A review of the peripheral levels of regulation by thyroid hormone

Thyroid hormone (TH) regulates many physiological processes that differ between tissues, developmental stages and in response to specific environmental cues. It can therefore play very different signaling roles depending on specific physiological contexts. Much progress has been made in resolving mechanisms for TH signaling over the past 2 decades, and there has been increasing emphasis on the role of peripheral levels of regulation in determining ultimate TH action. This progress has revealed a complex regulatory network, where TH bioavailability and bioactivity are peripherally regulated by sometimes subtle mechanisms at various levels of organization, including membrane receptors and transporters on the cell surface, intracellular deiodinase enzymes, thyroid receptor isoforms and cytosolic thyroid hormone binding proteins, and via accessibility and subtypes of thyroid hormone response elements in the promoters of target genes. The majority of this research comes from disease models, and so the biological relevance of each of these regulatory levels has not been comprehensively explored. This review synthesizes what is known of these local levels of TH regulation, with particular focus on their functional roles in regulating animal response to environmental cues. While thorough analysis for all of these regulatory levels in any one study is currently unrealistic, an appreciation for their collective importance is necessary to frame comparative analyses in a relevant context. This is important because common biomarkers for TH action can have very different meanings, not only for different tissues, but also for individuals, populations and species from different developmental or environmental backgrounds.