3,5-Diiodo-L-Thyronine (3,5-T₂) Exerts Thyromimetic Effects on Hypothalamus-Pituitary-Thyroid Axis, Body Composition, and Energy Metabolism in Male Diet-Induced Obese Mice

Abstract

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-T2) as a metabolically active iodothyronine affecting energy and lipid metabolism without thyromimetic side effects typically associated with T3 administration. Accordingly, 3,5-T2 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-T2 akin to those of T3 in diet-induced obese male C57BL/6J mice. 3,5-T2 treatment exerted a negative feedback regulation on the hypothalamus-pituitary-thyroid axis, similar to T3. This is demonstrated by decreased expression of genes responsive to thyroid hormones (TH) in pituitary resulting in a suppressed thyroid function with lower T4 and T3 concentrations in serum and liver of 3,5-T2-treated mice. Analyses of hepatic TH target genes involved in lipid metabolism revealed T3-like changes in gene expression and increased type I-deiodinase activity after application of 3,5-T2 (2.5 μg/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-T2 beyond hepatic thyromimetic actions. Altogether, the observed thyromimetic effects of 3,5-T2 in several mouse TH target tissues raise concern about indiscriminate administration of 3,5-T2 as powerful natural hormone for the treatment of hyperlipidemia and pandemic obesity.

3,5-T2 alters murine genes relevant for xenobiotic, steroid, and thyroid hormone metabolism

“…In a recently published study, chronic treatment with 3,5-T 2 (2.5 µg/g body weight (bw)) in diet-induced obese euthyroid mice resulted in reduction of body fat mass and improvement of hepatic lipid status. But in contrast to these beneficial effects, an undesired negative feedback inhibition of the hypothalamuspituitary-thyroid (HPT) axis accompanied by increased heart weight was observed at the dose effectively improving hepatic lipid metabolism and systemic lipid status (Jonas et al 2014). Such observations on doserelated thyromimetic actions, among others also on the pituitary and the heart, are in agreement with published results on mice and rats treated with 3,5-T 2 (Horst et al 1995, Goldberg et al 2012, Padron et al 2014.…”

“…The results in diet-induced obese mice by Jonas et al (2014) strongly suggest that 3,5-T 2 dose-dependently influences the expression of TH responsive genes possibly through binding and activating the TH receptor (TR) as shown for teleosts (Garcia et al 2007, Mendoza et al 2013, Navarrete-Ramirez et al 2014 and rats (Ball et al 1997).…”

“…1A and B). These treatment groups were partially identical to those already described in a previous publication, with respect to their HPT feedback axis and lipid metabolism (Jonas et al 2014). After treatment, mice were restricted from food for 6 h before being killed under anesthesia with isoflurane.…”

“…Total RNA from primary hepatocytes was isolated using the Aurum Kit (Bio-Rad) following the manufacturer's instructions. RNA purity and concentration as well as performance of cDNA synthesis and RT-qPCR were monitored as described in a study by Jonas et al (2014). The primers were designed with the Primer-Blast tool of National Center for Biotechnology Information.…”

New insights into the structure and mechanism of iodothyronine deiodinases

“…Removal of an additional iodine atom from the inner or the outer ring results in 3,3 0 -diiodothyronine (3,3 0 -T 2 ) or 3,5-T 2 respectively. While the former metabolite is believed to be inactive, the latter is increasingly recognized as a TH-receptor activating ligand in fish and, at higher concentrations, in mice (Mendoza et al 2013, Orozco et al 2014, Jonas et al 2015. T 4 can also be directly inactivated by the removal of an inner ring (5-)iodine resulting in reverse T 3 (rT 3 ).…”