3,5-Diiodo-L-Thyronine (T2) in Dietary Supplements: What Are the Physiological Effects? (2024)

The high prevalence of obesity in developed and emerging countries is a serious health concern. Its consequences include a significant decrease in the quality of life and life expectancy of affected individuals, not to mention the stress it places on health care delivery systems that must treat the multiple comorbidities associated with it. There is little doubt that we need to reduce our girth for the sake of our health. In addition, the desire to reduce body fat is increasingly driven by esthetic concerns, as evidenced by the growing emphasis on fitness and body building.

Given the well-known metabolic effects of thyroid hormones (THs) (1), it is not surprising that a TH metabolite, 3,5-diiodo-L-thyronine (T₂), has found its way into the formulations of a number of dietary supplements that claim to decrease body fat. They are available “over the counter,” and a quick internet search reveals that they are offered for sale using marketing verbiage such as “fat burner,” “appetite suppressant and fast fat annihilator,” “metabolic accelerator,” etc. Accompanying information may include inaccurate statements, such as “… T₂ is a supplement designed to stimulate the thyroid gland,” and it does not always disclose appropriate warnings about potential side effects, nor provide precise directions about the total daily dose that is safe to use. The T₂ content per pill may vary significantly among different supplements (50–300 μg), and in some cases, it is not explicitly stated. Oftentimes, T₂ is combined with other compounds with complementary or overlapping biological effects, making it difficult to discern which of the metabolic outcomes is the specific result of T₂ action. In these circ*mstances, there is significant risk of untoward effects.

The use of T₂ by humans as a metabolism inducer stems from initial findings by Horst et al (2) and Lanni et al (3), who observed that T₂ rapidly induced hepatic oxygen consumption and oxidative capacity. In the last 2 decades, work from Goglia's group and others (reviewed in Refs. 4, 5) expanded on these findings and confirmed T₂'s effects on mitochondrial function, fat mass, lipid metabolism, and its positive influence on insulin resistance (6), further supporting the case for T₂ use to enhance metabolism. A T₂ analog, TRC150094, is currently being evaluated for comparable metabolic effects (7). T₂ has an affinity for the thyroid receptor that is roughly 2 orders of magnitude lower than that of the most active TH, T₃. However, the results about T₂'s relative affinity may vary depending on the biochemical or physiological assay used (8) and be influenced by the purity of the T₂ preparation. Given its lower affinity for the TH receptors, most of the beneficial effects of T₂ on metabolism reported to date have resulted from doses that were significantly higher than the dose of T₃ that would be required for the same effect. However, except for its capability to suppress the hypothalamic-pituitary-thyroid (HPT) axis (9, 10), little has been reported regarding any undesirable thyromimetic effects of T₂.

Although the ability of T₂ to increase metabolism is not in doubt, it is not evident from the published studies what conditions allow for its safe and effective use in humans. This is due in part to the lack of comprehensive human studies, but it is also the result of the fragmented information available in the literature. Published studies often focus on different biochemical or physiological endpoints while using different experimental designs, models, and T₂ doses. There is also a considerable bias in the literature towards the beneficial effects of T₂, leaving its potential deleterious consequences insufficiently explored. If we consider that its thyromimetic effects may extend to many organs, there is a significant possibility that T₂ administration may result in long-term undesirable effects.

In one of the most complete studies available, published in the current issue of Endocrinology (11), Wenke Jonas and investigators in the laboratories of Joseph Kohrle and Annette Schurmann used a mouse model of obesity to analyze the physiological effects of T₂. In their thoughtfully designed, carefully performed, and thoroughly discussed experiment, the authors treated obese mice for 2 and 4 weeks with 2 different daily doses of T₂ or with a supraphysiological dose of T₃ and measured a number of metabolic and physiological endpoints during and after the treatment.

The higher dose of T₂ used was 80 times that of T₃. Thus, it allows for its estimated lower affinity for the TH receptors, assuming that the affinity of T₃ for the receptors is indeed 100 times that of T₂ (8). This high dose of T₂ essentially mimicked all the physiological effects obtained with the T₃ dose. These effects included suppression of the HPT axis, decreases in fat mass, serum leptin and cholesterol, and increases in lean mass, food intake, and hepatic expression of TH-dependent genes relevant to lipid metabolism (see summary of results in Table 1). After 4 weeks, this high dose of T₂ also caused cardiac hypertrophy and resulted in elevated metabolic rate and body temperature. These results demonstrate that at a dose that corrects for its decreased affinity for the TH receptor, T₂ is capable of producing the same biological effects as T₃.

At the lower dose, however, the authors found that T₂ did not reduce body weight, cholesterol, or fat mass. Nor it did change hepatic gene expression profiles. However, this low dose of T₂ exerted a profound effect on the HPT axis, resulting in a marked reduction in the serum levels of T₄ and T₃, and a significant decrease in the pituitary expression of the TSH β-subunit. These results suggest a preferential effect of T₂ on the HPT axis, and this occurs at least at the pituitary level.

There is still limited information about the mechanisms of action of T₂. Although alternative molecular pathways cannot be excluded, based on present evidence, it is likely that T₂ uses at least some of the same mechanisms, as does endogenous T₃. Identifying the cell membrane transporters preferentially used by T₂ and determining whether at some dose levels it can interfere with the function of the deiodinases or other proteins that bind TH will be most informative. Recent studies in a fish model (12) suggest that T₂ can act as a ligand of the β-isoforms of the TH receptor. This could explain the effects of T₂ on pituitary and liver, whose TH-dependent physiologies occur by signaling through that receptor isoform. However, the cardiac hypertrophy observed by the authors at higher doses suggests that T₂ can also use the α1 receptor, the most abundant in this tissue.

Every tissue features its own complement of transporters, deiodinases, receptors, and associated proteins. They are responsible for modulating TH availability and action in an appropriate, tissue-specific manner. As a result, TH signaling in particular tissues or developmental stages may be largely different from what one would predict based on circulating levels of TH. This complexity in the tissue-specific regulation of TH action provides opportunities for thyromimetic compounds with particular molecular properties to act in a tissue specific fashion when administered appropriately (13, 14).

In this regard, a case could be made for the therapeutic use of T₂ in a manner that discriminates between desirable and undesirable effects, especially if we consider its apparent tendency to accumulate in the liver (11) or if there are differences in transport, degradation, and receptor affinity in target tissues not yet identified. But given the pleiotropic effects of TH and the results from Jonas et al (11), more comprehensive studies in humans and animal models are clearly needed to fully evaluate any potential risks. The chronic effects of T₂ on important organs that are targeted by TH (eg, pituitary, heart, brain, bone, muscle) have not been sufficiently investigated, and it is possible that differences among species, methods of T₂ administration and overall experimental design may lead to inconsistent results. In addition, further molecular research aimed at clearly defining the mechanisms of action of T₂ and its interactions with other determinants of TH availability and signaling will also be of benefit.

In the meantime, the current literature and the results presented by Jonas et al (11) indicate that, in addition to increased metabolism and reduced fat mass, T₂ administration also leads to suppression of the HPT axis, increased food intake, and cardiac hypertrophy. A particular point of concern is the observation that the lower dose of T₂ used by the authors exerts negligible effects on adiposity and metabolic outcomes, yet results in a marked suppression of the HPT axis leading to reduced levels of circulating T₄ and T₃ (and presumably TSH), with unknown long-term consequences. The implication of this finding is that, for a given dose, the detrimental effects of T₂ on the HPT axis may preferentially occur before the intended metabolic ones. Thus, for the time being, these new data should compel users of T₂-containing supplements to assess their thyroid status, err on the side of caution, and limit their daily dose, as appropriate.

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