Thyroid hormone is critical for the development of different tis sues, in particular the brain, but it is also essential for an optimal function of most tissues in adult life. It is probably the most important factor regulating thermogenesis, as reflected by the increase in the basal metabolic rate in hyperthyroid subjects and the decrease observed in hypothyroid individuals. Thyroid hormone increases the synthesis as well the degradation of proteins, lipids, and carbohydrates, predominantly by stimulating the expression of key enzymes involved in these processes. Examples of these are the lipogenic enzymes, malic enzyme, fatty acid synthase, and glucose- 6- phosphate dehydrogenase, and the gluconeogenic enzyme phosphoenolpyruvate carboxykinase.
Special forms of substrate cycling take place between the cytoplasm and the mitochondrion, such as the glycerol- 3- phosphate/ dihydroxyacetone phosphate shuttle in which cytoplasmic and mitochondrial α- glycerophosphate dehydrogenase (αGPD) isoenzymes participate. This represents one way to enable oxidation of cytoplasmic NADH in the mitochondrion, which is impermeable to this cofactor. Thyroid hormone stimulates the expression of mitochondrial αGPD, and the increased electron flow via this enzyme is associated with an increased heat production relative to adenosine triphosphate (ATP) synthesis.
Thyroid hormone also increases the activity of Na+,K+- ATPase, an enzyme located in the plasma membrane of all tissues, in particular kidney, heart, and skeletal muscle, which is responsible for the maintenance of the Na+ and K+ gradients across this membrane. In myocytes, the increased Na+,K+- ATPase activity accelerates the repolarization of the sarcolemma following a depolarization stimulus that contributes to the tachycardia induced by thyroid hormone.
Another important target for thyroid hormone action is the Ca2+- ATPase located in the sarcoplasmic reticulum of muscle cells. Innervation of the myocyte triggers the release of large amounts of Ca2+ from the sarcoplasmic reticulum into the cytoplasm, where it binds to the actomyosin complex that initiates contraction. There are two Ca2+- ATPase isoenzymes, SERCA1 that is characteristic for fast- type skeletal muscle and SERCA2 that is characteristic for slow- type skeletal muscle and heart. T3 increases Ca2+- ATPase activity by stimulating the transcription of both SERCA1 and SERCA2 genes, which explains the increased relaxation rate of the muscle induced by T3.
It has been estimated that excess Ca2+ cycling in contracting muscle may account for up to 50% of the T3- dependent energy expenditure during work or shivering. The remainder of the T3- induced energy turnover in contracting muscle is largely accounted for by the change in the expression of two forms of the myosin heavy chain which are characterized by high (MHCα) and low (MHCβ) ATPase activities and contraction rates. T3 stimulates the expression of the MHCα gene, whereas it inhibits the expression of the MHCβ gene. A similar T3- induced shift in MHC expression is also observed in the heart.
In addition, T3 increases the expression of the uncoupling protein UCP1 in brown adipose tissue (BAT). This is an important mechanism by which T3 stimulates non- shivering cold- induced thermogenesis. UCP1 is an ion transporter located in the inner mitochondrial membrane which dissipates the proton gradient over this membrane generated by the respiratory chain, producing heat instead of ATP. Significant BAT depots have been demonstrated in the neck and shoulder region of normal adults, especially in cold- adapted subjects and more so in younger females than in older males. Cold exposure leads to a dramatic stimulation of D2 expression in BAT, and the resultant induction of local T3 pro duction plays an important role in the stimulation of BAT activity. This includes increased mobilization and burning of lipids as well as stimulated UCP1 expression, together resulting in a major increase in heat production.
UCP1 is expressed exclusively in BAT. Other members of the UCP family are expressed in other human tissues, including UCP2 in a variety of tissues including heart and skeletal muscle, UCP3 in skeletal muscle, and UCP4 and UCP5 in brain. The expression of UCP2 and UCP3 is also under positive control of thyroid hormone, but their role in T3- induced thermogenesis has not been established.
The regulation of the mitochondrial proteins UCP1 and αGPD by thyroid hormone is mediated predominantly by interaction of the nuclear T3 receptor with the promoters of these genes. However, there is also evidence for direct effects of thyroid hormone on the mitochondria, the mechanism of which is incompletely understood but may involve interaction of T3 and other iodothyronines such as 3,3’- T2 and 3,5- T2 with cytochrome c oxidase. Many studies have reported effects of thyroid hormone on cellular processes that are not mediated by the nuclear T3 receptor, including stimulation of transport of glucose, amino acids, and ions over the cell membrane, stimulation of actin polymerization in neurons, and stimulation of mitogen- activated protein kinase activity. The last is mediated by the binding of iodothyronines to integrin, a plasma membrane receptor. The interested reader is referred to an extensive review of these extranuclear actions of thyroid hormone.
Specific thyroid hormone- binding sites have also been detected in the cytoplasm in different tissues. A notable example is the NADPH- dependent cytoplasmic thyroid hormone- binding protein present in rat liver, which appears to be important for the trafficking of thyroid hormone to the nucleus or mitochondria.
