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

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-T-2) as a metabolically active iodothyronine affecting energy and lipid metabolism without thyromimetic side effects typically associated with T-3 administration. Accordingly, 3,5-T-2 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-T-2 akin to those of T-3 in diet-induced obese male C57BL/6J mice. 3,5-T-2 treatment exerted a negative feedback regulation on the hypothalamus-pituitary-thyroid axis, similar to T-3. This is demonstrated by decreased expression of genes responsive to thyroid hormones (TH) in pituitary resulting in a suppressed thyroid function with lower T-4 and T-3 concentrations in serum and liver of 3,5-T-2-treated mice. Analyses of hepatic TH target genes involved in lipid metabolism revealed T-3-like changes in gene expression and increased type I-deiodinase activity after application of 3,5-T-2 (2.5 mu g/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-T-2 beyond hepatic thyromimetic actions. Altogether, the observed thyromimetic effects of 3,5-T-2 in several mouse TH target tissues raise concern about indiscriminate administration of 3,5-T-2 as powerful natural hormone for the treatment of hyperlipidemia and pandemic obesity.