Rapid stimulation of hepatic oxygen consumption by 3,5-di-iodo-l-thyronine

Abstract

Tri-iodothyronine (T3) and thyroxine (T4) as well as 3,5-di-iodothyronine (T2) stimulated O2 consumption by isolated perfused livers from hypothyroid rats at a concentration as low as 1 pM by about 30% within 90 min. Application of T2 resulted in a faster stimulation than with application of T3 or T4. Inhibition of iodothyronine monodeiodinase by propylthiouracil, thereby blocking the degradation of T4 to T3 and of T3 to T2, demonstrated that only T2 is the active hormone for the rapid stimulation of hepatic O2 consumption: T3 and T4 lost all of their stimulative activity, whereas T2 was as potent as in the absence of propylthiouracil. Perfusion experiments with thyroid-hormone analogues confirmed the specificity of the T2 effect. The nucleus is unlikely to contribute to the rapid T2 effect, as can be deduced from perfusion experiments with cycloheximide and lack of induction of malic enzyme by T2. In conclusion, a new scheme of regulation of mitochondrial activity is proposed: T2 acts rapidly and directly via a mitochondrial pathway, whereas T3 exerts its long-term action indirectly by induction of specific enzymes.

Non-receptor-mediated actions are responsible for the lipid-lowering effects of iodothyronines in FaO rat hepatoma cells

“…The ability of THs to regulate energy utilization as well as their role in promoting mitochondrial uncoupling of substrate oxidation from ATP synthesis have been long recognized. T 2 , as T 3 , was shown to rapidly stimulate hepatic O 2 uptake when injected in perfused livers (Horst et al 1989), or added to mitochondria isolated from hypothyroid rats (Moreno et al 2002). Similar effects of T 3 have been observed in hepatocytes isolated from hypothyroid animals (Nobes et al 1990).…”

3,5-Diiodo-L-thyronine (T2) has selective thyromimetic effects in vivo and in vitro

“…We have excluded both selective TR interactions and discrepancies between standard in vitro assays of ligand binding and TR function as potential mechanisms. Previous studies have raised the possibility that T 2 may have extra-nuclear effects, independent of classical nuclear TRs (Horst et al 1989, Kvetny 1992, Lanni et al 1993, Goglia et al 1994. Both GH and TSH mRNA levels can be regulated at a posttranscriptional level by T 3 (Jones et al 1990, Krane et al 1991.…”

“…potency of T 3 in anti-goitre assays in vivo (Stasilli et al 1959). However, T 2 has rapid and specific effects on oxidative metabolism in rat liver and in mononuclear blood cells (Horst et al 1989, Kvetny 1992, Lanni et al 1992, Goglia et al 1994. T 3 regulates gene expression through TR interaction with TREs located in the promoter region of target genes.…”

Specific binding sites for 3,3′‐diiodo‐l‐thyronine (3,3′‐T2) in rat liver mitochondria

“…In fact, in spite of several reports showing rapid effects of triiodothyronine (T3) on mitochondria, the occurrence and the physiological significance of these effects is a long standing controversial issue of thyroid hormone action. In recent years, however, several reports have shown that two diiodothyronines (3,3'-T2 and 3,5-T2), under certain conditions, are the only iodothyronines which rapidly stimulate in vivo and in vitro mitochondrial respiration or cytochrome oxidase (COX) activity [1][2][3][4][5][6]. At the moment, the physiological significance of these effects is not clear and no insight into the mechanism by which diiodothyronines stimulate mitochondrial energy metabolism is available.…”