NROSCI/BIOSC 1070 and MSNBIO 2070 November 27, 2017 Gastrointestinal 3 Metabolic Rate and Energy Metabolism The metabolism of the body simply means all the chemical reactions in all of the cells. The metabolic rate is normally expressed in terms of the rate of heat liberation during the chemical reactions. Either directly or indirectly, all energy expenditure in the body eventually generates heat. For example, the breaking of peptide bonds liberates heat into the environment, as does muscular activity and even movement of blood through the cardiovascular system (as it overcomes friction). Thus, measurement of metabolism usually involves measurement of heat output from the body. The unit used to express metabolic rate is the calorie, which is defined as the quantity of heat required to raise 1 gram of water by 1 C. However, the calorie is much too small of a unit to be conveniently used, and thus typically the kilocalorie (1000 calories) is used as the base unit. The kilocalorie is abbreviated with a capital C. In everyday usage, we often refer to calories, but what is really meant is kilocalories. The most accurate way of measuring whole-body metabolic rate is direct calorimetry. The subject is placed in a special device, called a calorimeter, which consists of an air chamber that is so well insulated that no heat can leak through the walls. Heat formed by the subject s body warms the air of the chamber. However, the air temperature within the chamber is maintained at a constant level by forcing the chamber air through pipes submerged in water. The rate of heat gain by the water is measured by an accurate thermometer, and is equal to the rate at which heat is liberated from the subject s body. Because this technique is so difficult to perform, it is only used for research purposes. Indirect calorimetry depends on the fact that most of the energy expended in the body is derived from aerobic metabolism (i.e. metabolism that uses oxygen). Thus, whole-body metabolic rate can be estimated by measuring oxygen consumption. When 1 liter of oxygen is metabolized with glucose, 5.01 Calories of energy are released; when metabolized with fat 4.70 Calories are released; with protein, 4.6 Calories. As an average, 4.825 Calories/liter of oxygen is typically used in estimating metabolic rate. Thus, if 18.65 liters of oxygen are consumed in an hour, then estimated heat output would be: (18.65 x 4.825 = 90 Calories). ENERGY METABOLISM AND ENERGY OUTPUT An average man of 70 Kg who lies in bed all day uses about 1650 Calories of energy. The process of eating and digesting food requires about another 200 calories, so the same man who just lies in bed all day and eats a reasonable diet requires 1850 Calories of energy. If he sits in a chair all day, his total energy requirement reaches 2000-2250 Calories. However, intensive work requires more energy expenditure. For example, if an individual is employed in a physically demanding profession, he may require a daily energy expenditure of about 3000 Calories. November 27, 2017 Page 1 Gastrointestinal 3
It may surprise you that a sedentary individual requires 2/3 of the energy of someone who works strenuously for 8 hours/day. Even when a person is at complete rest, considerable energy is required to perform all of the chemical reactions in the body. This minimal level of energy required to exist is called the basal metabolic rate (BMR), and ranges from 65-70 Calories/ hour in a 70 Kg male. Although much of the BMR is accounted for by essential activities of the central nervous system, heart, kidneys, and other organs, the variations in BMR among different individuals are mainly related to differences in the amount of skeletal muscle and body size. Skeletal muscle, even under resting conditions, accounts for 20-30% of BMR. For this reason, BMR is usually corrected for differences in body size by expressing it as Calories per hour per square meter of body surface (which is calculated from height and weight). The normal BMR values for men and women are shown in the graph to the left. Much of the decline in BMR with age is probably related to the decrease of muscle mass and the replacement of muscle with adipose tissue, which has a lower rate of metabolism. Likewise, slightly lower BMRs in women than in men are due partly to their lower percentage of muscle mass and higher percentage of adipose tissue. However, other factors also are important, including the levels of two hormones: thyroid hormone and growth hormone. Hormones Influencing BMR 1) Thyroid Hormone When the thyroid gland secretes maximal amounts of thyroxine, the metabolic rate can increase by 50-100%. As discussed below, thyroxine increases the rates of chemical reactions in many cells of the body and therefore increases metabolic rate. 2) Growth Hormone Growth hormone can increase the metabolic rate by 15-20% due to effects on cellular metabolism. Thyroid Hormone The thyroid gland is located anterior to and on the sides of the trachea, immediately below the larynx. It is one of the largest glands in the body, and secretes two hormones that play an important role in regulating metabolism: thyroxine and triiodothyronine, which are commonly referred to as T4 and T3, respectively. The thyroid gland also secretes calcitonin, which plays an important role in calcium metabolism. November 27, 2017 Page 2 Gastrointestinal 3
About 93% of the metabolically active hormone secreted by the thyroid gland is T4, and the other 7% is T3. However, T4 is usually converted to T3 in the tissues. Both hormones have the same general effects, but T3 is more potent. The anatomy of the thyroid gland is shown to the left. The cuboidal epithelial cells secrete colloid into the middle of a division of the thyroid gland, which is called a follicle. The major constituent of colloid is the thyroid hormones, which can be stored for a considerable period of time. When needed, the hormones are absorbed from the center of the follicle by the cuboidal epithelial cells, and then secreted into the blood. T3 and T4 are unusual molecules, as they contain iodine. About 1 mg of iodine must be consumed per week in order for adequate quantities of T3 and T4 to be produced. To insure that iodine deficiencies are not common, table salt is typically iodized with one part sodium iodide to every 100,000 parts sodium chloride. Iodine is actively pumped into the lumen of the cuboidal epithelial cells, where it is sequestered. The first step in the synthesis of T3 and T4 is the oxidation of iodine, which can bind with the amino acid tyrosine. Tyrosine is first iodinated to form monoiodotyrosine, and this molecule is iodinated again to form diiodotyrosine. Then, the iodotyrosine residues are coupled with each other to form T3 or T4, depending on which two residues couple. As mentioned above, most of the hormone released from the thyroid is T4 (thyroxine), but an iodine is removed in the tissues by a deiodinaze enzyme to form T3. T3 and T4 must bind to a carrier protein in the blood to be transported. The carrier is made in the liver, and is typically thyroxine-binding globulin. However, after secretion of T3 and T4 it can take a long time for the effects of the hormones to become apparent. This is best demonstrated in the case of an individual whose thyroid gland has been removed, and is November 27, 2017 Page 3 Gastrointestinal 3
Physiological Effects of Thyroid Hormone injected with a single dose of thyroxine. Essentially no effects can be discerned for 2-3 days, and maximal effects do not occur until about 10 days after injection. This observation suggests that thyroxine is only slowly released from the carrier molecule. As noted above, T4 is typically deiodinated to form T3 as it circulates. Once T3 is released from the carrier, it passes into target cells by simple diffusion and binds to specific intracellular receptors that are bound to chromatin. By binding to these receptors, T3 affects the expression of specific genes. 1) Growth and Development Thyroid hormone plays an important role in stimulating growth. Children with a lack of thyroid hormone do not achieve an appropriate height. Furthermore, thyroid hormone is essential for proper development of the central nervous system. If the fetus does not secrete enough thyroid hormone, the brain will be much smaller than normal and retardation will occur. 2) Carbohydrate Metabolism Thyroid hormone stimulates almost all aspects of carbohydrate metabolism, including rapid uptake of glucose by cells, enhanced glycolysis, enhanced gluconeogenesis, increased rate of absorption of sugar from the GI tract, and even greater insulin secretion. These effects are due to a generalized increase in the production of cellular metabolic enzymes. 3) Fat Metabolism Almost all aspects of fat metabolism are also enhanced by thyroid hormone, including mobilization of lipids from fat tissue and acceleration of oxidation of free fatty acids by cells. Thus, fat stores of the body are rapidly depleted when thyroid hormone secretion is high. 4) Vitamin Requirements Because thyroid hormone increases the levels of many enzymes in the body and thus enhances enzymatic reactions, the demands for cofactors for those reactions is increased. It is for this reason that the demand for vitamins is enhanced in patients with high levels of thyroid hormone. Thus, an otherwise normal consumption of vitamins may be insufficient in a hyperthyroid patient. November 27, 2017 Page 4 Gastrointestinal 3
5) Metabolic Rate Because thyroid hormone increases metabolism in almost every cell of the body, excessive quantities of the hormone vastly increase BMR. In fact, BMR can double with extremely high levels of thyroid hormone. 6) Body Weight Typically, high levels of metabolism associated with high levels of thyroid hormone result in a drop in body weight. This does not always occur, however, as appetite and food intake also increase when thyroid hormone levels are raised. 7) Cardiovascular System Physiology Increased metabolic rate in almost every body tissue results in an increased oxygen usage and the formation of high levels of metabolic wastes. As we noted in the cardiovascular lectures, these agents serve as paracrine factors that increase blood flow to a region. Blood flow to the skin becomes especially high with high levels of thyroid hormone, as body heat increases and must be dissipated. The lowered peripheral resistance in almost every tissue demands that cardiac output must increase tremendously. This is achieved by increasing both heart rate and contractility. Mean blood pressure stays relatively normal, however. Note that thyroid hormone affects the rate of enzymatic reactions in the myocardial muscle itself. These effects coupled with excessive work can lead to cardiac failure in the chronic hyperthyroid patient. 8) Respiratory System Physiology Because of the enhanced levels of aerobic metabolism in hyperthyroid patients, oxygen demands of the body rise. This triggers an increase in both the rate and depth of respiration. 9) Gastrointestinal Physiology Increased levels of thyroid hormone are typically associated with increased food consumption, which obviously affects the gastrointestinal system. Furthermore, thyroid hormone directly stimulates increased gastrointestinal secretion and motility. As a result, a common complaint of hyperthyroid patients is diarrhea. November 27, 2017 Page 5 Gastrointestinal 3
10) Nervous System Physiology In general, neuronal excitability is increased as levels of thyroid hormones rise. This can result in a wide range of neurological and psychiatric problems, including tremor, psychoneurotic tendencies, anxiety, and even paranoia. In addition, hyperthyroid patients have great trouble in sleeping, despite the fact that their high level of metabolic activity leaves them feeling very tired. 11) Muscle Physiology Slight increases in the level of thyroid hormone results in a small increase in muscle strength and reactivity because of the generalized acceleration of metabolism. However, very high levels of thyroid hormone can result in protein catabolism and muscle weakness. Regulation of Thyroid Hormone Secretion Because thyroid hormone plays a predominant role in governing the rate of enzymatic reactions in the body, its secretion must be precisely controlled. Thyroid hormone secretion is regulated by a tropic hormone released from the anterior pituitary, thyroid stimulating hormone (TSH), which is also known as thyrotropin. TSH directly induces the secretion of T3 and T4, and also stimulates the trapping of iodine inside thyroid gland cells and increases the iodination of tyrosine. Even the size and number of thyroid gland cells increases upon exposure to TSH. Some of these effects occur within minutes, but others such as increases in the number of thyroid gland cells can require days. TSH is a fairly large protein, and binds to specific receptors on the surface of thyroid gland cells. The effects of TSH binding to this receptor are mediated by a second messenger, camp. As noted earlier in the course, TSH secretion is controlled by a hormone produced in the hypothalamus, thyrotropin releasing hormone (TRH). TRH is transported to the anterior pituitary through a portal circulation. When TRH binds to receptors on TSH-producing anterior pituitary gland cells, the second messenger phospholipase C is produced, which induces a cascade of other second messengers that eventually induce TSH release. The most potent stimulator for TRH release from the hypothalamus is exposure to cold. We will discuss the mechanism responsible for this TRH release later in the course, in the lecture on temperature and growth regulation. In addition, when levels of thyroid hormone in the blood become high, the release of TSH from the anterior pituitary is inhibited through negative feedback. Diseases of the Thyroid Although most of the effects of production of too much or too little thyroid hormone can be ascertained from the list above, several features of these clinical conditions require specific discussion. November 27, 2017 Page 6 Gastrointestinal 3
Hyperthyroidism In most patients with hyperthyroidism, the thyroid gland is 2-3 times its normal size due to a proliferation of cells. Furthermore, each glandular cell increases its rate of hormone production by several-fold. Nonetheless, it most forms of hyperthyroidism plasma TSH levels are quite low. So, what stimulates thyroid hormone secretion in these patients? Typically, they have generated antibodies to thyroid gland cells, including to TSH receptors. The antibodies bind to the receptors, and have the same general effects as TSH but are not under feedback inhibition. Thus, an unchecked release of thyroid hormone occurs. In other words, most hyperthyroid patients actually have an autoimmune disease that ends up stimulating thyroid hormone production and secretion. Occasionally, however, hyperthyroidism is due to cancer that develops in thyroid tissue. Thyroid secretory cells grow out of normally regulatory control, and spontaneously release large amounts of thyroid hormone. In addition to the symptoms of hyperthyroidism that can be predicted from the effects of thyroid hormone listed above, another common condition occurs: exophthalamos, or protrusion of the eyeballs. This condition is mainly due to degeneration of the extraocular muscles. Most probably, this degeneration is related to the autoimmune disease that typically produces hyperthyroidism. The antibodies to thyroid tissue that are developed somehow also damage the extraocular muscles. Exophthalamos can be a dangerous condition, as the eyelids do not close properly and the eyeballs can become dry. Hyperthyroidism is typically treated by destroying thyroid tissue. This can either be done surgically or by injecting radioactive iodine, which becomes concentrated in the thyroid tissue and eventually causes its death. Hypothyroidism Several mechanisms can lead to hypothyroidism. As in hyperthyroidism, an autoimmune disease can attack the thyroid gland, but instead of stimulating the gland it destroys it. Obviously, thyroid hormone secretion diminishes in such a case. Another common cause of hypothyroidism is endemic goiter due to a lack of iodine in the diet. In some regions, little iodine is present in the soil, and thus food from these areas contains little iodine. Without this element, thyroid hormone cannot be produced. In patients with endemic goiter, the thyroid gland becomes massive under the influences of TSH, which is secreted in large quantities due to the lack of feedback inhibition. Although the thyroid tissue proliferates, without iodine no functional thyroid hormone can be produced. These patients develop an enlarged neck due to the massively increased size of the thyroid gland. More commonly, idiopathic nontoxic colloid goiter leads to hypothyroidism. The thyroid gland enlarges under increased secretion of TSH, which occurs because thyroid hormone levels are low. As the name of this disease implies, the cause of the drop in thyroid hormone release is unknown. The physiological consequences of hypothyroidism can be predicted from the list of thyroid hormone actions provided above. The treatment of the disease is simple: administration of thyroid hormone, which can be done orally. Even if the thyroid gland has been completely November 27, 2017 Page 7 Gastrointestinal 3
removed surgically, patients can live a normal life provided they are administered thyroid hormone. A more severe outcome of hypothyroidism occurs if the disease afflicts an infant. This condition, called cretinism, is characterized by a failure of body growth and by mental retardation. Growth Hormone Another hormone that can affect cellular metabolism is growth hormone (GH; also known as somatotropin). GH is released from the anterior pituitary, and is a peptide. GH is typically bound to growth hormone binding protein when circulating in the plasma, which limits the excretion of the hormone by the kidney and thus increases its half life. GH stimulates protein synthesis, increases fat breakdown, increases hepatic glucose output, and stimulates bone and cartilage growth. Loss of GH production in adults results in a 15-20% decrease in cellular metabolism. Other Hormones Influencing Metabolism Glucocorticoids Glucocorticoids are steroids secreted by the adrenal cortex, which lies outside the adrenal medulla. The name glucocorticoid comes from the ability of these hormones to raise blood glucose levels. The major glucocorticoid is cortisol, which is a typical steroid whose actions are genomic. The release of cortisol is regulated by the secretion of ACTH (adrenocorticotropic hormone) from the anterior pituitary. In turn, ACTH secretion by the anterior pituitary is regulated by a hypothalamic hormone, CRH (corticotropin-releasing hormone). Cortisol is secreted continuously although its levels have a strong diurnal rhythm; secretion normally peaks in the morning and is lowest overnight. Cortisol acts as a negative feedback signal for ACTH release, thereby limiting the secretion of this glucocorticoid. Cortisol promotes gluconeogenesis in the liver, as well as the breakdown of skeletal muscle proteins to provide a substrate for gluconeogenesis. Furthermore, cortisol enhances fat breakdown (lipolysis) so that fatty acids are available to peripheral tissues for energy use. Thus, cortisol helps to prevent against hypoglycemia. If plasma glucose concentrations fall below a certain level, the adrenal cortex begins to secrete cortisol even without stimulation from ACTH. Thus, cortisol acts in synergy with glucagon, and is critical to maintain adequate blood glucose levels when the body is faced with a severe hypoglycemic challenge. In addition to these metabolic roles, glucocorticoids appear to have many other functions in the body. For example, these steroids appear to be involved in the response to stressful situations. Almost any type of stress, either physical or neurogenic, triggers an immediate and marked ACTH release from the anterior pituitary, which induces a release of cortisol from the adrenal cortex. Although one positive outcome of this cortisol release might be the increased availability of glucose, effects such as breakdown of skeletal muscle proteins do not seem November 27, 2017 Page 8 Gastrointestinal 3
conducive for producing an integrated response to stress. However, the release of ACTH and cortisol during stress may play physiological roles that are not currently understood. Cortisol also has a well-documented anti-inflammatory effect whose physiological role is not fully appreciated. Prior to the development of nonsteroidal antiinflammatory drugs such as ibuprofen, cortisol metabolites such as cortisone were commonly prescribed. Even today, topical cortisone creams (e.g., Cortaid) are commonly used as antiinflammatory agents for the skin, and injectable synthetic glucocorticoids (e.g., dexamethasone) are employed to reduce inflammation and swelling after tissue injury and surgery. Another effect of glucocorticoids is suppression of immune function; this topic will be reexamined during the immune system lectures. Too little or too much production of glucocorticoids can be life threatening. Too little glucocorticoid production can lead to Addison s disease, which usually results from an autoimmune disease attacking the adrenal gland. Loss of cortisol secretion makes it impossible for a person with this disease to maintain normal blood glucose levels between meals; the patient also cannot synthesize adequate quantities of glucose by gluconeogenesis. Furthermore, lack of cortisol reduces the mobilization of both proteins and fats from the tissues, thereby depressing many other metabolic functions. Because of lack of feedback inhibition, ACTH levels become extremely high in the blood. A paradoxical effect of these high ACTH levels is the darkening of the skin through increased deposition of melatonin, as ACTH in high concentration can stimulate melanocytes. Too much glucocorticoid secretion results in Cushing s syndrome. Usually this disease results from the presence of an ACTH-secreting tumor; for an unexplained reason such tumors are relatively common. The effects of this disease include greatly elevated blood glucose levels as well as muscle weakness due to excessive breakdown of structural proteins. Cushing s syndrome is usually treated surgically, by removing the ACTH-secreting tumor. November 27, 2017 Page 9 Gastrointestinal 3