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

Abstract

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).

Triiodothyroacetic acid in health and disease

“…Intrahepatic TA 3 levels increase upon TA 3 infusion in rats, which is in line with the important role of the liver in TA 3 clearance (Medina-Gomez et al 2008). TA 3 also effectively induces the expression of T 3 -responsive genes in the liver, including Dio1, to a similar extent as T 3 (Juge-Aubry et al 1995, Liang et al 1997, Alvarez et al 2004, MedinaGomez et al 2008.…”

“…Interestingly, Mirell and coworkers (Mirell et al 1989) found that TSH mRNA expression levels are unchanged 6 h after TA 3 administration, suggesting that the initial decline in serum TSH is not caused by alterations at transcriptional level, but rather points to direct inhibition of TSH secretion by TA 3 . In contrast, prolonged (>12 days) TA 3 administration to rats persistently suppressed pituitary TSH mRNA levels (Juge-Aubry et al 1995, Liang et al 1997, resulting in a dose-dependent decrease in serum T 3 and T 4 levels (Medina-Gomez et al 2008). Similar effects on TSH levels were found in mice treated with TA 4 , whereas no effects were observed on hypothalamic TRH mRNA expression (Horn et al 2013).…”

“…MCT8, MCT10 and Organic Anion Transporting Polypeptide (OATP)1C1 do not appear relevant for transport of TA 3 (Horn et al 2013, Groeneweg et al 2014. Studies in rodents suggest that the TA 3 transporter(s) are widely expressed, given the increase in TA 3 levels in many tissues after injection of TA 3 (Medina-Gomez et al 2008. However, the transporter(s) involved remain to be identified.…”

“…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). In addition, TA 3 inhibited leptin expression and secretion in rat brown and white adipocytes (MedinaGomez et al 2004).…”

Polymeric nanoparticles loaded with the 3,5,3´-triiodothyroacetic acid (Triac), a thyroid hormone: factorial design, characterization, and release kinetics

“…Triac concentrations may be up to 200 times the physiological concentration of T 3 . 7 On the other hand, high concentrations may cause various undesirable effects such as an increase of the heart rate and induction of arrhythmias, which might limit Triac's usefulness. 8 The solutions to these problems are among the main reasons for the development of new formulations such as polymeric nanoparticle systems.…”