Keeping it cool: Elucidating the actions of thyronamines in thermoregulation and cardiovascular function

3-Iodothyronamine (3-T1AM) is an endogenous and biologically active cooling substance whose pharmacological actions are opposite to those induced by the classical thermogenic thyroid hormone (TH) T3. Pharmacological doses of 3-T1AM injected into mice lead to profound hypothermia and bradycardia. To date, the mechanisms underlying these effects are still elusive. Given the novel concept that TH can act centrally on thermoregulation and cardiovascular function, we hypothesize that 3-T1AM also affect the central autonomic control of brown fat thermogenesis and heart function. Thus, this project aims to unravel these mechanisms using novel in vivo techniques (e.g. infrared camera, radiotelemetry, blood pressure measurements, stereotaxic injections) to investigate the effect of 3-T1AM and its metabolites in the intact animal. The cellular and tissue localization and characterization of 3-T1AM actions will help to elucidate the underlying molecular mechanisms. In summary, the study will contribute to a better understanding of the counterbalance and physiological homeostasis of thyroid hormone and thyronamine metabolism.

Thyroid hormone is one of the key players in modulating cardiovascular function, blood pressure and body temperature. Thyronamines are decarboxylated thyroid hormone metabolites linking endocrinology, cardiovascular function and metabolism. A single injection of 3-iodothyronamine (3-T1AM) led to rapid and coordinated major decreases in body temperature and heart rate. Several risk factors such as thyroid dysfunction and hypertonia have been identified to predispose to cardiovascular disorders; however, the underlying molecular mechanisms behind the hypothermia and bradycardia induced by 3-T1AM are still not completely understood. In contrast to the acute effects of 3-T1AM, we could not detect a significant change in heart rate, blood pressure, body and brown fat temperature after repeated administration of pharmacological 3-T1AM doses in mice. Although 3-T1AM is rapidly converted to several other metabolites in vivo, these strong and rapid pharmacological responses on cardiovascular function and thermoregulation were solely attributed to 3-T1AM, leaving potential contributions of downstream products untested. Here, our in vivo data conclusively demonstrate that 3-iodothyroacetic acid, the main degradation product of 3-T1AM, does not contribute to the cardiovascular or thermoregulatory effects observed after 3-T1AM administration, suggesting that the oxidative deamination constitutes an important deactivation mechanism for 3-T1AM. The lack of hypothermia and bradycardia clearly indicates that the amino group in the ethylamine side chain is indispensable for the rapid effects of 3-T1AM. However, this project lead to the discovery of an entirely novel hormone called N-acetyl-3-iodothyronamine (NAc-3-T1AM), which is produced by liver and white fat from 3-T1AM, and increases heart rate and blood pressure by activating α-adrenergic signaling on cardiomyocytes, constituting a previously unknown molecular link between thyroid hormone signaling and the autonomic nervous system.