The effects of the thyroid hormones can be divided into two broad classes. There are effects on the metabolism and specialized functions of cell typified by, but by no means limited to, the regulation of the basal metabolic rate. Secondly, there are effects on cell growth and differentiation, originally elucidated in the context of the metamorphosis of the aquatic legless tadpole into an amphibious four-legged frog. These effects, by definition, occur only during a certain window of time during the developmental process. The majority of effects of thy roid hormones are now believed to be mediated through interactions of T3 with one of its nuclear receptors resulting in changes in gene expression. It is appropriate, therefore, that we begin this section with a consideration of the nuclear receptor for T3.

 A. Thyroid Hormone Receptor

 It is well accepted that the thyroid hormones cross the plasma membranes of target cells, not by diffusion, but with the help of specific transport proteins. Although several proteins have been implicated, the one that has received the most attention is the same protein that was recently shown to be involved in the secretion of T4 and T3 from the thyrocyte, the monocarboxylate transporter, MCT8. In humans, mutations in this protein result in neurological symptoms, indicating the importance of its presence in neural tissue in particular. In other target tissues, the role of MCT8 and other possible thyroid hormone transporters is currently under investigation.

The nuclear receptor for thyroid hormones, TR, belongs to the nuclear receptor superfamily which in humans contains 48 members, including the receptors for the classical steroid hormones, vitamin D, and several nonsteroidal lipids. TR affinity for T3 is 10–15 times greater than for T4, providing the basis for the designation of T4 as an inactive prohormone from which is derived the active hormone, T3.

There are several isoforms of TR, of which the four best studied are represented in Figure 1. The isoforms are encoded by two genes, THRA (TRα1 and TRα2) on chromosome 17 and THRB (TRβ1 and TRβ2) on chromosome 3. The subtypes of each gene product are the result of alternative splicing during mRNA processing. TRα1 and the two TRβ isoforms have approximately the same affinity for T3 and ability to activate gene transcription. TRα2 does not bind T3 due to the splicing of an alternate exon at the carboxy terminus, inactivating the ligand binding domain; the alteration at the C terminus of TRα2 also disrupts its dimerization properties, leading to changes in its ability to bind DNA.

Fig1. Thyroid hormone receptor (TR) isoforms. At the top of the figure is shown the generic organization of the nuclear receptor family of proteins with the DNA-binding and ligand binding domains indicated. Four TR isoforms are depicted below with differences in primary structure indicated by different colors. The genes THRA (chromosome 17) and THRB (chromosome 3) encode TRα and TRβ, respectively. The subtypes of each gene product are the result of alternative splicing during mRNA processing. The functional characteristics of each TR isoform are indicated on the right side of the figure.

TRα and TRβ isoforms are expressed differentially during development with TRα1 appearing in early stages and TRβ forms at later stages. The TR isoforms are expressed widely and in overlapping patterns in adult tissues, although neither appears to be expressed in the testis. TRα1 and TRα2 are present in relatively high concentrations in brain, skeletal and cardiac muscle, kidney, lungs, liver, and brown fat whereas the TRβ2 isoform is predominantly expressed in the anterior pituitary gland, hypothalamus, retina, and the cochlea.

Studies of mice in which one or more of the isoforms has been removed by targeted gene deletion have resulted in complex phenotypes due, in part, to redundancy of the expression and function of the isoforms. It is likely that both TRβ isoforms participate in the regulation of TRH and TSH secretion by T3 and in cochlear development. Deletions of TRα1 reveal that this isoform is important in cardiac and intestinal function, and in temperature adaptation to cold. When both Thra and Thrb genes are inactivated in mice, the phenotype differs from that in the complete absence of T3, due to the activity of unliganded TR in repressing expression of certain genes (see below). In general these studies show that TRα, TRβ1, and TRβ2 have specific functions but can also substitute for one another in some cases.

As described in Chapter 1, the ability to bind to regulatory regions (elements; RE) of target genes is a critical component of the action of all steroid nuclear receptors, a class which includes the thyroid hormone receptor even though the hormone itself is not a steroid. One hall mark of the thyroid receptor is that, even in the absence of ligand, the unoccupied receptor is associated with the nuclear chromatin; this is because the receptor is not anchored to cytoplasmic proteins and its nuclear localization signal is operative. Although the TR can bind to DNA as a homodimer, the TR-RXR heterodimer is much more common and we will limit our discussion to this form of the receptor complex.

The unliganded thyroid receptor is function ally active and can repress the transcription of genes that are activated by T3, as shown in the top portion of Figure2. In the absence of T3, the unliganded TR-RXR heterodimer is shown binding to a TRE and corepressor proteins. This complex blocks transcription. When T3 is bound, the heterodimer replaces corepressors with coactivators, alowing recruitment of additional transcription factors to the transcriptional start site and increased transcription. Similar molecular mechanisms operate with genes whose expression is decreased by T3.

Fig2. Transcriptional activation and repression by T3. A simplified model for the switch from the repressed to the activated state of a gene whose expression is stimulated by T3. In the absence of the hormone, the unliganded receptor heterodimer (RXR-TR) binds to a specific regulatory element (TRE) upstream of the transcriptional start site (bold arrow) and recruits one or more co-repressor proteins (CoR), which inhibit the activity of the transcriptional complex. When T3 is present, the hormone-receptor complex releases the corepressor(s) and recruits coactivators (CoA), which stimulate the activity of the transcriptional complex. B. Measurement of transcriptional activation (purple bars) shown in panel A. The blue bars show the measurement of transcriptional activity of genes whose expression is repressed by T3. In this case, the unliganded receptor heterodimer, bound to a negative TRE, recruits coactivators and, in the presence of T3, recruits corepressors, diminishing transcriptional activity (not shown in A). The dashed line represents a “basal state” in which intermediate amounts of T3 are present.

B. Membrane Mediated Actions of Thyroid Hormone

 The ability of physiological concentrations of thyroid hormone to bring about cellular changes within seconds to minutes, rather than the hours required for genomic effects, has been the subject of research for many years and several high affinity binding sites for the hormone have been studied. Recently, attention has focused on integrin αvβ3, a structural protein of the plasma mem brane which has a binding domain for iodothyronines and can initiate events leading to cell division and angiogenesis. In other studies, T3 activates PI3 kinase and MAP kinase pathways in the cytoplasm, affecting the phosphorylation and trafficking of specific proteins and leading in some cases to changes in the expression of certain genes. Rapid actions of thyroid hormone that are manifested at the plasma include those on glucose uptake, Ca2+-ATPase, Na+/H+ antiporter, endocytosis and the activity of the EGF (epidermal growth factor) receptor.

C. Basal Metabolic Rate and Thermogenesis

The basic metabolic rate (BMR) is a measure of the energy expended by an organism at rest, under thermal neutral conditions and after completion of the intestinal absorption of food. BMR is proportional to both the oxygen consumption and the surface area (body volume) of the organism. In warm-blooded animals, the conversion of chemical energy to heat is required to maintain constant internal termperature in response to cold. This is known as adaptive thermogenesis. One of the earliest recognized hallmarks of thyroid hormone action was its ability to stimulate the metabolic rate by increasing oxygen consumption, particularly in the skeletal muscle, cardiac muscle, liver, gastrointestinal tissues, and kidney. Typical data obtained in the rat are shown in Figure 3. In humans the BMR can vary as much as two- to three-fold depending on thyroid hormone status. In fact, for the first half of the twentieth century, until the development of the radioimmunoas say in the 1960s, BMR was the standard metric for determining thyroid status. Despite this long history, however, it has not yet been possible to identify a unifying explanation to describe the effects of thyroid hormone on BMR or on adaptive thermogenesis, i.e., the increase in metabolic rate to maintain constant body temperature in response to environmental cold. It seems likely, however, that both the uncoupling of oxidative phosphorylation (increasing the amount of heat per ATP molecule) and increasing the utilization of ATP, such as through the stimulation of Na+/K+ -ATPase activity or other ion channels, contribute to increased heat production. T3 has wide-ranging effects on intermediary metabolism, as discussed in the following, which also play a role in modulating BMR and mediating adaptive thermogenesis.

Fig3. Thyroid hormone and O2 consumption. Oxygen consumption in rat tissues was measured in thyroidectomized rats with (purple) and without (green) treatment with T4 for 4–6 days. The basis of the paradoxical response of the pituitary has not been elucidated. Modified from Barker, S.B. (1964) Physiological activity of thyroid hormones and analogues. In The Thyroid Gland (R. Pitt-Rivers and W. R. Trotter, eds.), p. 200, Butterworths, London.

Brown adipose tissue (BAT) is distinguished from white adipose tissue by the nature of its lipid stores, its much larger number of mitochondria, its richer supply of capillaries, and its synthesis of the uncoupling protein, UCP1. These characteristics render BAT an excellent thermogenic tissue. It also contains a substantial amount of D2 (Type II iodothyronine deiodinase) enabling it to generate T3 within its cells. BAT has long been recognized as the thermogenic target for T3 in small mammals and young humans, but its presence and role in adult humans was questionable. Recently, however, the availability of imaging techniques has revealed physiologically important amounts of BAT in adult humans, suggesting that this tissue is the site of T3-regulated adaptive thermogenesis.

D. Metabolic Actions

Table 1 summarizes some of the major effects of T3 on the body’s metabolic systems. As noted in the previous section, both BMR and adaptive thermogenesis are increased by T3 and decreased in its absence. Several pathways involved in lipid and carbohydrate metabolism are affected by T3 both directly and by altering tissue responses to other hormones such as insulin. In addition there is interaction between thyroid hormone and the nutrient signaling through such receptors as PPARα and PPARγ, and the transcription factors ChREBP (carbohydrate response element binding protein) and SREBP (sterol response element binding protein). Overall, an elevated level of thyroid hormone is associated with an overall accelerated metabolism, with net increased lipid and cholesterol breakdown; low thy roid hormone levels have the opposite metabolic effects.

Table1. Effects of T3 on Metabolic Processes

E. Neurodevelopment

Thyroid hormone is necessary for the normal growth and development of many tissues and organs, but nowhere are the effects of a deficiency in hormone availability more profound than in the nervous system. Figure 4 shows the timeline of a number of important processes of neurodevelopment in the human fetus and infant. The fetal thyroid gland appears during the first trimester of pregnancy and hormone secretion is detected during the second trimester. Although the fetal hypothalamic-pituitary-thyroid axis is not active until the third trimester and achieves full function at birth, TH receptors are expressed in the brain throughout development, suggesting an important role for maternal hormone avail ability to the fetus. If the maternal supply of the hormone is compromised, the resulting cognitive and motor deficits of the fetus will depend on the timing of the deficit. An adequate exposure to hormones in infancy and early childhood is required for the normal brain development that continues to take place during this period.

Fig4. Thyroid hormone and development of the nervous system in humans. The top portion of the figure shows the relative contribution by the maternal (M) and fetal/child (C) thyroid glands to the child’s total thyroid hormone availability in utero and in early childhood. Below this graph, and using the same timeline, are some major neurodevelopmental events. Deficiency of thyroid hormone during development will have the most adverse effects on those events taking place during the time of deprivation, both before, and after birth. Adapted from Endocrinology, Jameson and De Groot, eds. 6th ed. 2010. p.1657.

اخر الاخبار

اخبار العتبة العباسية المقدسة

بالتعاون مع جامعة ستانفورد.. جامعة الكفيل تعتمد منهجًا متطورًا لطب الطوارئ

سماحة السيد الصافي يستقبل وفد شركة (سيتي فارما) الباكستانية المختصة في الأدوية

شعبة فاطمة بنت أسد تعلن أسماء الفائزات في مسابقة ميثاق العدالة

المجمع العلمي يطلق البرنامج التطويري الربيعي لطلبة الحفظ بنسخته الخامسة في كربلاء

المزيد

الآخبار الصحية

اللحظات الأخيرة قبل الموت.. هذا هو تسلسل "فقدان الحواس"

وخز الأطراف وضعف الذاكرة.. علامات على نقص فيتامين هام

عادة صباحية بسيطة.. تأثيرها قد يحسن ضغط الدم

عادات يومية تدمر قلبك بصمت.. خبراء يطلقون التحذير

المزيد

الآخبار التكنلوجية

الذكاء الاصطناعي يفك لغز آثار أقدام الديناصورات

القمر أولا.."سبيس إكس" تؤجل خططها الخاصة بالرحلات إلى المريخ

الذكور أم الإناث؟ دراسة "تنسف الشائع" بشأن التوحد

خبير يكشف عن اقتراب العلماء من فك شفرات "لغات الحيوانات" !

المزيد

مواضيع ذات صلة

Adrenal Replacement in ACTH Deficiency

Rathke cleft cysts

Biological Actions of Oxytocin

GHD with Accompanying Features

Biological Actions of Arginine Vasopressin (AVP)

Structures of Oxytocin and Vasopressin

Syndrome of Inappropriate Antidiuresis

Hypothalamic Diabetes Insipidus

The Physiology of oxytocin (OT)

Regulation and Biological Actions of Growth Hormone and Prolactin

Hypothalamic Control of Growth Hormone Secretion

Corticotropin-Releasing Hormone