The thyroid gland is located in the neck, immediately below the larynx and anterior to the trachea. It consists of two lobes joined at the centre by the isthmus. It is an endocrine gland which produces two major thyroid hormones, thyroxine (T4) and triiodothyronine (T3) that have wide ranging effects on the body. The thyroid gland produces a larger amount of T4, which can then be converted into the much more potent thyroid hormone T3.
Thyroid hormones alter gene transcription. Inside cells, triiodothyronine binds to intracellular thyroid receptors which are on, or close to genes in the DNA. The thyroid hormone-receptor complex forms a complex with the retinoid-X receptor at thyroid hormone response elements on DNA. This then alters gene expression of specific genes. This can affect the following:
- Body temperature
- Heart rate and blood flow
- Body weight
- Cholesterol concentration in plasma
- Muscle function
- Central and peripheral nervous system
Here we will briefly discuss some of the functions of the thyroid hormones. For more information on symptoms of thyroid disease, or the synthesis of thyroid hormones, please see the related thyroid articles.
EFFECTS ON BODY TEMPERATURE
Thyroid hormones raise body temperature through three main mechanisms that all revolve around the utilisation and synthesis of ATP. Both these processes generate heat, so thyroid hormones use this as a way to raise body temperature. ATP acts like a source of energy in biological systems, so is needed to power the transport of ions across cell membranes, or the metabolism of glucose consumed in our diet for example.
The first is by increasing the activity of “futile” metabolic cycles. Thyroid hormones raise the expression of enzymes for opposing metabolic pathways, for instance, both glycolytic and gluconeogenic pathway enzymes. This causes a simultaneous use of and synthesis of ATP as both pathways occur at the same time and both these processes produce heat.
The second mechanism is through the pump/leak model. Thyroid hormones raise the expression of ion transporters in cell membranes. This increases the rate at which ion transport occurs across cell membranes, causing the membranes to become leaky to ions. Cell membranes have normal resting potentials which are maintained through the action of sodium/potassium ATPases. These ATPases use ATP as energy to pump ions across the cell membrane to maintain these resting potentials. When thyroid hormones cause cell membranes to become leakier to ions, these ATPases have to work much harder to maintain the normal resting potentials and therefore use much more ATP as they do so. The extra utilisation of ATP produces heat.
The final way in which thyroid hormones raise body temperature is by reducing the thermodynamic efficiency of ATP production. This occurs in mitochondria, organelles found in body cells that play a major role in respiration and energy production. Two cofactors, known as NADH and FADH2 are reduced by the tricarboxylic cycle (also known as the Krebs cycle). These are oxidised by complex I and II respectively which are part of the respiratory chain in the mitochondrial membrane, which generates electrons and protons. These electrons and protons are important, because they enable the production of water from oxygen without the production of harmful free radicals.
The protons generated by the oxidation of reduced cofactors are also important for the synthesis of ATP. Protons are pumped across the inner mitochondrial membrane by respiratory chain proton pumps, making the intermembrane space highly acidic as a result. This creates a gradient by which protons can flow back in the opposite direction across the mitochondrial membrane, so ATP synthase pumps these protons down this concentration gradient back into the mitochondrial matrix. The energy generated from protons flowing down their concentration gradient releases energy and this energy is used to add ADP to phosphate to produce ATP. This ATP can then be used to fuel lots of biological processes in the body.
Thyroid hormones can alter the expression of uncoupling proteins. These enable protons that have passed across the inner mitochondrial membrane to flow back down their concentration gradient, but the resulting energy is no longer used to power ATP synthesis via ATP synthase. Instead, this energy is released as heat, which raises body temperature.
The respiratory chain comprises of a number of enzymes which transport electrons along the inner mitochondrial membrane and eventually catalyse the conversion of oxygen into water, without producing harmful free radicals. What we’re interested in, is how protons generated from the oxidation of coenzymes, enables the flow of protons along the inner membrane to create a concentration gradient across this membrane.
Normally, the concentration gradient generated enables protons to flow with ease back across the membrane and the resultant energy is used to power the synthesis of ATP. However, T3 upregulates the expression of uncoupling proteins. These make the membrane permeable to protons, causing them to flow across without their energy being used for ATP synthesis. The resultant heat produced raises body temperature.
Thyroid hormones increase the expression of LDL receptors on hepatocytes. This causes an increased uptake of cholesterol from the blood, thereby reducing plasma cholesterol levels.
As we saw earlier, thyroid hormones increase the expression of metabolic enzymes. Not only does this increase the production of heat through the use of and synthesis of ATP, but it also raises the rate of metabolism of biomolecules. Such effects increase the rate of protein, fat and carbohydrate catabolism and anabolism. Thyroid hormones also increase the number and surface area of mitochondria. As we saw earlier, this increases the amount of ATP that cells can synthesise, which enables metabolic rate to be increased. As well as raising the metabolism of biomolecules, thyroid hormones also act to increase appetite, along with the rate of secretion of digestive juices and GI motility. These effects can therefore alter body weight, depending on the rate of metabolism.
The rate of secretion from endocrine glands is increased by thyroid hormones, including insulin from the pancreas, parathyroid hormone from the parathyroid glands and adrenocorticotropic hormone by the anterior pituitary gland. This can cause many effects on the body, such as increased glucose uptake into the cells, increased bone formation and increased glucocorticoid release from the adrenal glands.
Thyroid hormones increase the expression of beta receptors in the myocardium. Therefore, when sympathetic tone is increased and higher levels of catecholamines circulate in the bloodstream, the myocardium is more sensitive to noradrenaline and adrenaline, causing a raised heart rate and a stronger force of myocardial contraction, ultimately raising cardiac output.
Thyroid hormones also cause vasodilation to increase blood flow to tissues. This is in part due to an increased release of metabolites from tissues, following the increased metabolic rate that they promote.
As thyroid hormones increase metabolic rate, the level of oxygen consumption rises, leading to a rise in carbon dioxide production. This results in an increased rate and depth of breathing, in order to expel the additional carbon dioxide from the blood and normalise blood pH.
EFFECTS ON THE CENTRAL NERVOUS SYSTEM
The central nervous system becomes more active when there is a higher level of thyroid hormones circulating in the bloodstream. This can alter mental state, causing excitedness and anxiety and also affects the rate of stimulation of muscles via the degree of signalling at the neuromuscular junction.
There are of course many more functions of the thyroid hormones, as their effects are so wide ranging. For this reason, their levels in the blood must be tightly controlled to prevent an excess or a deficiency of T3 and T4 and in many cases, hyperthyroidism or hypothyroidism can cause a range of symptoms which reflect the function of thyroxine and triiodothyronine.