Chapter One Local Regulation of Thyroid Hormone Signaling

Thyroid hormone (TH) plays important signaling roles in mammalian growth, development, and thermogenesis. Traditionally its actions were thought to be regulated predominately through modulation of free plasma concentrations, intracellular breakdown by deiodinase enzymes and nuclear processing by thyroid receptors. In the past decade, however, there has been some departure from this classical model, whereby regulatory changes at different levels of organization simultaneously modulate its bioavailability and bioactivity. Here I review the recent literature to emphasize how subtle changes at these various levels of regulation can underlie tissue-specific and temporal (development and disease) changes in mammalian systems. For instance, it has become increasingly clear that TH acts both centrally to control sympathetic output and peripherally to regulate metabolism in target tissues. An interesting caveat is that central actions by TH may simultaneously alter its effects at peripheral tissues. In addition to T3, other TH derivatives (e.g., rT₃ and T₂) have also been shown to possess physiological activity, meaning intracellular processing by deiodinase enzymes is likely more complex than previously thought. Importantly, these TH derivatives can act both through the traditional genomic thyroid receptor pathways for transcriptional control, or more direct, fast-acting, nongenomic mechanisms. This fine-tuning means tissue-specific, ontogenic, and pathological changes in TH processing at any one level can have different consequences for TH bioavailability and bioactivity depending on parallel changes in upstream and/or downstream pathways.