The long-term goal of this research is to understand the chemical, pharmacological, and physiological aspects of thyroid hormone action such that safer and more effective therapeutic agents can be developed that act at targets of the thyroid hormone endocrine system. We recently discovered a novel class of endogenous compounds called thyronamines that are chemical derivatives of thyroxine (T4) and may be decarboxylated and deiodinated metabolites of T4. 3-Iodothyronamine (T1AM), the most active member identified to date of this class, has no affinity for the nuclear thyroid hormone receptors TR1 and TR2;instead, T1AM is a potent agonist of an orphan GPCR called TAAR1 and is an inhibitor of catecholamine plasma membrane vesicular packaging transporters. In rodents and humans T1AM is found in circulation and tissues, and measured tissue levels are substantially higher than circulating levels, although it remains possible that the measured circulating levels are "free" and not "total" T1AM. Circulating T1AM is tightly bound to a unique serum binding protein which we have recently identified as apoB-100, the major protein component of low density lipoprotein (LDL) and very low density lipoprotein (VLDL) particles. Acute administration of T1AM rapidly induces hypothermia, bradycardia, and hyperglycemia in rodents. In addition, acute, high-dose T1AM induces a profound fueling shift away from carbohydrates and toward fat burning in Siberian hamsters, a hibernating rodent, as well as mice. This fueling change is characterized by a change in respiratory quotient (RQ) to 0.7 that persists for 48 hours after a single dose of T1AM in the hibernating rodent. T1AM has very unusual pharmacokinetic properties for a biogenic primary phenethylamine. The plasma half-life of T1AM is 5.5 hr in mice whereas half-lives of 1-2 min are the norm for chemically similar biogenic amines such as seratonin and dopamine. In addition, we have found that 2-week daily dosing of T1AM with doses approaching the 5g/kg range lead to significant weight loss in diet-induced obese mice. Results from pair-feeding studies unambiguously demonstrate that the observed chronically administered, low-dose T1AM induced reduction in body weight results from a decrease in energy intake and not an increase in energy expenditure. Thus it appears that T1AM is an endogenous anorectic agent, with a biological activity on feeding behavior similar to leptin and melanocortins, which are endogenous signaling molecules that act via central pathways in the actuate nucleus of the hypothalamus. The research proposed for the next grant period seeks to better define the biosynthetic origins of T1AM, the mechanisms by which it is transported and delivered to tissues, and the nature and mechanism behind the observed reduction in body weight. The research plan is designed around the following specific aims: (1) Identify and characterize T1AM serum binding protein(s);(2) Determine whether T1AM is derived from T4, and whether this conversion happens in the thyroid gland or in the extrathyroidal periphery;and (3) Develop chronic dosing procedures for T1AM and study the effects of chronic T1AM treatment on body weight loss in rodent obesity models. PUBLIC HEALTH RELEVANCE: Thyroid hormone has important actions for maintaining health in both children and adults. These actions must be in balance as both over-and under-abundance of thyroid hormone can result in serious disorders and disease. The primary form of thyroid hormone made in the thyroid gland is thyroxin, which is metabolized into other biologically active products such as iodothyronines and thyronamines. The purpose of this research is to understand the actions of thyroid hormone and its bioactive metabolites at the molecular, cellular, and tissue level such that safer and more effective therapeutic agents that target the actions of thyroid hormone can be developed.