Thyroid hormone is essential for the regulation of a range of processes including neural development, bone development, somatic growth, cardiac function, and metabolism. The regulation of thyroid hormone action is accomplished through tight control of thyroid hormone production by the hypothalamic-pituitary-thyroid axis, local and systemic activation and inactivation of thyroid hormone by deiodinase enzymes, and differential expression of thyroid hormone receptor (TR) isoforms in target tissues. A variety of animal models, and observations from humans with deficits of thyroid hormone action, have identified specific roles for thyroid hormone receptor isoforms. Many actions of thyroid hormone can be mediated by either TRalpha or beta, but others are quite specific for one TR isoform. TR isoform-specific actions have been identified in the brain, developing ear, retina, pituitary, heart, liver, and in brown adipose tissue (BAT). This proposal will utilize genetic models and pharmacological agents to identify and study the mechanism of TR isoform-specific actions in metabolism, adaptive thermogenesis, and cardiac function. The proposed studies will especially focus on the integration of thyroid-mediated signals in metabolic control with actions in white adipose tissue (WAT), BAT, liver, and heart. The importance of TRalpha in adrenergic signaling is demonstrated by our TRalphaP398H mutant mouse, with the phenotype of visceral obesity, insulin resistance, fatty liver, defective adaptive thermogenesis, and a marked deficit of catecholamine-mediated lipolysis in WAT. The specific aims of this study include; (1) To characterize the role ofTRalpha and beta in metabolic regulation in WAT and BAT, focusing on the action of TRalpha in mediating catecholamine sensitivity, (2) To characterize the metabolic phenotype in TRalphaP398H mutant mice including; serum lipoprotein profile, hepatic gene expression, body fat composition, insulin sensitivity, and response to changes in thyroid status, gonadal status and with PPARalpha and gamma agonist treatment, (3) To characterize the role of TRalpha in cardiac function and gene expression, including dynamic effects of exercise and the short and long-term influence of catecholamines on the heart, (4) To utilize in vitro models to determine the mechanisms of TRalpha -specific gene regulation and especially the influence of the TRalpha dominant negative mutations on gene regulation. The results of these studies will provide important insights into the role of TR in metabolic signaling, with implications for understanding underlying mechanisms and developing novel treatments for obesity, insulin resistance, and cardiovascular disease.