PROJECT SUMMARY 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). 3-Iodothyronamine (T1AM), the most active member identified to date of this class, has no affinity for the nuclear thyroid hormone receptors TRa and TRb;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. Circulating T1AM is tightly bound to a unique serum binding protein and total T1AM levels are on par with those of total T4. T1AM is found in a variety of tissues and is present in the thyroid gland and white adipose tissue at significantly enriched levels. T1AM rapidly induces hypothermia, bradycardia, and hyperglycemia in rodents. In addition, 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. Our recent work shows that in addition to similarities in chemical structure, T1AM shares striking similarities in production level, distribution, and actions with the thyroid hormones T4 and T3. This leads to a new working hypothesis that T1AM is a novel hormone with biological properties that will closely resemble those of other members of the steroid/thyroid hormone class. The research proposed for the next grant period seeks to directly test this hypothesis and is organized into the following Specific Aims: (1) Identify and characterize T1AM serum binding protein;(2) Determine whether T1AM is derived from T4, and whether this conversion happens in the thyroid gland or in the extrathyroidal periphery;(3) Develop chronic dosing procedures for T1AM and study resulting changes in blood chemistry and metabolic read-outs;(4) Determine and characterize T1AM-induced gene expression changes.