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This study was supported by grants from PAPIIT 208511 and Consejo Nacional de Ciencia y Tecnologia (CONACYT) 166357. A.M. received Fellowship 227955 from CONACYT. Work from the V.L. laboratory is funded by the French Ministry of Research and Technology (Agence Nationale de la Recherche program) and the Ministry of Ecology (Programme National de Recherche sur les Perturbateurs Endocriniens program). A.M. is a doctoral student from Programa de Doctorado en Ciencias Biomedicas, Universidad Nacional Autonoma de Mexico. Endocrine soc Chevy chase; International audience; Several liganded nuclear receptors have alternative ligands acting in a tissue-specific fashion and playing important biological roles. We present evidence that 3,5-diiodothyronine (T-2), a naturally occurring iodothyronine that results from T-3 outer-ring deiodination, is an alternative ligand for thyroid hormone receptor beta 1 (TR beta 1). In tilapia, 2TR beta isoforms differing by 9 amino acids in the ligand-binding domain were cloned. Binding and transactivation studies showed that T-2 activates the human and the long tilapia TR beta 1 isoform, but not the short one. A chimeric human TR beta 1 (hTR beta 1) that contained the 9-amino-acid insert showed no response to T-2, suggesting that the conformation of the hTR beta 1 naturally allows T-2 binding and that other regions of the receptor are implicated in TR activation by T-2. Indeed, further analysis showed that the N terminus is essential for T-2-mediated transactivation but not for that by T-3 in the long and hTR beta 1, suggesting a functional interaction between the N-terminal domain and the insertion in the ligand-binding domain. To establish the functional relevance of T-2-mediated TR beta 1 binding and activation, mRNA expression and its regulation by T-2 and T-3 was evaluated for both isoforms. Our data show that long TR beta 1 expression is 106-fold higher than that of the short isoform, and T-3 and T-2 differentially regulate the expression of these 2 TR beta 1 isoforms in vivo. Taken together, our results prompted a reevaluation of the role and mechanism of action of thyroid hormone metabolites previously believed to be inactive. More generally, we propose that classical liganded receptors are only partially locked to very specific ligands and that alternative ligands may play a role in the tissue-specific action of receptors.