significantly increased the body weight and serum triglyceride levels in D.I.O. zebrafish in both conditions. Moreover, 3,5-T2 sustained or increased inflammation in the anterior (AI) and mid (MI) intestine when administered with the obesity-inducing diet, as indicated by the immunoexpression of the inflammatory markers tumor-necrosis factor-α (TNFα), cyclooxygenase 2 (COX2), calnexin, caspase 3, and proliferating cell nuclear antigen (PCNA). On the contrary, when 3,5-T2 was administered after the obesity-inducing diet, partly reverted the intestinal alteration induced by D.I.O. In addition, brain inflammation, as indicated by the increase in the activation of microglia, was detected in D.I.O. zebrafish and D.I.O. treated with 3,5-T2. These findings reveal that the effects of 3,5-T2 on fish intestine and brain can deviate from those shown in obese mammals, opening new avenues to the investigation of the potential impact of this thyroid metabolite in different diseases including obesity.

Thyroid hormones significantly influence energy expenditure by affecting the activity of metabolic active tissues, among which, mammalian brown adipose tissue (BAT) plays a significant role. For a long time, the modulation of BAT activity by 3,3′,5-triiodo-l-thyronine (T3) has been ascribed to its direct actions on this tissue; however, recent evidence indicates that T3, by stimulating specific brain centers, activates the metabolism of BAT via the sympathetic nervous system. These distinct mechanisms of action are not mutually exclusive. New evidence indicates that 3,5-diiodo-l-thyronine (3,5-T2), a thyroid hormone derivative, exerts thermogenic effects, by influencing mitochondrial activity in metabolically active tissues, such as liver, skeletal muscle, and BAT. At the moment, due to the absence of experiments finalized to render a clear cut discrimination between peripheral and central effects induced by 3,5-T2, it is not possible to exclude that some of the metabolic effects exerted by 3,5-T2 may be mediated centrally. Despite this, some evidence suggests that 3,5-T2 plays a role in adrenergic stimulation of thermogenesis in BAT. This mini-review provides an overview of the effects induced by T3 and 3,5-T2 on BAT thermogenesis, with a focus on data suggesting the involvement of central adrenergic stimulation. These aspects may reveal new perspectives in thyroid physiology and in the control of energy metabolism.

Thyroid hormones significantly influence energy expenditure by affecting the activity of metabolic active tissues, among which, mammalian brown adipose tissue (BAT) plays a significant role. For a long time, the modulation of BAT activity by 3,3',5-triiodo-lthyronine (T3) has been ascribed to its direct actions on this tissue; however, recent evidence indicates that T3, by stimulating specific brain centers, activates the metabolism of BAT via the sympathetic nervous system. These distinct mechanisms of action are not mutually exclusive. New evidence indicates that 3,5-diiodo-l-thyronine (3,5-T2), a thyroid hormone derivative, exerts thermogenic effects, by influencing mitochondrial activity in metabolically active tissues, such as liver, skeletal muscle, and BAT. At the moment, due to the absence of experiments finalized to render a clear cut discrimination between peripheral and central effects induced by 3,5-T2, it is not possible to exclude that some of the metabolic effects exerted by 3,5-T2 may be mediated centrally. Despite this, some evidence suggests that 3,5-T2 plays a role in adrenergic stimulation of thermogenesis in BAT. This mini-review provides an overview of the effects induced by T3 and 3,5-T2 on BAT thermogenesis, with a focus on data suggesting the involvement of central adrenergic stimulation. These aspects may reveal new perspectives in thyroid physiology and in the control of energy metabolism. [ABSTRACT FROM AUTHOR]

The conversion of white adipose cells into beige adipose cells is known as browning, a process affecting energy metabolism. It has been shown that 3,5 diiodo-l-thyronine (T2), an endogenous metabolite of thyroid hormones, stimulates energy expenditure and a reduction in fat mass. In light of the above, the purpose of this study was to test whether in an animal model of fat accumulation, T2 has the potential to activate a browning process and to explore the underlying mechanism. Three groups of rats were used: (i) receiving a standard diet for 14 weeks; (ii) receiving a high-fat diet (HFD) for 14 weeks; and (iii) receiving a high fat diet for 10 weeks and being subsequently treated for four weeks with an HFD together with the administration of T2. We showed that T2 was able to induce a browning in the white adipose tissue of T2-treated rats. We also showed that some miRNA (miR133a and miR196a) and MAP kinase 6 were involved in this process. These results indicate that, among others, the browning may be another cellular/molecular mechanism by which T2 exerts its beneficial effects of contrast to overweight and of reduction of fat mass in rats subjected to HFD.

The thyroid hormones (THs) 3,3′,5,5′-tetraiodo-l-thyronine (T4) and 3,5,3′-triiodo-l-thyronine (T3) influence many metabolic pathways. The major physiological function of THs is to sustain basal energy expenditure, by acting primarily on carbohydrate and lipid catabolism. Beyond the mobilization and degradation of lipids, at the hepatic level THs stimulate the de novo fatty acid synthesis (de novo lipogenesis, DNL), through both the modulation of gene expression and the rapid activation of cell signalling pathways. 3,5-Diiodo-l-thyronine (T2), previously considered only a T3 catabolite, has been shown to mimic some of T3 effects on lipid catabolism. However, T2 action is more rapid than that of T3, and seems to be independent of protein synthesis. An inhibitory effect on DNL has been documented for T2. Here, we give an overview of the mechanisms of THs action on liver fatty acid metabolism, focusing on the different effects exerted by T2 and T3 on the regulation of the DNL. The inhibitory action on DNL exerted by T2 makes this compound a potential and attractive drug for the treatment of some metabolic diseases and cancer. [ABSTRACT FROM AUTHOR]

Experimental studies have highlighted that the administration of 3,5-diiodo-L-thyronine (T2) to rats fed diets rich in lipids induces a decrease of cholesterol and triglycerides plasma levels and body weight (BW) without inducing liver steatosis. On the basis of these observations we carried out some experimental in vivo studies to assess the effects of multiple high doses of T2 on the pituitary thyroid axis of rats fed diet rich in lipids. Fifteen male Wistar rats were divided into three groups of five animals each. The first group (N group) received standard diet, the second group was fed with a high fat diet (HFD group), while the third group (HFDT2 group) was additionally given T2 intraperitoneally at a dose level of 70 µg/100 g of BW three times a week up to four weeks. At the end of the treatment, blood sample from each animal was collected, centrifuged and the serum was stored at -20°C. The serum concentrations of thyroidstimulating hormone (TSH), triiodothyronine, thyroxine, adrenocorticotropic hormone, triglycerides, cholesterol, glucose, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase were then determined. In addition, liver of rats was examined by histology in order to assess the presence and degree of steatosis. The administration of T2 to rats fed with a high fat diet suppressed TSH secretion (P=0.013) while no steatosis was observed in the liver of these animals. Our data show that multiple administrations of high doses of T2 to rats fed diets rich in lipid inhibit TSH secretion and prevent the onset of liver steatosis in these animals.

The role of 3,5-diiodo-L-thyronine (T), initially considered only a 3,3′,5-triiodo-L-thyronine (T) catabolite, in the bioenergetic metabolism is of growing interest. In this study we investigated the acute effects (within 1 h) of T administration to hypothyroid rats on liver mitochondria fatty acid uptake and β-oxidation rate, mitochondrial efficiency (by measuring proton leak) and mitochondrial oxidative damage (by determining HO release). Fatty acid uptake into mitochondria was measured assaying carnitine palmitoyl transferase (CPT) I and II activities, and fatty acid β-oxidation using palmitoyl-CoA as a respiratory substrate. Mitochondrial fatty acid pattern was defined by gas-liquid chromatography. In hypothyroid + T vs hypothyroid rats we observed a raise in the serum level of nonesterified fatty acids (NEFA), in the mitochondrial CPT system activity and in the fatty acid β-oxidation rate. A parallel increase in the respiratory chain activity, mainly from succinate, occurs. When fatty acids are chelated by bovine serum albumin, a T-induced increase in both state 3 and state 4 respiration is observed, while, when fatty acids are present, mitochondrial uncoupling occurs together with increased proton leak, responsible for mitochondrial thermogenesis. T administration decreases mitochondrial oxidative stress as determined by lower HO production. We conclude that in rat liver mitochondria T acutely enhances the rate of fatty acid β-oxidation, and the activity of the downstream respiratory chain. The T-induced increase in proton leak may contribute to mitochondrial thermogenesis and to the reduction of oxidative stress. Our results strengthen the previously reported ability of T to reduce adiposity, dyslipidemia and to prevent liver steatosis. [ABSTRACT FROM AUTHOR]

Short-term effects of 3,5-L-diiodothyronine (T) administration to hypothyroid rats on FF-ATP synthase activity were investigated in liver mitochondria. One hour after T injection, state 4 and state 3 respiration rates were noticeably stimulated in mitochondria subsequently isolated. FF-ATP synthase activity, which was reduced in mitochondria from hypothyroid rats as compared to mitochondria from euthyroid rats, was significantly increased by T administration in both the ATP-synthesis and hydrolysis direction. No change in β-subunit mRNA accumulation and protein amount of the α-β subunit of FF-ATP synthase was found, ruling out a T genomic effect. In T-treated rats, changes in the composition of mitochondrial phospholipids were observed, cardiolipin (CL) showing the greatest alteration. In mitochondria isolated from hypothyroid rats the decrease in the amount of CL was accompanied by an increase in the level of peroxidised CL. T administration to hypothyroid rats enhanced the level of CL and decreased the amount of peroxidised CL in subsequently isolated mitochondria, tending to restore the CL value to the euthyroid level. Minor T-induced changes in mitochondrial fatty acid composition were detected. Overall, the enhanced FF-ATP synthase activity observed following injection of T to hypothyroid rats may be ascribed, at least in part, to an increased level of mitochondrial CL associated with decreased peroxidation of CL. [ABSTRACT FROM AUTHOR]

Apoptotic cell death can occur by two different pathways. Type 1 is initiated by the activation of death receptors (Fas, TNF-receptor-family) on the plasma membrane followed by activation of caspase 8. Type 2 involves changes in mitochondrial integrity initiated by various effectors like Ca2+, reactive oxygen species (ROS), Bax, or ceramide, leading to the release of cytochrome c and activation of caspase 9. The release of cytochrome c is followed by a decrease of the mitochondrial membrane potential ΔΨm. Recent publications have demonstrated, however, that induction of apoptosis by various effectors involves primarily a transient increase of ΔΨm for unknown reason. Here we propose a new mechanism for the increased ΔΨm based on experiments on the allosteric ATP-inhibition of cytochrome c oxidase at high matrix ATP/ADP ratios, which was concluded to maintain low levels of ΔΨm in vivo under relaxed conditions. This regulatory mechanism is based on the potential-dependency of the ATP synthase, which has maximal activity at ΔΨm=100–120 mV. The mechanism is turned off either through calcium-activated dephosphorylation of cytochrome c oxidase or by 3,5-diiodo-l-thyronine, palmitate, and probably other so far unknown effectors. Consequently, energy metabolism changes to an excited state. We propose that this change causes an increase in ΔΨm, a condition for the formation of ROS and induction of apoptosis. [Copyright &y& Elsevier]

Simple Summary: The obesity induced by overconsumption of nutrients leads to systemic inflammation and alters metabolic homeostasis by acting on central nervous system and peripheral tissues such as intestine. The 3,5-diiodo-L-thyronine (3,5-T2) is well-known for its positive role on fat mass and lipid metabolism, and at date, it is widely used as a drug for the treatment of obesity. However, the safe and effective dose as well as the possible adverse effects of this molecule have not been sufficiently explored. In this study, we analyzed the role of 3,5-T2 in regulating central and peripheral inflammation in diet-induced obese (D.I.O.) model of zebrafish. We found that 3,5-T2 sustained the intestinal alteration caused by D.I.O., as indicated by the high levels of pro-inflammatory cytokines, accompanied by a significant effect of 3,5-T2 on body weight and central inflammation in D.I.O. zebrafish. Therefore, the suggested potential use of 3,5-T2 to contrast obesity should be viewed with caution. We conclude that the zebrafish model can help to better understand the fundamental beneficial and side effects of 3,5-T2, which is of great importance to define the possible use of this metabolite of thyroid hormones as a drug in different diseases including obesity. The 3,5-diiodo-L-thyronine (3,5-T2) is an endogenous metabolite of thyroid hormones, whose administration to rodents fed high-fat diet (HFD) prevents body weight increase and reverts the expression pattern of pro-inflammatory factors associated to HFD. The diet-induced obese (D.I.O.) zebrafish (Danio rerio) has been recently used as an experimental model to investigate fundamental processes underlying central and peripheral obesity-driven inflammation. Herein, we aim to understand the role of 3,5-T2 in regulating central and peripheral inflammation in D.I.O. model of zebrafish. 3,5-T2 (10 nM and 100 nM) was administered with the obesity-inducing diet (D.I.O. with 3,5-T2) or after 4 weeks of obesity-inducing diet (D.I.O. flw 3,5-T2). 3,5-T2 significantly increased the body weight and serum triglyceride levels in D.I.O. zebrafish in both conditions. Moreover, 3,5-T2 sustained or increased inflammation in the anterior (AI) and mid (MI) intestine when administered with the obesity-inducing diet, as indicated by the immunoexpression of the inflammatory markers tumor-necrosis factor-α (TNFα), cyclooxygenase 2 (COX2), calnexin, caspase 3, and proliferating cell nuclear antigen (PCNA). On the contrary, when 3,5-T2 was administered after the obesity-inducing diet, partly reverted the intestinal alteration induced by D.I.O. In addition, brain inflammation, as indicated by the increase in the activation of microglia, was detected in D.I.O. zebrafish and D.I.O. treated with 3,5-T2. These findings reveal that the effects of 3,5-T2 on fish intestine and brain can deviate from those shown in obese mammals, opening new avenues to the investigation of the potential impact of this thyroid metabolite in different diseases including obesity. [ABSTRACT FROM AUTHOR]

Since the realization that the cellular homologs of a gene found in the retrovirus that contributes to erythroblastosis in birds (v-erbA), i.e. the proto-oncogene c-erbA encodes the nuclear receptors for thyroid hormones (THs), most of the interest for THs focalized on their ability to control gene transcription. It was found, indeed, that, by regulating gene expression in many tissues, these hormones could mediate critical events both in development and in adult organisms. Among their effects, much attention was given to their ability to increase energy expenditure, and they were early proposed as anti-obesity drugs. However, their clinical use has been strongly challenged by the concomitant onset of toxic effects, especially on the heart. Notably, it has been clearly demonstrated that, besides their direct action on transcription (genomic effects), THs also have non-genomic effects, mediated by cell membrane and/or mitochondrial binding sites, and sometimes triggered by their endogenous catabolites. Among these latter molecules, 3,5-diiodo-L-thyronine (3,5-T2) has been attracting increasing interest because some of its metabolic effects are similar to those induced by T3, but it seems to be safer. The main target of 3,5-T2 appears to be the mitochondria, and it has been hypothesized that, by acting mainly on mitochondrial function and oxidative stress, 3,5-T2 might prevent and revert tissue damages and hepatic steatosis induced by a hyper-lipid diet, while concomitantly reducing the circulating levels of low density lipoproteins (LDL) and triglycerides. Besides a summary concerning general metabolism of THs, as well as their genomic and non-genomic effects, herein we will discuss resistance to THs and the possible mechanisms of action of 3,5-T2, also in relation to its possible clinical use as a drug. [ABSTRACT FROM AUTHOR]

When administered to rats receiving a high-fat diet (HFD), 3,5-diiodo-L-thyronine (3,5-T2) [at a dose of 25 μg/100 g body weight (BW)] is known to increase energy expenditure and to prevent HFD-induced adiposity. Here, we investigated which cellular and molecular processes in visceral white adipose tissue (VAT) contributed to the beneficial effect of 3,5-T2 over time (between 1 day and 4 weeks following administration). 3,5-T2 programmed the adipocyte for lipolysis by rapidly inducing hormone sensitive lipase (HSL) phosphorylation at the protein kinase A-responsive site Ser563, accompanied with glycerol release at the 1-week time-point, contributing to the partial normalization of adipocyte volume with respect to control (N) animals. After two weeks, when the adipocyte volumes of HFD-3,5-T2 rats were completely normalized to those of the controls (N), 3,5-T2 consistently induced HSL phosphorylation at Ser563, indicative of a combined effect of 3,5-T2-induced adipose lipolysis and increasing non-adipose oxidative metabolism. VAT proteome analysis after 4 weeks of treatment revealed that 3,5-T2 significantly altered the proteomic profile of HFD rats and produced a marked pro-angiogenic action. This was associated with a reduced representation of proteins involved in lipid storage or related to response to oxidative stress, and a normalization of the levels of those involved in lipogenesis-associated mitochondrial function. In conclusion, the prevention of VAT mass-gain by 3,5-T2 occurred through different molecular pathways that, together with the previously reported stimulation of resting metabolism and liver fatty acid oxidation, are associated with an anti adipogenic/lipogenic potential and positively impact on tissue health. [ABSTRACT FROM AUTHOR]

The conversion of white adipose cells into beige adipose cells is known as browning, a process affecting energy metabolism. It has been shown that 3,5 diiodo-l-thyronine (T₂), an endogenous metabolite of thyroid hormones, stimulates energy expenditure and a reduction in fat mass. In light of the above, the purpose of this study was to test whether in an animal model of fat accumulation, T₂ has the potential to activate a browning process and to explore the underlying mechanism. Three groups of rats were used: (i) receiving a standard diet for 14 weeks; (ii) receiving a high-fat diet (HFD) for 14 weeks; and (iii) receiving a high fat diet for 10 weeks and being subsequently treated for four weeks with an HFD together with the administration of T₂. We showed that T₂ was able to induce a browning in the white adipose tissue of T₂-treated rats. We also showed that some miRNA (miR133a and miR196a) and MAP kinase 6 were involved in this process. These results indicate that, among others, the browning may be another cellular/molecular mechanism by which T₂ exerts its beneficial effects of contrast to overweight and of reduction of fat mass in rats subjected to HFD.

Fatty liver or nonalcoholic fatty liver disease (NAFLD), a problem of increasing clinical significance and prevalence worldwide, is associated with increased risk for the development of cirrhosis and hepatocellular carcinoma. Although several therapeutic approaches can be used in the context of NAFLD, dietary and physical activities are still the most frequently used strategies. Some pharmacological agents show promising results although no conclusions can be drawn from recent clinical trials. Thyroid hormones [THs; thyroxine (T4) and 3,3',5-triiodo-L-thyronine (T3)] coordinate a diverse array of physiological events during development and lipid/energy homeostasis and have some potentially therapeutic actions which include inducing weight loss, and lowering plasma cholesterol levels and tissue adiposity. The thyroid hormones exert their physiological effects by binding to specific nuclear receptors [thyroid hormone receptors (TR)] of which the TRβ isoform is liver specific and has been considered a putative target for the treatment of dyslipidemia and fatty liver. In view of this, the aim of the review is (1) to provide an overview of the action of T3 on lipid metabolism with implications for liver steatosis and (2) to provide an update on the current knowledge concerning the administration of TRβ selective thyromimetics (GC-1 and MB07811), as well as of 3,5-diiodo-L-thyronine and its novel functional analogue TRC150094 in animal models of overweight and related disorders including primarily fatty liver.

Thyroid hormone 3,5,3'-triiodo-l-thyronine (T3) is known to affect cell metabolism through both the genomic and non-genomic actions. Recently, we demonstrated in HepG2 cells that T3 controls the expression of SREBP-1, a transcription factor involved in the regulation of lipogenic genes. This occurs by activation of a cap-independent translation mechanism of its mRNA. Such a process is dependent on non-genomic activation of both MAPK/ERK and PI3K/Akt pathways. The physiological role of 3,5-diiodo-l-thyronine (T2), previously considered only as a T3 catabolite, is of growing interest. Evidences have been reported that T2 rapidly affects some metabolic pathways through non-genomic mechanisms. Here, we show that T2, unlike T3, determines the block of proteolytic cleavage of SREBP-1 in HepG2 cells, without affecting its expression at the transcriptional or translational level. Consequently, Fatty Acid Synthase expression is reduced. T2 effects depend on the concurrent activation of MAPKs ERK and p38, of Akt and PKC-δ pathways. Upon the activation of these signals, apoptosis of HepG2 cells seems to occur, starting at 12h of T2 treatment. PKC-δ appears to act as a switch between p38 activation and Akt suppression, suggesting that this PKC may function as a controller in the balance of pro-apoptotic (p38) and anti-apoptotic (Akt) signals in HepG2 cells., (© 2013.)