Thyroid hormone and the adipocyte.

The role of thyroid hormone in the regulation of lipid metabolism has been of interest ever since a relationship between thyroidal state and body weight was identified. The myxedema report published in 1888 proposed that obesity is a criterion for the diagnosis of hypothyroidism (1). Several years later, Murray (2) reported that overtreatment with thyroid extract could induce all the signs and symptoms of hyperthyroidism except exophthalmos and goiter. Thus, there is a long-standing history associating thyroid dysfunction with alterations in body weight and, by inference, with changes in body fat content. The relationship between body fat, thyroidal state, and metabolism became firmly established with the measurement of basal metabolic rates (3). These studies clearly showed that hyperthyroidism was associated with an increase in metabolic rate (oxygen consumption) and that hypothyroidism was associated with a decrease in metabolic rate. Moreover, the changes in metabolic rate were associated with alterations in lipid and carbohydrate metabolism (4). However, the mechanisms leading to these changes are complex because alterations in thyroidal state affect multiple systems and multiple target tissues. Some insight into the thyroidal regulation of fat tissue has been obtained from animal studies. Thyroid hormone regulates the rate of both fat synthesis (lipogenesis) and lipolysis. For example, Diamant et al. (5) demonstrated that the enzymes in the lipogenic pathway are regulated by thyroid hormone in both the liver and adipose tissue. A fat-free diet rich in sucrose also induces these enzymes (6). Moreover, we showed that thyroid hormone and dietary sucrose act synergistically to control the content of these enzymes (7). Therefore, it is not surprising that total body lipogenesis is enhanced in hyperthyroid rats (8). However, earlier studies have suggested that hyperthyroidism may lead to decreased lipogenesis in white adipose tissue (9). Thus, the effect of thyroidal state on the overall contribution of white adipose tissue to lipogenesis is not clear and is complicated further by the dietary status of the animal. The role of thyroid hormone in regulating lipolysis is also complex and controversial. Ben Cheikh et al. (10) showed that in the fed state adipocytes from hypothyroid rats had markedly reduced sensitivity to catecholamine-induced lipolysis, whereas there was no change in catecholamine-induced lipolysis in adipocytes from hyperthyroid rats. They noted similar findings in the basal rates of lipolysis from adipocytes obtained in either the fed or fasting state. The lack of enhanced rates of lipolysis from hyperthyroid adipocytes in that study stands in contrast to the known weight loss associated with hyperthyroidism and the loss of body fat. For example, Oppenheimer et al. (11) showed that the loss of body fat occurred early after administration of thyroid hormone and coincided with increased total body oxygen consumption. Thus, hyperthyroidism must be associated with enhanced lipolysis while at the same time stimulating other metabolic pathways. There are also a few human studies that have looked at the effect of thyroid hormone on adipocyte lipolysis. These in vitro studies showed that basal lipolysis is unchanged in hyperthyroid patients, but -adrenergic-stimulated lipolysis was markedly enhanced in adipocytes from hyperthyroid subjects (12). In part, this enhanced response is related to enhanced2-adrenoceptor number on adipocytes (13). However, almost all of the human studies rely on in vitro techniques to examine the adipocyte responses. With the advent of newer technology, some of the controversial issues discussed above will be answered. In this issue of JCEM, Haluzik et al. (14) make use of a new microdialysis technique to study the effect of thyroidal state on lipolysis in vivo. They measured local release of norepinephrine (NE) and showed that NE concentrations at the adipocyte are greater in hyperthyroid patients and significantly less in hypothyroid patients compared with euthyroid controls. Moreover, they show that perfusion with isoprenaline leads to greater NE release in hyperthyroid patients with a concomitant greater rate of lipolysis. Their study clearly