Evidence for thyromimetic action of 3,5-T2 in diet-induced obese mice

Abstract

The thyroid hormones (TH) L-thyroxine (T4) and 3,5,3'- triiodothyronine (T3) are strong modulators of energy homeostasis. TH exert their classical, non-acute effects on metabolic pathways through gene-specific modulation of transcriptional activity of T3 receptors (TR). Recent findings revealed 3,5-diiodo-L-thyronine (3,5-T2) as a metabolically active iodothyronine affecting energy and lipid metabolism without thyromimetic side effects as typically caused by T3. Accordingly, 3,5-T2 is proposed to be a potential hypolipidemic agent for treatment of obesity and its associated secondary diseases, especially in liver. The objective of the present study was to investigate if chronic 3,5-T2 treatment affects the HPT axis and liver energy and lipid metabolism in a pattern similar to T3. High fat diet-induced obese adult male mice received for 2 weeks a daily application of two different doses of 3,5-T2 (0.25 and 2.5 µg/g bw), T3 (0.03 µg/g bw) or saline. Treatment with 3,5-T2 led to a negative feedback regulation of the HPT axis, similar to T3 as demonstrated by decreased gene expression of Trhr, Dio2 and Tshb in pituitary resulting in a suppressed thyroid function as obvious from lower T4 levels in serum and liver. Analyses of hepatic TH target genes involved in lipid metabolism (e.g. Me1, Scd1, Cyp7a1) revealed changes in gene expression level after 2.5 µg/g bw of 3,5-T2 similar to T3 treatment. Besides enhanced hepatic mRNA level of nuclear respiratory factor 1 and mitochondrial transcription factor A an increase in protein expression of cytochrome c and cytochrome c oxidase IV indicates that 2.5 µg/g bw 3,5-T2, like T3, stimulates mitochondrial metabolism. The results show similar thyromimetic effects of 3,5-T2 and T3, suggesting that chronic 3,5-T2 action is mainly mediated by nuclear-based TR and 3,5-T2 mimics T3 action by interfering with the HPT axis and expression of T3-responsive genes.