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 - PubMed (original) (raw)

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

Wenke Jonas et al. Endocrinology. 2015 Jan.

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.

PubMed Disclaimer

Figures

Figure 1.

Figure 1.. Study design.

Diet-induced obese C57BL/6J male mice were treated with either 3,5-T2 or T3 for 14 days to validate the thyromimetic potential of 3,5-T2 in relation to T3. Metabolic parameters were measured in a second cohort of mice after 3,5-T2 treatment for 28 days.

Figure 2.

Figure 2.. Profile of TH after a 14-day treatment as measured by LC-MS/MS.

Serum (A–D) and hepatic (E–G) TH concentrations. Data are shown as boxplots. *, P < .05; **, P < .01; ***, P < .001 vs control or as indicated (n = 6–8).

Figure 3.

Figure 3.. Treatment of mice with 3,5-T2 or T3 affected regulation of HPT axis and its negative feedback mechanisms.

Pituitary gene expression (A), expression of hepatic target genes (B) and of mitochondrial biogenesis in liver tissue (C), hepatic CS activity (D), and hepatic Dio1 activity (E). Data are expressed as mean ± SEM. *, P < .05; **, P < .01; ***, P < .001 vs control or as indicated (n = 6–8).

Figure 4.

Figure 4.. 3,5-T2 treatment reduced fat mass in obese mice without affecting body weight.

Effect of 3,5-T2 treatment on (A) body weight, (B) relative body composition, (C) sc fat pad (scWAT) and epididymal fat pad (eWAT) weight, and (D) serum leptin concentrations after 14 days in comparison with T3 (n = 6–8); 28 days of 3,5-T2 application (E) reduced weight of scWAT and eWAT, (F) increased heart weight, and (G) did not affect liver weight (n = 7–8). Data are expressed as mean ± SEM. *, P < .05; **, P < .01; ***, P < .001 vs control or as indicated.

Figure 5.

Figure 5.. Energy expenditure and food intake were increased by a 28-day treatment with 3,5-T2.

A, Daily food intake during a 14-day intervention. B, Energy expenditure during a 21-hour measurement from days 26 to 27 of intervention and (C) adjustment of TEE by ANCOVA with lean mass as covariate, (D) body temperature at day 24 of intervention, (E) 24-hour locomotor activity measurement, and (F) 24-hour cumulative food intake as measured at days 25–26 of intervention. Adjusted TEE was presented at a common lean mass of 28.4 g. Data are expressed as mean ± SEM. *, P < .05; **, P < .01; ***, P < .001 vs control or as indicated (n = 6–11).

Figure 6.

Figure 6.. 3,5-T2 treatment caused (A) decrease of total serum cholesterol after 14 days and (B) reduction of hepatic triglyceride content after 28 days of application.

Data are shown as boxplots. *, P < .05; **, P < .01; ***, P < .001 vs control or as indicated (n = 6–8).

Comment in

References

    1. Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev. 2014;94(2):355–382. - PMC - PubMed
    1. Brent GA. Mechanisms of thyroid hormone action. J Clin Invest. 2012;122(9):3035–3043. - PMC - PubMed
    1. Flamant F, Gauthier K. Thyroid hormone receptors: the challenge of elucidating isotype-specific functions and cell-specific response. Biochim Biophys Acta. 2013;1830(7):3900–3907. - PubMed
    1. Oppenheimer JH. Thyroid hormone action at the nuclear level. Ann Intern Med. 1985;102(3):374–384. - PubMed
    1. Piehl S, Heberer T, Balizs G, Scanlan TS, Köhrle J. Development of a validated liquid chromatography/tandem mass spectrometry method for the distinction of thyronine and thyronamine constitutional isomers and for the identification of new deiodinase substrates. Rapid Commun Mass Spectrom. 2008;22(20):3286–3296. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources