3-Iodothyroacetic acid lacks thermoregulatory and cardiovascular effects in vivo

Abstract

Background and purpose: 3-Iodothyronamine (3-T1 AM) is an endogenous thyroid hormone derivative reported to induce strong hypothermia and bradycardia within minutes upon injection in rodents. Although 3-T1 AM is rapidly converted to several other metabolites in vivo, these strong pharmacological responses were solely attributed to 3-T1 AM, leaving potential contributions of downstream products untested. We therefore examined the cardiometabolic effects of 3-iodothyroacetic acid (TA1 ), the main degradation product of 3-T1 AM.

Experimental approach: We used a sensitive implantable radiotelemetry system in C57/Bl6J mice to study the effects of TA1 on body temperature and heart rate, as well as other metabolic parameters.

Key results: Interestingly, despite using pharmacological TA1 doses, we observed no effects on heart rate or body temperature after a single TA1 injection (50 mg·kg(-1) , i.p.) compared to sham-injected controls. Repeated administration of TA1 (5 mg·kg(-1) , i.p. for 7 days) likewise did not alter body weight, food and water intake, heart rate, blood pressure, brown adipose tissue (BAT) thermogenesis or body temperature. Moreover, mRNA expression of tissue specific genes in heart, kidney, liver, BAT and lung was also not altered by TA1 compared to sham-injected controls.

Conclusions and implications: Our data therefore conclusively demonstrate that TA1 does not contribute to the cardiovascular or thermoregulatory effects observed after 3-T1 AM administration in mice, suggesting that the oxidative deamination constitutes an important deactivation mechanism for 3-T1 AM with possible implications for cardiovascular and thermoregulatory functions.

Figure 1

Effects of single TA₁ injection on heart rate and body temperature. (A) Body temperature and (B) heart rate were measured using radiotelemetry before and during 6 h post injection (X) in TA₁-injected (50 mg·kg⁻¹) compared with sham-injected animals. Data are presented as mean ± SEM of 8–12 male mice for each group. The area under the curve was calculated for the first hour post injection, including a positive control using 3-T₁AM (50 mg·kg⁻¹, grey bars). *P < 0.05 (Student's t-test)

Figure 2

Effects of repeated TA₁ treatment on metabolic effects, cardiac function and thermoregulation. (A) There was no significant difference between sham-injected and TA₁-injected animals (5 mg·kg⁻¹) in body weight, food or water intake. (B) No significant effect was observed on heart rate and blood pressure (systolic, diastolic and mean arterial blood pressure). (C) Infrared thermography was used to quantify surface heat over the interscapular brown fat depot, inner ear and tail tip. Data are presented as the average of the last three injection days of five animals for each group, dashed line indicates the mean value of all animals before treatment (n.s.: P < 0.05).

Figure 3

Effect of repeated TA₁ treatment on gene expression and thyroid hormone levels. (A) mRNA expression of TH-regulated genes assessed by real-time PCR, (B) total T₄ and T₃ serum levels, and (C) mRNA expression of cardiac, blood pressure and metabolic genes in sham-injected and TA₁-injected (5 mg·kg⁻¹) animals. Data are represented as mean ± SEM of five animals for each group. ACC1/2, acetyl-CoA carboxylase; ADRB1/2/3, β_1/2/3-adrenoceptors; ANGT, angiotensinogen; CHRM2, muscarinic M₂ receptor; DIO 1/2, deiodinase type 1/2; HCN2/4; potassium/sodium hyperpolarization-activated cyclic nucleotide-gated ion channel 2/4; Klf2, krüppel-like factor 2; MCD, malonyl-CoA decarboxylase; PEPCK, phosphoenolpyruvate carboxykinase; PYRK, pyruvate kinase; SecS, selenoprotein S; UCP1, uncoupling protein 1. ***P < 0.001 (Student's t-test).