Endocrine Abstracts

We have recently discovered a novel, endogenous iodine containing aryl-ethylamine derivative that we believe is a metabolite of thyroxine, the major form of thyroid hormone produced in the thyroid gland of vertebrates. This compound is 3-iodothyronamine (T1AM), and it does not bind to or activate nuclear thyroid hormone receptors – the established target receptors of thyroid hormones – but instead functions as a potent agonist of trace amine associated receptor 1 (TAAR1), an orphan G protein-coupled receptor (GPCR), to rapidly modulate cAMP levels in cells expressing the GPCR. In addition, T1AM is an agonist of alpha-2a-adrenergic receptors and inhibits certain plasma membrane and vesicular monoamine transporters; however, it is not clear that any of these receptors or transporters are physiological targets of T1AM. The in vivo pharmacology of T1AM in many ways induces physiological changes that occur naturally in hibernating animals. Rodents treated with single pharmacological doses of T1AM display profound changes in thermal regulation, cardiac performance, and blood glucose homeostasis. Similar to the in vitro cell-based experiments, these in vivo effects occur with rapid kinetics suggesting that they are mediated by non-transcriptional mechanisms. In addition to displaying all of the above effects, hibernating rodents treated with single-dose T1AM demonstrate a fuel utilization preference away from carbohydrates and toward lipids. This presentation will focus on the pharmacological and physiological properties of T1AM and explore the potential therapeutic utility of this biogenic amine.