Abstract
Despite remarkable progress since the molecular characterization of the thyroid hormone receptors (7,8), the mechanism(s) whereby thyroid hormone regulates energy metabolism remain obscure. There have been proposals that thyroid hormone increases the sensitivity to catecholamine in catecholamine responsive tissues, perhaps by increasing the density of the beta-adrenergic receptors on the cell surface (11,12) or by increasing the release of catecholamines both systemically and locally (13). Indeed, earlier studies by Bianco and colleagues (14) have shown that nonshivering thermogenesis from activation of brown adipose tissue is dependant upon both thyroid hormone and catecholamine release at that tissue.
Newer tools and technology are beginning to provide further insight into the mechanisms behind the regulation of energy metabolism by thyroid hormone. The creation of mice that lack either the TR-beta or TR-alpha gene should help in defining which of these receptors is responsible for discrete actions of thyroid hormone on fat and carbohydrate metabolism. For example, Pelletier et al. (15) recently found that mice deficient in TR-alpha have a higher basal metabolic rate and are leaner and more resistant to diet-induced obesity. Because there was evidence of increased conversion of thyroxine (T4) to T3 in these mice, one could postulate that enhanced intracellular formation of T3 acted on the TR-beta receptor to increase metabolism.
Another new tool came from elucidating the crystal structure of the rat alpha 1 TR ligand-binding domain (16). The extension of these and similar studies allowed the development of TR-beta specific agonists, such as GC-1 (17 –19). Unfortunately, this agonist is not completely specific for the TR-beta receptor, and subsequent studies have raised the possibility that some of its observed actions, or lack thereof, are related to its tissue distribution rather than its specificity for the TR-beta receptor (20). Nevertheless, development of newer compounds that are more specific for the TR-beta receptor have shown promise in stimulating metabolic processes without inducing cardiac toxicity (21).
In this issue of Thyroid, Castillo and colleagues (10) take advantage of the TR-beta–specific agonist GC-24 to investigate the mechanism by which this compound regulates metabolism and inhibits weight gain. As expected, GC-24 stimulated gene expression in isolated brown adipocytes based on activation of genes regulated by TR-beta. Primary myocytes were unaffected by GC-24, which is understandable based on a relatively higher expression of TR-alpha in this cell type (22) or the lack of significant uptake of GC-24 in myocytes. However, the real surprise came when they studied the effect of GC-24 in animals placed on a high fat diet. Animals on a regular diet given GC-24 had reduced weight gain and enhanced metabolic rates. Animals on a high fat diet did not have significant changes in gene expression in brown adipose tissue or skeletal muscle. Additionally, the energy expenditure in the animals treated with GC-24 and on a high fat diet was no different from untreated animals on this diet. Yet, the animals on the high fat diet treated with GC-24 did not gain as much weight as the animals on the high fat diet alone. What, then, is the explanation for these findings? It was not due to a decrease in caloric intake, but could it be related to a decrease in food absorption? Do these TR-beta specific agonists have effects on gastrointestinal function? Is it possible that there are nongenomic effects of GC-24 that alter food distribution and utilization without changing overall energy expenditure? Or, are the measurements of energy expenditure still too crude to measure subtle differences that are important for overall control of body weight? While the publication on the potential benefit of TR-beta–specific agonists is now 10 years old (20), we still have much to learn about their mode of action.