Potent thermogenic action of triiodothyroacetic acid in brown adipocytes

Medina-Gómez, Gema; Hernández, Arturo; Calvo, Rosa-Maria; Martin, Eva Denise; Obregón, Marı́a Jesús

doi:10.1007/s00018-003-3158-9

Cited by 23 publications

(13 citation statements)

References 53 publications

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“…In BAT, LPL mRNA was induced by the lowest T 3 and TRIAC doses (Fig. 6) and was inhibited by the highest T 3 dose, similarly to our previous findings in cultured brown adipocytes (34). An inhibitory pattern in LPL expression was observed in WAT, with maximum inhibition observed following the highest T 3 dose, the lowest TRIAC dose, and after cold exposure.…”

Section: Low Doses Of Triac Inhibit Less Plasma T 4 and Tsh Than Tsupporting

confidence: 70%

“…Our previous studies using brown adipocytes have shown that TRIAC at very low concentrations (0.2 nM) had more thermogenic effect than T 3 (34), increasing the adrenergic stimulation of both UCP-1 mRNA and D2 activities. Therefore we hypothesized that TRIAC could also be a thermogenic agent in vivo that might increase energy expenditure and regulate T 3 production (by increasing D2) in BAT.…”

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confidence: 99%

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Thermogenic effect of triiodothyroacetic acid at low doses in rat adipose tissue without adverse side effects in the thyroid axis

Medina-Gómez

Calvo²,

Obregón³

2008

American Journal of Physiology-Endocrinology and Metabolism

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Medina-Gomez G, Calvo RM, Obregon M-J. Thermogenic effect of triiodothyroacetic acid at low doses in rat adipose tissue without adverse side effects in the thyroid axis. Am J Physiol Endocrinol Metab 294: E688-E697, 2008. First published February 19, 2008 doi:10.1152/ajpendo.00417.2007.-Triiodothyroacetic acid (TRIAC) is a physiological product of triiodothyronine (T 3) metabolism, with high affinity for T 3 nuclear receptors. Its interest stems from its potential thermogenic effects. Thus this work aimed 1) to clarify these thermogenic effects mediated by TRIAC vs. T 3 in vivo and 2) to determine whether they occurred predominantly in adipose tissues. To examine this, control rats were infused with equimolar T 3 or TRIAC doses (0.8 or 4 nmol ⅐ 100 g body wt Ϫ1 ⅐ day Ϫ1 ) or exposed for 48 h to cold. Both T 3 doses and only the highest TRIAC dose inhibited plasma and pituitary thyroid-stimulating hormone (TSH) and thyroxine (T 4) in plasma and tissues. Interestingly, the lower TRIAC dose marginally inhibited plasma T 4. T3 infusion increased plasma and tissue T 3 in a tissue-specific manner. The highest TRIAC dose increased TRIAC concentrations in plasma and tissues, decreasing plasma T 3. TRIAC concentrations in tissues were Ͻ10% those of T 3. Under cold exposure or high T3 doses, TRIAC increased only in white adipose tissue (WAT). Remarkably, only the lower TRIAC dose activated thermogenesis, inducing ectopic uncoupling protein (UCP)-1 expression in WAT and maximal increases in UCP-1, UCP-2, and lipoprotein lipase (LPL) expression in brown adipose tissue (BAT), inhibiting UCP-2 in muscle and LPL in WAT. TRIAC, T 3, and cold exposure inhibited leptin secretion and mRNA in WAT. In summary, TRIAC, at low doses, induces thermogenic effects in adipose tissues without concomitant inhibition of TSH or hypothyroxinemia, suggesting a specific role regulating energy balance. This selective effect of TRIAC in adipose tissues might be considered a potential tool to increase energy metabolism. thermogenesis; leptin; lipoprotein lipase; deiodinases THE MAIN PATHWAYS of triiodothyronine (T 3 ) metabolism are deiodination, conjugation with glucuronides and sulfates, and modification of the alanine chain producing acetic and propionic metabolites. Triiodothyroacetic acid (TRIAC, also known as Tiratricol) is a physiological product of T 3 metabolism, derived by deamination and oxidative decarboxylation of the alanine chain (55). In humans, TRIAC production by the liver and other tissues accounts for ϳ14% of T 3 metabolism (17). This production is increased under certain physiological conditions, such as fasting (29). Serum TRIAC concentrations in humans are very low (42-140 pM) (17,35,38). The free fraction in serum is lower than that of T 3 , due to higher binding to plasma proteins, especially to transthyretin (18,35). TRIAC has a faster metabolic clearance rate and shorter half-life than T 3 in humans (35), due to its rapid hepatic metabolism, via the formation of sulfates and glucuronides, especially in humans (36, 51).

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Section: Low Doses Of Triac Inhibit Less Plasma T 4 and Tsh Than Tsupporting

confidence: 70%

mentioning

confidence: 99%

Thermogenic effect of triiodothyroacetic acid at low doses in rat adipose tissue without adverse side effects in the thyroid axis

Medina-Gómez

Calvo²,

Obregón³

2008

American Journal of Physiology-Endocrinology and Metabolism

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“…We have previously observed a similar inhibition of D2 activity when using triiodothyroacetic acid (Triac), a natural thermogenic compound, in brown adipocytes (46). Triac increased D2 activity at doses lower than T 3 with a maximum at 1 nM, and at higher doses, Triac inhibited D2 activity.…”

Section: Figmentioning

confidence: 81%

The T3 Receptor β1 Isoform Regulates UCP1 and D2 Deiodinase in Rat Brown Adipocytes

2010

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Brown adipose tissue (BAT) thermogenesis increases when uncoupling protein-1 (UCP1) is activated adrenergically and requires T 3 . In humans, UCP1 activation in BAT seems involved in body weight maintenance. BAT type 2 deiodinase (D2) increases in response to adrenergic agents, producing the T 3 required for UCP1 expression. T 3 actions are mediated by thyroid hormone nuclear T 3 receptors (TR), TR␣ and TR␤. Studies in mice suggest that TR␤ is required for UCP1 induction, whereas TR␣ regulates body temperature and adrenergic sensitivity. In the present study, we compare the effects of T 3 vs. specific TR␤1 and TR␣1 agonists [GC-1 and CO23] on the adrenergic induction of UCP1 and D2 in cultured rat brown adipocytes. T 3 and GC-1 produced similar increases on UCP1, whereas CO23 increased UCP1 only at high doses (50 nM). GC-1 at low doses (0.2-10 nM) was less potent than T 3 , increasing the adrenergic stimulation of D2 activity and mRNA. At higher doses, GC-1 further stimulated whereas T 3 inhibited D2 activity but not D2 mRNA, suggesting posttranscriptional effects. CO23 had no effect on D2 activity but increased D2 mRNA. T 3 , GC-1, or CO23 by themselves did not increase UCP1 or D2 mRNA. High T 3 doses shortened D2 half-life and increased D2 turnover via proteasome, whereas GC-1 did not change D2 stability. The ␣1-and ␣2-adrenergic D2 responses increased using high T 3 doses. In summary, T 3 increases the adrenergic stimulation of UCP1 and D2 expression mostly via the TR␤1 isoform, and in brown adipocytes, D2 is protected from degradation by the action of T 3 on TR␤1. (Endocrinology 151: 5074 -5083, 2010)

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“…In rat adipocytes, TA 3 appeared more potent in upregulating Ucp1 and Dio2 expression than T 3 (Medina-Gomez et al 2003). Also in vivo, low doses of TA 3 resulted in upregulation of Ucp1 in BAT and induced ectopic Ucp1 expression in WAT, without affecting tissue TH levels (Medina-Gomez et al 2008).…”

Section: Adipose Tissuementioning

confidence: 91%

Triiodothyroacetic acid in health and disease

Groeneweg

Peeters

Visser

et al. 2017

Journal of Endocrinology

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Thyroid hormone (TH) is crucial for development and metabolism of many tissues. The physiological relevance and therapeutic potential of TH analogs have gained attention in the field for many years. In particular, the relevance and use of 3,3′,5-triiodothyroacetic acid (Triac, TA 3 ) has been explored over the last decades. Although TA 3 closely resembles the bioactive hormone T 3 , differences in transmembrane transport and receptor isoformspecific transcriptional activation potency exist. For these reasons, the application of TA 3 as a treatment for resistance to TH (RTH) syndromes, especially MCT8 deficiency, is topic of ongoing research. This review is a summary of all currently available literature about the formation, metabolism, action and therapeutic applications of TA 3 .

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Potent thermogenic action of triiodothyroacetic acid in brown adipocytes

Cited by 23 publications

References 53 publications

Thermogenic effect of triiodothyroacetic acid at low doses in rat adipose tissue without adverse side effects in the thyroid axis

Thermogenic effect of triiodothyroacetic acid at low doses in rat adipose tissue without adverse side effects in the thyroid axis

The T3 Receptor β1 Isoform Regulates UCP1 and D2 Deiodinase in Rat Brown Adipocytes

Triiodothyroacetic acid in health and disease

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