Cellular thyroid hormone signalling mechanisms during weight maintenance

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Thyroid hormone and their metabolites (THM) are key regulators of energy expenditure (EE) and metabolism. Weight changes and obesity alter circulating THM to some extent and lead to adaptations of the hypothalamus-pituitary-thyroid (HPT) axis and its feedback regulation. Intracellular metabolism and action of THM is affected both by changes of circulating THM and by altered nutritional, neuronal, immunological and endocrine signals reaching target cells and tissues relevant to EE. During the first funding period we established sensitive assays of metabolically relevant protein hormones and THM in the blood of Z-project patients as well as in the blood and tissues of mice undergoing the MAINTAIN weight cycling protocol. As serum THM showed only modest changes we will now test the hypothesis that high intracellular levels of EE-regulating THM (e.g. 3,5T2 and 3T1AM), locally generated by deiodinase (D) activities contribute to and adapt to the metabolic response by intracrine THM signalling mechanisms. These might be regulated primarily by other factors than circulating serum THM. As miR-146 is known to antagonize signalling of TRβ, the isoform involved in THM regulated lipid metabolism, brown adipose tissue (BAT) thermogenesis and HPT feedback regulation, we will explore in vivo and in vitro whether miR146 interferes with energy metabolism by reducing intracrine THM signalling cascades. These as well as targets for action of the intracellularly abundant 3,5T2 will be analyzed in cellular models. Immunological detection methods will be developed for tissue-derived hormones 3,5T2 and irisin. We will continue to contribute our expertise in multiplex and LC-MS/MS hormone measurements for the Z-study and other CRG projects. Our project will provide insight into mechanisms of action of intracellular abundant THM, which might prove useful as diagnostic tools and/or therapeutic strategies for weight maintenance.