Chapter 21

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Chapter 21 - Endocrine System: Regulation of Energy Metabolism and Growth

To maintain homeostasis in our bodies it is necessary that the activity of all the cells is coordinated. Thischapter focuses on how hormones regulate metabolic pathways in different cells to control energy balance. The various reactions concerned with either storing or utilizing energy constitute energy metabolism.Control of energy metabolism involves dealing with two critical facts:

1. Food intake is intermittent and the body needs to store nutrients during periods of intake and breakdown nutrients for use in between periods of intake.2. The nervous system depends upon glucose as its primary energy source. Hence, minimum levels ofglucose need to be maintained at all times.

Review of Cellular Metabolism Key concepts of cellular metabolism relate to how the body controls energy metabolism: Anabolism Many of the intermediates of the metabolic pathways involved in energy metabolism, such as acetyl-CoA,are used to synthesize larger biomolecules. For example, acetyl-CoA can be converted into triglycerides andcholesterol, and intermediates of glycolysis and Kreb's citric acid cycle can be converted into amino acids andused to synthesize proteins. Regulation of Metabolic Pathways Whether intermediates are used to produce energy or to construct larger biomolecules depends upon theactivity of the enzymes controlling metabolic pathways. The activity of enzymes is regulated by:

1. Changing the concentration of the enzymes by controlling their synthesis.2. Changing the activity of individual enzyme molecules by allosteric and covalent regulation.

The control of metabolic pathways also depends upon separating the pathways into differentcompartments within the cell. For example, glycolysis occurs in the cytosol while the Kreb's cycle occurswithin the matrix of mitochondria. Metabolic functions can also be divided among the various cell types that constitute tissues. For example,muscle cells are designed primarily for energy utilization in performing their primary function of movementand fat cells in adipose tissue are designed for energy storage. Energy Intake, Utilization and Storage The smaller molecules resulting from digestion have three possible fates:

1. Biomolecules can be used for energy.2. Biomolecules can be used to synthesize other molecules for function, growth and repair. 3. Biomolecules can be used to synthesize larger molecules for storage (e.g. glycogen andtriglycerides).

The uptake, utilization and storage of the three major classes of biomolecules is as follows: Carbohydrates Monosaccharides transported in the blood are taken into the cell by transporters. Glucose is the primarymonosaccharide used by the body and can be oxidized for energy, used as a substrate for other metabolicreactions, or incorporated into glycogen for storage. Glycogen in turn can be broken down into glucose. Proteins Amino acids transported in the blood are taken into the cell by transporters. Once inside the cell aminoacids may be either broken down for energy or used to synthesize proteins. Proteins form an energy reservewhich can be catabolized when needed as during starvation. Use of amino acids for energy production resultsin the production of NH3 (ammonia) as a toxic waste product which is converted into the less toxic urea by the

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liver.

Lipids Lipids are transported in the blood primarily as triglycerides in lipoproteins. The triglycerides inlipoproteins are broken down by lipoprotein lipase into fatty acids and monoglycerides. Fatty acids go intonearby cells. Monoglycerides are metabolized by the liver. Once inside the cell, fatty acids can be oxidized for energy or combined with glycerol to produce newtriglycerides for storage. Triglycerides in the cell can be broken down again into fatty acids and glycerol by theprocess of lipolysis. These products can then be released into the bloodstream for use by other cells. Energy Balance The endocrine system regulates energy balance to ensure that a steady supply of nutrients is alwaysavailable. The body mobilizes its energy stores when the rate of energy intake is insufficient to meets itsenergy needs. Energy input Energy input is the absorbed nutrients in the diet. A person's energy intake is the total energy content ofall the nutrients absorbed.

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Energy output The molecules absorbed for energy are oxidized and about 40% of the released energy is used for ATPproduction while 60% produces heat. Processes of cells requiring energy:

1. Mechanical work2. Chemical work3. Transport work

Metabolic Rate Metabolic rate is the amount of energy expended per unit time. Basal metabolic rate is the metabolic ratewhen both the metabolic rate and the work performed are minimal. BMR is estimated by measuring oxygenconsumption. BMR is expressed as the rate of energy expenditure per unit of body weight. BMR averages 20-25kilocalories per kilogram of body weight. Most of the BMR is due to the nervous system and skeletal muscles. Negative and Positive Energy Balance The body is in energy balance when the energy input equals the energy output. Energy output equals thework performed plus the heat released. An imbalance occurs when energy input does not equal energy outputand this inequality results in either a positive or negative energy balance. In positive energy balance energy in the form of nutrients is taken in at a greater rate than what isexpended as heat and work. Weight gain occurs. In negative energy balance the energy intake is less than the rate at which the energy is expended. Weightloss occurs.

Energy balance is not maintained from moment to moment but over time as the body switches back and forthbetween the absorptive state (positive energy balance) and the post-absorptive state (negative energy balance). Themetabolism in each of these states is as follows:Metabolism During the Absorptive State The absorptive state lasts for about 3-4 hours after a meal. During this state energy is stored in macromoleculesand the metabolic reactions are primarily anabolic. Different cells of the body behave differently in this state: Body Cells in General Cells primarily use glucose for energy. Fatty acids and amino acids can also be used particularly if they areconsumed in excess. Amino acids are also used to synthesize proteins. Proteins serve a structural and functional

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role in the body and are not used to store energy. Hence, the protein mass in the body is stable and does notincrease simply in response to the absorption of excess amino acids. Skeletal Muscle Cells Skeletal muscle cells behave like other cells except that they can also convert glucose to glycogen. The musclecells contain approximately 70% of the body's stored glycogen.

Liver Cells Liver converts glucose to glycogen or fatty acids, and fatty acids to triglycerides. Glycogen is stored in the liver,where approximately 24% of the body's glycogen is stored, while triglycerides are transported to adipose tissue forstorage. Amino acids taken up by the liver may be used to synthesize proteins but most are converted to keto acidswhich can be used for energy or converted into fatty acids and ultimately triglycerides. Triglycerides are transported to adipose tissue in particles called very-low-density lipoproteins, VLDL (the"bad" cholesterol). Cells, particularly adipocytes, have lipoprotein lipase in their membranes which break downtriglycerides into fatty acids which can be absorbed into the cell, and monoglycerides, which are reabsorbed by theliver. Adipocytes Lipoprotein lipase on the cell membranes of adipocytes facilitate the absorption of fatty acids from triglycerides.Triglycerides absorbed from the diet are carried by chylomicrons and triglycerides synthesized by the liver arecarried by VLDLs. Adipocytes also absorb excess glucose from the diet and converts it into triglycerides forstorage.

Energy Reserves Triglyceride synthesis is the final common pathway for nutrients absorbed in excess of the body needs. Most ofthe bodies energy reserves are stored in fat.

Metabolism During Postabsorptive State The postabsorptive state corresponds to the time between meals when nutrients are not being absorbed.This state is primarily a catabolic state. During this state the cells of the nervous system rely on glucose as thesole energy source and the primary function of the postabsorptive state is to maintain plasma glucose levels. The body can draw on glycogen supplies for only a few hours. After this glucose is synthesized from aminoacids, glycerol and other breakdown products of catabolism by a process called gluconeogenesis. The supplyof glucose is maintained for the nervous tissue while most other tissues turn to other sources of energy,particularly fatty acids. This is called glucose sparing.

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The behavior of different cells in the body during this state is as follows: Body Cells in General Most cells utilize fatty acids for energy. Skeletal Muscle Glucose is obtained from glycogen by glycogenolysis. Glycogen is catabolized to glucose-6-P which canonly be used inside the muscle cell. The glucose-6-P is catabolized to lactate which can travel to the liver.Skeletal muscle can also catabolize proteins to amino acids.

Liver Cells The liver is the primary store for glucose for other cells in the body except skeletal muscle cells whichhave their own store. The reason the liver can share its glucose is because liver cells contain glucose-6-phosphatase which converts glucose-6-phosphate to glucose as it is produced by glycogenolysis. The liver isalso the primary site for gluconeogenesis. The glucose produced by either gluconeogenesis or obtained byglycogenolysis can leave the liver and travel to other cells. During the post-absorptive state the liver converts some fatty acids to ketone bodies which are released inthe bloodstream and travel to other tissue. The nervous system can acquire the ability to use ketone bodiesduring prolonged fasting. Adipocytes Adipose cells supply fatty acids for body cells and spares glucose for use by the nervous tissue.Triglycerides are broken down to fatty acids, and glycerol which travels to the liver and is catabolized byglycolysis.

Regulation of Energy Metabolism The cells of the body depend upon molecular switches to convert between absorptive and post-absorptivemetabolism. The pancreatic hormones are what primarily turn these switches on or off.

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Role of Insulin The metabolic adjustments from the post-absorptive to the absorptive state is triggered by insulin. Insulin issecreted by the beta cells of the pancreatic islets (a.k.a. islets of Langerhans) of the pancreas. Insulinpromotes synthesis of energy storage molecules and other processes characterized by the absorptive state. Factors Affecting Insulin Secretion (Table 21.3)

Insulin secretion increases with increases in: 1. plasma glucose 2. plasma amino acids3. parasympathetic nervous system activity4. glucose-dependent insulinotropic peptide (GIP) secreted by cells in the wall of the GI tract.

Insulin secretion decreases with increases in sympathetic nervous system activity and epinephrinesecretion.

Actions of Insulin Insulin promotes energy storage by stimulating synthesis of:

1. fatty acids and triglycerides in the liver and adipose tissue 2. glycogen in liver and skeletal muscle3. proteins in most tissues.

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Insulin opposes breakdown of proteins, triglycerides, and glycogen and suppresses gluconeogenesis by liver. Insulin promotes the transport of nutrients across the cell membrane and into the cell. Insulin does this bystimulating uptake of amino acids and glucose. Glucose uptake is enhanced by increasing the number of glucosetransporters called GLUT 4 in the cell membrane. Insulin has no effect on the uptake of glucose by the liver and nervous tissue which continually absorb glucose.Exercising muscle will also increase its uptake of glucose by independently increasing the number of glucosetransporters in the sarcolemma. An additional effect of insulin is to promote growth by supporting the growth effects of growth hormone.

Role of Glucagon Glucagon is an antagonist of insulin. Glucagon is secreted by the alpha cells of the pancreatic islets. Itpromotes processes of the post-absorptive state. Factors Affecting Glucagon Secretion Glucagon secretion is inhibited by increased plasma concentration of both glucose and insulin. Hence,glucagon secretion increases with a decrease in both blood glucose and insulin. Glucagon secretion is enhanced by increases in both sympathetic nervous system activity and plasmaepinephrine concentration. Actions of Glucagon The overall effect of glucagon is to draw on the basic fuel molecules, glucose and ketone bodies, fromenergy reserves. Glucagon accomplishes this by promoting catabolic reactions that include:

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1. Glycogenolysis in the liver that makes glucose available. 2. Lipolysis in the liver and adipose tissue that results in the breakdown of triglycerides to fatty acidsand the production of ketone bodies. 3. Protein breakdown.

At the same time, glucagon suppresses the reactions that increase energy storage including: 1. Glycogenesis.2. Triglyceride synthesis3. Protein synthesis

Finally, to make more fuel molecules available glucagon promotes gluconeogenesis and ketone bodysynthesis.

Control of Blood Glucose by Insulin and Glucagon Stability of blood glucose levels is important. Normal fasting levels of blood glucose should be 70-110 mg/dL.Fasting levels greater than 140 mg/dL is hyperglycemia and often indicates diabetes mellitus. Levels below 60mg/dL is hypoglycemia. Increased blood glucose stimulates increased insulin secretion and inhibits glucagon secretion.

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Insulin then decreases plasma glucose by:1. Increasing glucose uptake by cells by adding GLUT 4 transporters to the cell membrane.2. Increasing glycogen synthesis in cells and thereby decreasing glucose concentration. 3. Suppressing gluconeogenesis.

Decreased blood glucose stimulates glucagon secretion and inhibits insulin secretion. Glucagon increasesblood glucose by:

1. Promoting gluconeogenesis and glycogenolysis in the liver.

2. Stimulating lipolysis in adipose tissue which makes fatty acids available as an alternate energy sourceto glucose.

Amino Acids Stimulate Both Insulin and Glucagon Secretion When amino acids are absorbed, and glucose is not, the stimulation of insulin secretion would cause glucoselevels to decrease. By stimulating glucagon secretion glucose levels are kept from falling. When amino acidsare absorbed with glucose, insulin secretion is greater than glucagon secretion because both glucose and aminoacids stimulate insulin secretion but glucose inhibits glucagon secretion. Effects of Epinephrine and Sympathetic Nervous Activity The decrease in plasma glucose in the post-absorptive state acts on glucose receptors in the central nervoussystem and stimulates sympathetic activity including secretion of epinephrine by the adrenal medulla.Sympathetic activation increases glycogenolysis and gluconeogenesis in the liver and lipolysis in adiposetissue. Epinephrine also increases glycogenolysis in the skeletal muscle. The sympathetic nervous system influence is most important during stress. When the body is challenged thesympathetic activity increases levels of plasma glucose and fatty acids. The extra availability of fuel enablesthe body to more readily respond to a stressful situation. Hormonal Regulation of Growth Growth in this context refers to changes associated with an increase in height. Growth is associated withincreases in the size of the bones, particularly in the length of long bones and in the size and number of cells insoft tissue.

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Growth Hormone (GH) has an important influence on the changes associated with growth. Other hormonesthat play a supportive role include insulin, thyroid hormones and the sex hormones. Effects of Growth Hormone GH promotes growth by stimulating protein synthesis and an increase in cell size (hypertrophy). It alsostimulates cell division (hyperplasia). GH increases plasma concentration of glucose, fatty acid and glycerol by:

1. Inhibiting glucose uptake in adipose tissue and skeletal muscle.2. Stimulating lipolysis in adipose tissue. 3. Stimulating gluconeogenesis in the liver.

This makes glucose available for growing cells. GH promotes uptake of amino acids by various cells which facilitates protein synthesis.

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Growth hormone needs to be associated with adequate diet to promote growth. An adequate diet hassufficient quantities of essential nutrients such as essential amino acids, minerals such as calcium for bonegrowth, and calories to provide energy for growth. GH promotes growth to a large degree by the actions of intermediary chemical messengers. GH promotes theproduction of somatomedins by the liver and in some other target tissues. Somatomedins are also calledinsulin-like growth factors (IGF). Two have been identified IGF 1 and IGF 2. Factors Affecting GH Secretion Secretion of GH is regulated by growth hormone releasing hormone (GHRH) and growth hormoneinhibiting hormone (GHIH, a.k.a. somatostatin) which are both released by the hypothalamus. GHRH isprobably more important and is regulated by neural imputs to the hypothalamus. GHRH secretion is affected by:

1. Changes in nutrient levels:decreased plasma glucose increase secretiondecreased plasma fatty acids increase secretionincreased plasma amino acids increase secretion

2. Sleep, exercise or stress increases secretion3. Circadian rhythms: secretion increases during the night

GH secretion declines with age after puberty. Bone Growth Bone is a dynamic tissue that responds to forces placed upon it by remodeling. Remodeling in bone is dueto the presence of osteoblasts which build up bone in the process of deposition and osteoclasts that tear downbone tissue in the process of resorption.

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Osteoblasts lays down osteoid (the organic component of bone) which becomes calcified by the depositionof calcium crystals (hydroxyapatite). When osteoblasts become surrounded by bone tissue they are calledosteocytes. Osteocytes remain in contact with each other and osteoblasts by processes that extend throughchannels called canaliculi. Osteoclasts resorb bone by secreting acids that dissolve the calcium and phosphate crystals and enzymesthat breakdown the osteiod. Growth hormone increases the circumference of the bone by increasing the activity of the osteoblasts on theouter surface. This increase in the deposition of bone on the outer surface is associated with resorption of boneon the inner surface by osteoclasts. Growth in the length of bone is due to GH's effect on the chondrocytes at the epiphyseal growth plate ateither end of the bone. This cartilage is replaced by bone. In late adolescence, the epiphyseal growth plate stops growing and is completely replaced by bone makinga further increase in the length of bone impossible. This is called epiphyseal plate closure. Abnormal GH Secretion Deficiency of GH during childhood causes dwarfism. Other causes of dwarfism:

Decrease responsiveness to GH due to:a. defective GH receptorsb. insufficient production of somatomedinc. failure of tissue to respond to somatomedin

Excessive production of GH causes:Gigantism if before the epiphyseal plate closure and,Acromegaly if after the epiphyseal plate closure

Other Hormones that Affect GrowthThyroid hormones - needed for synthesis of GH and permissive for its action.Insulin - needed for secretion of IGF-1 and for normal protein synthesis.Sex Hormones - actively promote growth by stimulating secretion of GH and IGF-1.Androgens - directly stimulate protein synthesis in many tissues.Glucocorticoids - inhibit growth at high concentrations by bone resorption and protein catabolism.

Thyroid Hormones These hormones are secreted at steady rates and maintain the status quo. The hormone is formed in follicleslined by a single layer of follicular cells. Thyroid hormones are stored within the colloid contained within thefollicles in the form of a protein called thyroglobulin. Also, contained within the colloid are enzymes neededfor thyroid hormone synthesis, and iodide (ionized form of iodine).

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Steps of Thyroid Hormone Synthesis1. Tyrosine residues of thyroglobulin are iodinated. One iodide added to tyrosine forms mono-iodotyrosine (MIT), two iodides added forms di-iodotyrosine (DIT).2. Two iodinated residues join by a covalent bond. Two DIT form T4 (tetraiodothyronine). One MITand one DIT forms T3 (tri-iodothyronine).3. Thyroid hormones remain stored as part of thyroglobulin for up to three months.4. TSH (thyroid stimulating hormone) acting by cAMP causes phosphorylation (activation) of theenzymes needed for thyroid hormone synthesis.5. Follicular cells take in thyroglobulin by endocytosis.6. The endosome fuses with a lysosome.7. Lysosomal enzymes cause release of T3 and T4.8. T3 and T4 diffuse across the membrane into the bloodstream. These lipophilic hormones are thentransported in the blood by protein carriers.

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Thyroid hormone secretion is maintained at a constant level by negative feedback. Thyroid hormonereleased in the blood feeds back to the hypothalamus and inhibits secretion of thyrotropin releasing hormone(TRH) which stimulates secretion TSH. Action of Thyroid Hormones Thyroid hormone alters the rate of protein synthesis by increasing the rate of RNA transcription. Theprimary action is to raise the body's metabolic rate. Oxygen consumption increases and heat generation alsoincreases. Thyroid hormone increases the metabolic rate and one way this is accomplished is by increasing theactivity of the sodium/potassium pump in the cells. This is associated with an increased consumption ofATP which necessitates that more ATP is produced. The fuel oxidized to produce ATP causes heatproduction. Thyroid hormone also promotes an increase in the numbers of mitochondria and in theconcentrations of enzymes involved in oxidative phosphorylation. Thyroid hormone at higher than normal concentrations promote glycogenolysis, breakdown of muscleproteins, lipolysis, gluconeogenesis and ketone synthesis. Lower than normal concentrations causeglycogenesis and protein synthesis. Hence, at different concentrations the enzyme has opposite effects. Thyroid hormones promote synthesis of beta-adrenergic receptors and thus permit many tissues to respondto sympathetic nervous activity and to circulating epinephrine. Thyroid hormones are necessary for normal growth and development, particularly of the nervous system.A deficiency of thyroid hormone in infants cause cretinism in which mental development is retarded andgrowth is stunted.

Glucocorticoids Glucocorticoids at normal concentrations are needed for maintenance of a variety of essential body functions. Athigh concentrations, glucocorticoids assist in activating the bodies stress response.

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Factors Affecting Secretion Secretion of glucocorticoids by the adrenal cortex is stimulated by adrenocorticotropic hormone whose ownsecretion is stimulated by corticotropin releasing hormone. Cortisol is the primary glucocorticoid. It is normallysecreted in spurts that can vary in frequency and exhibit a circadian rhythm. Stress of various kinds is an important stimulus for cortisol secretion. Actions of Glucocorticoids The primary actions of glucocorticoids are to maintain normal concentrations of enzymes involved in thecatabolism of proteins, fats and glycogen and the conversion of amino acids into glucose in the liver. Glucocorticoidsare necessary for survival during prolonged fasting. Glucocorticoids are required for growth hormone secretion in association with thyroid hormone, maintain thevasoconstrictive response of blood vessels to hormones, and have a variety of effects on the functions of theimmune system, nervous system and kidneys. Glucocorticoids secreted above resting levels promote energy mobilization and glucose sparing by:

1. Decreasing uptake of glucose and amino acids in many tissues.2. Stimulating lipolysis.3. Stimulating catabolism of muscle proteins.4. Inhibiting protein synthesis.5. Stimulating gluconeogenesis.

At doses above physiological levels glucocorticoids depress the immune response. This has given rise to their usewith auto-immune diseases and to prevent rejection with transplantation of organs.

Role in the Stress Response Cortisol is important in helping the body adapt to stress. Cortisol works with the sympathetic nervous system andhormones that elevate blood pressure in the body's general adaptation syndrome to stress. Effects of Abnormal Glucocorticoid Secretion Hypersecretion of cortisol is known as Cushing's syndrome. The signs of this disease include:1. Hyperglycemia2. Protein depletion

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a. muscle wastingb. breakdown of connective tissuec. easy bruising

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3. Lipolysis4. Redistribution of adipocytes

a. hump backb. pot bellyc. moon face

Hyposecretion is known as Addison's Disease. Signs include:

1. Hypoglycemia2. Poor stress tolerance

3. Hyponatrium4. Hyperkalemia

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