# NROSCI-BIOSC 1070 Human Physiology November 19, 2014 Gastrointestinal 4 (Metabolism)

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NROSCI-BIOSC 1070 Human Physiology November 19, 2014 Gastrointestinal 4 (Metabolism)

Metabolism Definition: all the chemical reactions in all the cells of the body Quantification: heat production by the body ★ Defined as the quantity of heat required to raise 1 gram of water by 1°C, and abbreviated by “c” (lower case) ★ Since this value is so small, the Kilocalorie (1000 calories) is used as a base. The Kilocalorie is defined by “C” (upper case) ★ 2000 Calories (typical daily intake)=enough heat to raise 2,000 Kg (2,000 L) of water by 1°C

Measurement: direct calorimetry (direct measurement of heat production) Subject in insulated, air-filled chamber Heat from subject’s body warms air Air pumped through pipes in cool water bath Rate of heat gain by water = rate of heat liberation of body (~ metabolic rate)

Indirect Calorimetry Defined by rate of oxygen utilization > 95% of energy expended in body is derived from reactions involving oxygen Good approximation of metabolic rate Amount of energy released when 1 L of O 2 reacts with… - Glucose = 5.01 Calories of energy - Starches = 5.06 Calories of energy - Fat = 4.70 Calories of energy - Protein = 4.60 Calories - Average = 4.825 Calories/L O 2

Average man who lays in bed all day uses ~1650 Calories of energy If the man lies in bed but eats, he utilizes ~1850 Calories of energy Up to 3000 Calories per day can be utilized if an individual is involved in strenuous activity Caloric Utilization

Basal Metabolic Rate Minimal energy required to exist – processes to “just keep you alive” Highly variable depending on sex, age, body size, etc. Skeletal muscle accounts for ~20-30% of BMR (might help explain above) Most of BMR: accounted for by CNS, heart, kidney, and other organ functions

BMR Decline of BMR with age: decreased muscle mass, increased adipose tissue (lower rate of metabolism) Lower BMR in females: generally lower muscle mass Thyroid and growth hormones also affect BMR

93% of secreted thyroid hormone is thyroxine (T4) T4 T3 TSH from anterior pituitary

T4 T3 Deiodination of T4 in tissues Over several days: almost all T4 is converted to T3

Thyroid Hormone(s) Are both hormones the same in their actions? – yes, but they act with different efficacy Differ in rapidity and intensity of action T3 is ~4 times as potent as T4 T3 – lower plasma concentration, shorter half life

Anatomy of the Thyroid Gland 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.

Normal thyroid gland Histological section Anatomy of the Thyroid Gland

Synthesis of Thyroid Hormone 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.

Question for Discussion Why were iodine tablets given to Japanese citizens after the recent nuclear power plant disaster?

Transport of Thyroid Hormone 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. 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.

Half-Life of Thyroid Hormone This is best demonstrated in the case of an individual whose thyroid gland has been removed, and is 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. After secretion of T3 and T4 it can take a long time for the effects of the hormones to become apparent.

Effects of Thyroid Hormones Growth and Development ✴ Thyroid hormone plays an important role in stimulating growth. ✴ Essential for proper nervous system development 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.

Effects of Thyroid Hormones 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. 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. ✴ Thus, an otherwise normal consumption of vitamins may be insufficient in a hyperthyroid patient.

Effects of Thyroid Hormone 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.

Effects of Thyroid Hormone 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.

Effects of Thyroid Hormone 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. ✴ 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. ✴ 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.

Effects of Thyroid Hormone 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. 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.

Effects of Thyroid Hormone 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.

Effects of Thyroid Hormone 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.

Control of Thyroid Hormone Secretion: TSH Effects of TSH: Increased release of T3 and T4 via proteolysis of thyroglobulin Increased rate of iodide trapping Increased iodination of tyrosine Thyroid gland hyperplasia, increased secretion, and overall hypertrophy TSH does this by binding to receptors on basal membrane of follicular cells – cAMP second messenger

What Controls TSH Secretion? TRH (thryotropin-releasing hormone) from the hypothalamus. Temperature plays a primary role in controlling the secretion of TRH into the portal blood system. Feedback on anterior pituitary and hypothalamus by T3 and T4

Hypothalamus Anterior Pituitary Thyroid Gland TRH TSH T3 and T4 Nuclear Receptors T3 and T4 - + + + Temperature (low body temp) + -

Diseases Affecting Thyroid Hormone Secretion Autoimmune diseases affecting the thyroid gland Can cause both hypo- and hyperthyroidism Cancer in thyroid gland or anterior pituitary Iodide deficiency

Hyperthyroidism Thyroid gland increased to two to three times normal size – hyperplasia; also greatly increased secretion of thyroid hormone Plasma TSH less than normal in nearly all patients Immunoglobulin antibodies that bind to TSH receptors on membranes of cuboidal thyroid follicular cells; TSH agonists Cause: excess of thyroid antigens released – formation of antibodies against thyroid gland Continual activation of cAMP system of cells

Anterior Pituitary Thyroid Gland T3 and T4 Nuclear Receptors T3 and T4 - + B cells producing antibodies That bind to TSH receptors + Hyperthyroidism Hypothalamus -

Hyperthyroidism – note apparent hyperplasia and infolding of thyroid epithelium

Note enlarged right lobe

Hyperthyroidism Symptoms easily predicted by considering what excess thyroid hormone would do Also – exophthalamos (protrusion of the eyeballs) in the most common form of the disease (Grave’s disease) Protrusion caused by antibodies attacking extraocular muscles Treatment: surgical resection of gland or delivery of radioactive iodide

Hypothyroidism Commonly, again, autoimmunity develops against the thyroid gland Now, autoimmunity destroys glandular tissue Deterioration/fibrosis of gland Decreased secretion of thyroid hormone

Hypothalamus Anterior Pituitary ThyroidGland TRH TSH Nuclear Receptors T3 and T4 + + Temperature (low body temp) + B cells producing antibodies That destroy Thyroid - Hypothyroidism

Note lymphoid tissue, small follicles Hypothyroidism

Goiter: a hallmark of some types of hypothyroidism

2 Types of Goiters in Hypothyroidism Endemic goiter – due to lack of iodide in the diet – low production of thyroid hormone – increased TSH secretion – increased stimulation of thyroid gland Idiopathic nontoxic colloid goiter – same situation as above, but cause of low thyroid hormone production is unknown “ Hypo ” thus refers to gland secretions and not size

Clinical Implications (Hypothyroidism) Symptoms easily predicted from consideration of a low level of thyroid hormone Treatment often involves oral ingestion of thyroid hormone If pathology occurs early in development – cretinsim – marked by failure of body growth and mental retardation

Growth Hormone Peptide released from anterior pituitary Bound in plasma by GH binding protein Stimulates protein synthesis, fat breakdown, hepatic glucose output, and bone/cartilage growth

Glucocorticoids Steroid hormones secreted by the adrenal cortex Most predominant hormone is cortisol Effects: Raise blood glucose levels Stimulate gluconeogenesis in liver, breakdown of skeletal muscle proteins, fat breakdown Plays an important role in protecting the body against hypoglycemia

Adrenal Cortex glomerulosa fasciculata reticularis Fasciculata: glucocorticoids

Hypothalamus Anterior Pituitary Adrenal Cortex CRH ACTH Cortisol Nuclear Receptors Cortisol - + + + Low plasma glucose + - Note similarities to T3- T4 secretion; Same general pattern, Also “ independent ” Stimulus for release

Other Actions of Glucocorticoids Besides essentially combating hypoglycemia, these steroids are involved in response to stressful situations Cortisol also has an anti-inflammatory effect (inhibits T-cell proliferation) May contribute to “flash bulb memories”

Applications Before development of nonsteroidal anti- inflammatory drugs, cortisol metabolites (i.e. cortisone) prescribed for swelling Topical creams (i.e. Cortaid) and injectable glucocorticoids (i.e. dexamethasone) are available Prednisone is a commonly-prescribed cortisol analog

Side Effects of Glucocorticoid Therapy Difficulty sleeping Increased appetite Increased sweating Indigestion Mood changes Nervousness

Addison’s Disease Autoimmune disease attacking the adrenal gland Loss of cortisol secretion – impossible to maintain normal blood glucose levels between meals Reduced mobilization of proteins and fats from tissues – decrease in several metabolic functions High ACTH levels – darkening of skin (stimulation of melanocytes and deposition of melanin)

Question for Discussion Which Presidential candidate benefited from Addison’s disease?

Cushing’s Syndrome Produced by an ACTH secreting tumor Results in elevated blood glucose as well as muscle weakness

Question for Discussion Why does prolonged glucocorticoid therapy lead to water retention?

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