Endocrine Abstracts

3-Iodothyronamine (T1AM) is a novel endogenous derivative of thyroid hormone (TH), recently described by Scanlan et al. (Nat. Med. 10: 638, 2004). In vitro, T1AM can stimulate the production of cAMP via activation of a heterologously expressed G protein-coupled receptor (GPCR) now referred to as trace amine-associated receptor 1 (TAAR1; Lindemann et al. Genomics 85: 372, 2005). In adult, unanesthetized C57Bl6/J mice, T1AM produces profound and long-lasting anergia, bradycardia, hypophagia, and hypothermia (−10 °C @ T_ambi=24 °C). In an effort to better understand these manifestations of T1AM, we evaluated its effect on metabolic rate. In addition, experiments were performed to characterize T1AM’s effect on blood sugar and the pancreatic hormones glucagon and insulin. Finally, the effect of T1AM on an in vitro cellular model of glucose-stimulated insulin release was investigated. Within minutes of its injection (i.p.) into male mice housed at T_amb=22 °C, and prior to the development of hypothermia, T1AM (25 mg/kg) reversibly depressed metabolic rate ∼50% of vehicle-injected controls, as measured by oxygen consumption (ml/g/min). Also within minutes, T1AM dose-dependently elevated blood sugar, reaching a maximum of ∼320 mg/dL, almost 3 times normal, by 3.5 hrs post injection. By 2 hrs post-injection, T1AM had produced a dose-dependent increase in circulating glucagon (∼400 pg/ml) that was nearly twice the vehicle controls. Furthermore, T1AM (50 mg/kg) administered to fasted mice (26 hrs) prior to their receiving a bolus of D-glucose (3 g/kg, i.p.) blocked the sugar’s ability to stimulate circulating insulin levels compared to vehicle-treated mice. Finally, in vitro studies revealed T1AM could dose-dependently prevent glucose-stimulated insulin release from cultures of rat INS1823/13 insulinoma cells. Taken together, these results support the thesis that T1AM is a rapid-acting novel modulator of metabolism with actions opposite in direction to those of TH. As such, T1AM and its related compounds may signal via one or more GPCRs to fine-tune TH’s effects and thereby help the organism efficiently meet its metabolic needs minute-to-minute.