REVIEW Emerging role of thyroid hormone metabolites D. Gnocchi, 1 K. R. Steffensen, 1 G. Bruscalupi 2 and P. Parini 1,3 1 Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden 2 Department of Biology and Biotechnology ‘Charles Darwin’, Sapienza University of Rome, Rome, Italy 3 Metabolism Unit, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden Received 19 June 2015, revision requested 28 July 2015, revision received 2 January 2016, accepted 3 January 2016 Correspondence: P. Parini, MD, PhD, Professor, Division of Clinical Chemistry, Department of Laboratory Medicine, and Metabolism Unit, Department of Medicine, Karolinska Institutet at Huddinge University Hospital, Huddinge, S-141 86 Stockholm, Sweden. E-mail: paolo.parini@ki.se Abstract Thyroid hormones (THs) are essential for the regulation of development and metabolism in key organs. THs produce biological effects both by directly affecting gene expression through the interaction with nuclear receptors (genomic effects) and by activating protein kinases and/or ion channels (short-term effects). Such activations can be either direct, in the case of ion channels, or mediated by membrane or cytoplasmic receptors. Short-term-activated signalling pathways often play a role in the regulation of genomic effects. Several TH intermediate metabolites, which were previ- ously considered without biological activity, have now been associated with a broad range of actions, mostly attributable to short-term effects. Here, we give an overview of the physiological roles and mechanisms of action of THs, focusing on the emerging position that TH metabolites are acquiring as important regulators of physiology and metabolism. Keywords genomic effects, metabolic disorders, short-term effects, thyroid hormone metabolites, thyroid hormones. In higher organisms, thyroid hormones (THs), 3,3 0 ,5- triiodo-L-thyronine (T 3 ) and 3,3 0 ,5,5 0 -tetraiodo-L-thyr- onine (thyroxine or T 4 ), are very conserved hormones, and this reflects their key role in the regulation of development and metabolism. THs directly modify gene expression through the interaction with nuclear receptors (genomic effects) and also activate short- term signalling pathways (short-term effects). Thyroid hormones play a central role in the regu- lation of glucose, lipid and cholesterol metabolism, and thus, defects in TH metabolism and in TH-acti- vated signalling pathways may result in severe patho- logical conditions. For such a reason, a deeper knowledge of TH mechanism of action is actually the purpose of several research groups. One of the main objectives of this review was to try to charac- terize TH analogues devoid of thyrotoxic effects, even if the molecules tested up to now turned out to generate side effects. In the last decades, the study of TH metabolites led to important discoveries about their biological role and the signalling pathways they activate. Some of these pathways overlap with those activated by THs, contributing to and probably fine-tuning TH effects, whereas some others seem to be peculiar. A better characterization of the biology of TH metabolites might thus possibly open new therapeutic perspectives to improve the therapeutic strategies for the treatment of metabolic disorders. THs and their metabolites: synthesis, metabolism and transport Thyroid hormones Thyroid hormones are synthesized in the colloid internal part of the thyroid follicles. Iodine is reduced to iodide ion in the intestine, where it enters the © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12648 184 Acta Physiol 2016, 217, 184–216