Thyroid Gland

Intermediary metabolism includes all the biochemical reactions that involve in the conversion of dietary nutrients into energy or cellular components. The energy derived through metabolism will be utilized to maintain homeostasis, growth, production, and reproduction in animals.

It is a bi-lobed gland present on either side of the trachea, derived from the foregut endoderm layer, and produces thy­roid hormones (THs), i.e., triiodothyronine (T₃) and tetraiodothyronine (T₄). These hormones are responsible for multifaceted functions including organ development, growth, homeostasis, oxidative metabolism, reproduction, and production.

16.1.1 Histology

The endodermal-derived thyroid progenitor cells form thy­roid follicles that constitute the thyroid gland. Thyroid follicles are often referred to as the manufacturing units of THs. Within these follicles are the specialized epithelial cells known as “thyrocytes” that serves as a site of synthesis, storage, and secretion of TH. The thyrocytes have polarized apical and basal membranes, which help in regulating spe­cific bidirectional transport of substances back and forth from

Fig. 16.1 Histology of the thyroid gland. [The thyroid gland is composed of follicles and parafollicular cells that are responsible for the manufacturing of thyroid hormones and calcitonin, respectively]

the lumen.

16.1.2 Synthesis of Thyroid Hormones

16.1.2.1 Synthesis of Thyroglobulin

Thyroglobulin (TG) is a homodimeric (660 kDa) glycopro­tein synthesized in thyrocytes and subsequently stored in the lumen. The thyroglobulin is secreted and stored in the follic­ular lumen and is commonly termed as “colloid”. Each TG monomer has about 70 tyrosine residues and it acts as a scaffold for the synthesis of THs. The TSH-dependent stim­ulation of TSHR present on the basal membrane of thyrocytes increases the rate of TG gene expression and its subsequent translation. TG undergoes post-translational modifications that favor protein folding, trafficking, iodination, and hormonogenesis during its transit into the lumen.

16.1.2.2 Iodine Uptake

The dietary iodide absorbed from the GIT reaches thyroid gland via systemic circulation. A specialized “Sodium (Na⁺)- Iodide (I^-) symporter (NIS)” present on the basolateral mem­brane helps in the secondary active transport of iodide into the cytoplasm of thyrocytes. Another apical membrane­bound iodide transport protein known as “Pendrin” helps in the rapid efflux of cytoplasmic I^- into the lumen. These carrier proteins confer the unique ability of thyrocytes to concentrate I^- by 30-60 fold within their cytoplasm and this exclusive phenomenon occurring is referred to as “iodide trapping.” During the efflux of I^- into the follicular lumen, it is converted into Iodine (I) by the apical membrane-bound enzyme “thyroid peroxidase (TPO)” (Fig. 16.2).

16.1.2.3 Organification

In a process known as “Organification,” the highly reactive iodine reacts with the tyrosine residues present on the TG to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). While roughly half of the tyrosine residues present in each TG monomer can be iodinated depending on the availability of superficial tyrosine molecules.

16.1.2.4 Coupling

This refers to the combination of MIT and DIT molecules within TG to form triiodothyronine (T₃), tetraiodothyronine

Fig. 16.2 Iodide trapping in thyrocytes [The iodide in the circulation is actively transported by the NIS protein and stored inside the thyrocytes or used for thyroid hormonogenesis. TP thyroid peroxidase; TG thyroglobulin; AC adenylyl cyclase; NIS sodium-Iodide symporter; BM basal membrane; LM luminal membrane; RER rough-endoplasmic reticulum]

Fig. 16.3 Organification and coupling reactions in thyroid hormonogenesis [Iodination of tyrosine residues in the TG is catalyzed by TPO and results in the production of MIT and DIT, which will be further to yield THs. [MIT monoiodotyrosine; DIT di-iodo tyrosine; T₃ triiodothyronine; T₄ tetraiodothyronine reverse; rT₃ triiodothyronine]

(T₄), and reverse-triiodothyronine (rT₃). Although they col­lectively comprise the thyroid gland secretions, only T₃ and T₄ are active hormonal forms that can elicit biological effects in the target tissues. Only a few out of the many MIT and DIT molecules embedded in TG undergo thyroid hormonogenic coupling reactions (Fig. 16.3).

16.1.2.5 Endocytosisand Lysosomal Degradation

The TSH-dependent stimulation of thyrocytes ensues endocytic reuptake of TG surrounding the apical membrane. Thus, the reinternalized TG is conveyed to lysosomes for enzymatic degradation resulting in the liberation of T₃, T₄, MIT, and DIT. The thyroid hormones are then released into the bloodstream through monocarboxylate transporter 8 (MCT8) present on the basal membrane. While the MIT, DIT, and TG molecules will be degraded to reutilize iodine for further synthesis of thyroid hormones.

16.1.2.6 Transport in Blood

THs are lipophilic and therefore require plasma proteins for their circulatory transport. More than 99% of THs in the circulation will be bound to the carrier proteins and liberated rapidly when required. The plasma proteins, such as thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA or transthyretin), and serum albumin act as the carrier proteins of THs. The TBG is the major plasma protein that binds to THs, it has a greater affinity to T₄ than T₃and hence a long half-life (Table 16.1). They act mainly as an extra-thyroid pool of THs, preventing their rapid metabo­lism and excretion from the animal’s body.

16.1.3 Mechanism of Action

16.1.3.1 Transport Across the Cell Membrane

Only free or unbound THs are carried through the MCT 8 present on the cell membranes of target cells. Since T₃ binds to the nuclear thyroid receptors (TRs) with a great affinity when compared to T₄, it is considered as the more

Table 16.1 Properties of thyroid hormones

potent and active form of TH. While T₄ is the major secretory product of the thyroid gland, subsequent conversion of T₄ into the active T₃ form by intracellular deiodinases takes place in target cells. 5^,-deiodinase type 1 (D1), 5'-deiodinase type 2 (D2), and 5-deiodinase type 3 (D3) are different forms of deiodinases distributed in various tissues. The D1 and D2 enzymes are responsible for the conversion cum activation of T₄ to T₃. Whereas D3 catalyzes the conversion of T₃ to rT₃ causing its inactivation. Therefore, MCT 8 and deiodinases are essential factors in determining the magnitude of biological response in target tissues.

16.1.3.2 IntracellularSignaling

Produced either from the thyroid gland or by the conversion of prohormone T₄ in peripheral tissues, T₃ initiates a signal­ing cascade by binding to thyroid receptors (TRs) localized in the nucleus.

Fig. 16.4 Mechanism of thyroid signaling in the target cells [The thyroid hormones in the circulation are taken up by the target tissues and exert their biological effects by binding to the thyroid receptors residing in the nucleus. T₃ triiodothyronine; T₄ tetraiodothyronine dissociation of corepressors and recruitment of coactivators take place when T₃ binds to the TR complex, resulting in the transcription of TH regulated genes (Fig. 16.4).

reverse; rT₃ triiodothyronine; TRE thyroid response element; D2 5'- -deiodinase type 2; D3 5'-deiodinase type 3; RXR retinoid X receptor; TR thyroid receptors; MCT 8 monocarboxylate transporter 8]

16.1.4 Biological Effects

16.1.4.1 Effect on Carbohydrate Metabolism

THs stimulate intestinal absorption, glycolysis, glycogenoly­sis, and gluconeogenesis in various tissues. The enhanced glucose production by the aforementioned pathways is necessary to maintain basal metabolic rate (BMR), thermo­genesis, and animal growth (Fig. 16.5).

16.1.4.1.1 Effect on Intestinal Absorption

THs increase the absorption of glucose from the small intes­tine by upregulating the activities of Sodium (Na⁺)-Glucose cotransporter 1 (SGLT1) and Na⁺-K⁺ ATPase pump.

16.1.4.1.2 EffectonLiver

The liver is a major organ regulating glucose homeostasis in animals. THs have direct effects on glucose uptake, production, and oxidation in hepatocytes. They increase both the uptake and secretion of glucose from hepatocytes by stimulating the expression of glucose transporter- 2 (GLUT2). Simultaneously, upregulation of glycolytic enzymes enhances subsequent oxidation of glucose via the glycolytic pathway. The key enzyme encoding genes of gluconeogenesis such as pyruvate carboxylase, phosphoenol­pyruvate carboxykinase (PEPCK), and glucose-6-phospha- tase are positively regulated by the THs. Moreover, THs also stimulates the rate of glycogenolysis in hepatocytes due to an increased rate of oxidation of glucose. Together, THs stimu­late glycolysis, gluconeogenesis, and glycogenolysis in the liver leading to a concomitant rise in blood glucose levels.

Fig. 16.5 Effect of thyroid hormone on metabolism. [The thyroid hormones increase the rate of glycogenolysis, gluconeogenesis, and lipolysis resulting in an elevated BMR to support the survival and production in animals. [" increase; BMR basal metabolic rate]

16.1.4.1.3 EffectonPancreas

THs play a crucial role in the development, maturation, and functioning of cells in the islets of Langerhans. They inhibit glucose-stimulated insulin release from the β cells leading to glucose intolerance.

16.1.4.1.4 Effect on Glucose Uptake in Skeletal and Adipose Tissue

The insulin-dependent upregulation of GLUT4 leads to increased glucose uptake in the skeletal muscles. In the same way, THs enhance the glucose uptake in adipocytes, which help in lipogenesis.

16.1.4.2 Effect on Protein Metabolism

Thyroid hormones stimulate both protein catabolism and anabolism in tissues. The degradation of proteins in skeletal muscles results in the elevation of plasma amino acid con­centration to support gluconeogenesis in various tissues. In the liver, THs stimulate the synthesis of intracellular and secretory proteins. Altogether, THs stimulate protein turn­over in the liver and skeletal muscle cells.

16.1.4.3 Effect on Fat Metabolism

Thyroid hormones stimulate the hepatic production of cho­lesterol by upregulating the HMG-CoA reductase gene. Thus, the increased amount of cholesterol is utilized to manufacture bile acids. They stimulate lipolysis in both white adipose tissue (WAT) and brown adipose tissue (BAT) to produce free fatty acids, which are used for thermogenesis. Further, THs also enhance lipogenesis to counter the depletion of lipid stores.

16.1.4.4 Effect on BMR and Thermogenesis

The altered levels of intracellular Na⁺ and Ca²⁺ by THs augment the activity of Na⁺-K⁺ ATPase pump and sarcoplas- mic/endoplasmic reticulum Ca²⁺-dependent ATPase (SERCA) in skeletal muscle, heart, and other cells. The enhanced activity of the above-mentioned ion pumps corresponds to a proportional rise in the hydrolysis of ATP with subsequent generation of heat and elevation of BMR. Furthermore, the increased ATP requirement is ensured through the catabolism of glucose, fatty acids, and amino acids. In addition, exposure to cold invokes the activity of D2 and subsequent conversion of T₄ to T₃ in brown adipose tissue (BAT), initiating a thermogenic response. Altogether, THs increase metabolic heat production due to enhanced oxidation of glucose and fatty acids, a phenomenon that is commonly referred to as non-shivering thermogenesis.

16.1.4.5 Effect on Mitochondrial Functioning

and Biogenesis

THs have a direct effect on mitochondrial biogenesis by binding to TRs localized in mitochondria leading to increased mtRNA and protein synthesis. In addition, the upregulation of nuclear transcription factors like nuclear respiratory factor 1 (NRF-1) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1a) will further activate the transcription of nuclear genes that encode mitochondrial proteins. They increase ATP synthesis by stimulating ATP synthase needed for the functioning of Na⁺-K⁺ ATPase and SERCA. Furthermore, THs lead to the uncoupling of oxida­tive phosphorylation by stimulating proton leak from the inner mitochondrial membrane by uncoupling proteins 1/2/ 3 (UCP1/2/3) or by inhibiting the movement of reducing equivalents into mitochondria. This uncoupling leads to the generation of heat with a consequent decrease in ATP synthesis.

16.1.4.6 Miscellaneous Effects

The increased oxygen demand at the tissue level due to elevated mitochondrial respiration is met by increasing car­diac output, systemic blood pressure, and respiratory rate. THs have stimulatory effects on neuronal activity, GIT motil­ity, sleep, and milk production.

16.1.2 Hypothalamic-Pituitary-Thyroid Axis

The secretion of THs is regulated primarily by TRH and TSH (Fig. 16.6) released from the hypothalamic-pituitary axis. TRH from the hypothalamus stimulates the secretion of TSH from the pituitary gland. Then, the TSH acts on the thyroid gland and stimulates the production of THs. Increased circulatory levels of THs exert negative feedback signals on the secretion of both TRH and TSH. Other hormones such as leptin, somatostatin, dopamine, and corti­sol also can modulate their secretion.

Fig. 16.6 Regulation of thyroid hormone secretion. [The increased circulatory levels of THs exert a feedback inhibition on the secretion of TRH and TSH from the hypothalamus and anterior pituitary, respectively. [" increase; BMR basal metabolic rate; PVN para-ventricular nucleus, GIT gastrointestinal tract; TRH thyrotropin releasing hormone; TSH thyroid-stimulating hormone]

Know More...

• Thyroid hormones have permissive effect on GH and absence of which leads to stunting of animal’s growth.

• Iodinated casein: Resembles thyroid hormones and used in dairy cows to increase milk production.

• Hypothyroidism: Decreased circulatory levels of thyroid hormones. Seen in panhypopituitarism, iodine deficiency, and congenital deficiency of thy­roid peroxidase. It results in “cretinism”, characterized by impaired physical growth and neu­ral development.

• Hyperthyroidism: Increased circulatory levels of thyroid hormones, often due to hyperactivity of thyroid gland seen in grave’s disease and thyroid adenoma.

• Goiter: The pathological condition characterized by abnormal enlargement of thyroid gland. Goiter can be caused due to iodine deficiency (endemic goiter) and in grave’s disease (toxic goiter).

16.2