Endogenous 3-Iodothyronamine (T1AM): More Than We Bargained For

Abstract

In 2004, the discovery of a new biogenic amine called 3-iodothyronamine (3-T1AM, or simply T1AM) that possessed interesting biological activity was reported (1). Theoretically a decarboxylation and deiodination product of T4, T1AM was extracted from rodent tissue and blood and was identified using liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS) against authentic synthetic molecular standards. Rodents treated with high single doses of T1AM display a rapidly induced behavioral anergia, hypothermia, reduction in cardiac drive, and hyperglycemia, the mechanism of which involves central nervous system processes (2–4). These hypometabolic actions of T1AM suggest a potential use in ischemic disorders and injuries, and indeed T1AM treatment is neuroprotective in a mouse stroke model (5). Siberian hamsters, a hibernating rodent species, rapidly switch fuel utilization upon T1AM treatment from carbohydrate to pure lipid burning (6). This dramatic effect of single-dose T1AM treatment is sustained for several days and results in selective loss of fat mass and reduction in body weight, suggesting that T1AM may play an important role in regulating energy utilization and metabolism. It has been noted that many of the biological actions of excess T1AM run in the opposite direction of excess T3, or hyperthyroidism, and this and its possible biogenesis from thyroid hormone encourages speculation that T1AM may represent a new and underappreciated arm of the thyroid hormone endocrine axis (7). Since the discovery of T1AM, a prevailing question has been what are the endogenous levels of this putative thyroid hormone metabolite in circulation and tissues? The central importance of this question toward developing a clear understanding of the physiological capacity of T1AM is undeniable; assorted efforts to quantify this substance from tissue and serum samples have been under way for the past 6 yr, and these efforts have met with, at best, limited success (8, 9). Why has the quantitative analysis of what looks on the surface like a fairly ordinary biogenic amine been such a challenge? Research over the past 6 yr has established that T1AM possesses biological properties unlike any other biogenic amine, including an exceptionally long circulating half-life and a tenacious affinity for a serum factor recently identified as apolipoprotein B-100 containing lipoprotein particles (Roy, G., B. Hettinger, T. S. Scanlan, unpublished results). These unanticipated biological properties of T1AM have likely hampered efforts to develop a reliable method of quantitative analysis. However, the past year has brought important new developments— namely two different, yet complementary methods for quantitative assay of endogenous T1AM. The first advance appeared in October, 2010, from Saba et al. (10) at the University of Pisa who reported levels of T1AM in rat tissue and blood as measured by LC/ MS/MS after chemical extraction, and these levels were compared with those of T3 and T4 extracted and quantified by the same method. This approach revealed that rat serum contained 0.30 nM T1AM—a level more than 150 times lower than total T4 and about five times lower than total circulating T3. A few human serum samples were also evaluated with this method and showed similar subnanomolar T1AM concentrations. In contrast, tissue T1AM levels in rat liver, heart, kidney, muscle, and other tissues exceeded T4 and T3 tissue levels by 3to 10-fold depending on the tissue. The principle finding of low circulating and high tissue-associated T1AM concentration suggested that T1AM was either being produced in tissues or accumu-