The thyroid hormones (THs, thyroxine (T4) and triiodothyronine (T3)) have important effects on development, growth, and metabolism (1, 2). Some of the most prominent effects of TH occur during fetal development and early childhood. In humans, the early developmental role of TH is illustrated by the distinctive clinical features of cretinism observed in iodine-deficient areas. In childhood, lack of TH can cause delayed growth. However, in this latter case, many of the effects of TH may be metabolic rather than developmental, as growth is restored rapidly after the institution of TH treatment. In adults, the primary effects of THs are manifested by alterations in metabolism. These effects include changes in oxygen consumption, protein, carbohydrate, lipid, and vitamin metabolism. The clinical features of hypothyroidism and hyperthyroidism emphasize the pleiotropic effects of these hormones on many different pathways and target organs.

At the clinical level, identification of quantitative markers of TH action has been difficult (3). At the extreme ends of the clinical spectrum, which extends from hypothyroidism to hyperthyroidism, the diagnosis of a thyroid abnormality is usually apparent. Clinical suspicion of a thyroid abnormality can be confirmed using laboratory tests for THs and thyroid stimulating hormone (TSH). However, more subtle forms of thyroid dysfunction, such as subclinical hypothyroidism or hyperthyroidism, pose a greater challenge. Although the level of circulating TSH provides a sensitive and quantitative indicator of TH action at the level of the hypothalamic-pituitary axis, there are few reliable peripheral markers of TH action (3,4). The effect of TH on basal metabolism has been re-evaluated using measurements of resting energy expenditure (REE). In hypothyroid patients taking varying levels of TH replacement, there is a strong inverse correlation between REE and the TSH level (5). Nevertheless, TSH remains the most sensitive and useful indicator of TH action. As discussed below, tissue-selective metabolism of THs, and variable tissue sensitivity to their effects, underscores the need to develop additional markers of TH activity in peripheral tissues.

Since the initial description of TH effects on metabolic rate more than 100 years ago (6), many theories have been proposed to explain its mechanism of hormone action. The proposed models include: uncoupling oxidative phosphorylation, stimulation of energy expenditure by the activation of Na+-K+ ATPase activity, and direct modulation of TH transporters and enzymes in the plasma membrane and mitochondria (7). Recently, there has been increasing evidence for non-genomic actions (see later under non-genomic actions of TH) (7); however, the major effects of TH occur via nuclear receptors that mediate changes in gene expression.

In 1966, Tata proposed that TH increased gene expression with attendant increases in protein synthesis and enzyme activity (8). In 1972, high affinity nuclear binding sites for TH were documented (Kd approximately 10-10 M for T3) (9,10). The receptor-binding affinity of various THs and analogues correlated with their biologic potencies, consistent with the view that most biologic effects are mediated via the nuclear receptor (11– 13). Over the past 20 years, there has been a dramatic surge of new information on TH action resulting from the cloning of the TH receptors (14 – 15), the identification of regulatory DNA elements in TH responsive genes (2, 16), and the generation of TR isoform knockout mice (17, 18). In this chapter, we will focus on our current understanding of nuclear TH receptor action.