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.