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. This chapter 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 break down nutrients for use in between periods of intake.
2. The nervous system depends upon glucose as its primary energy source. Hence, minimum levels of glucose 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 and cholesterol, and intermediates of glycolysis and Kreb's citric acid cycle can be converted into amino acids and used to synthesize proteins.    
Regulation of Metabolic Pathways
     Whether intermediates are used to produce energy or to construct larger biomolecules depends upon the activity 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 different compartments within the cell. For example, glycolysis occurs in the cytosol while the Kreb's cycle occurs within 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 movement and 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 and triglycerides). 
     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 primary monosaccharide used by the body and can be oxidized for energy, used as a substrate for other metabolic reactions, 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 amino acids may be either broken down for energy or used to synthesize proteins. Proteins form an energy reserve which can be catabolized when needed as during starvation. Use of amino acids for energy production results in the production of NH3 (ammonia) as a toxic waste product which is converted into the less toxic urea by the liver.    
    
  Lipids 
     Lipids are transported in the blood primarily as triglycerides in lipoproteins. The triglycerides in lipoproteins are broken down by lipoprotein lipase into fatty acids and monoglycerides. Fatty acids go into nearby cells. Monoglycerides are metabolized by the liver. 
     Once inside the cell, fatty acids can be oxidized for energy or combined with glycerol to produce new triglycerides for storage. Triglycerides in the cell can be broken down again into fatty acids and glycerol by the process 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 always available. The body mobilizes its energy stores when the rate of energy intake is insufficient to meets its energy needs. 
   Energy input 
     Energy input is the absorbed nutrients in the diet. A person's energy intake is the total energy content of all the nutrients absorbed. 
   Energy output
     The molecules absorbed for energy are oxidized and about 40% of the released energy is used for ATP production while 60% produces heat. 
     Processes of cells requiring energy:
1. Mechanical work
2. Chemical work
3. Transport work
Metabolic Rate
   Metabolic rate is the amount of energy expended per unit time. Basal metabolic rate is the metabolic rate when both the metabolic rate and the work performed are minimal. BMR is estimated by measuring oxygen consumption. 
   BMR is expressed as the rate of energy expenditure per unit of body weight. BMR averages 20-25 kilocalories 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 the work performed plus the heat released. An imbalance occurs when energy input does not equal energy output and 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 is expended 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. Weight loss occurs. 
     Energy balance is not maintained from moment to moment but over time as the body switches back and forth between the absorptive state (positive energy balance) and the post-absorptive state (negative energy balance). The metabolism 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 macromolecules and 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 are consumed in excess. Amino acids are also used to synthesize proteins. Proteins serve a structural and functional role in the body and are not used to store energy. Hence, the protein mass in the body is stable and does not increase 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 muscle cells 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 for storage. Amino acids taken up by the liver may be used to synthesize proteins but most are converted to keto acids which 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 down triglycerides into fatty acids which can be absorbed into the cell, and monoglycerides, which are reabsorbed by the liver.  
   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 are carried by VLDLs. Adipocytes also absorb excess glucose from the diet and converts it into triglycerides for storage. 
   Energy Reserves
     Triglyceride synthesis is the final common pathway for nutrients absorbed in excess of the body needs. Most of the 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 the sole 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 amino acids, glycerol and other breakdown products of catabolism by a process called gluconeogenesis. The supply of 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. 
     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 can only 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 which have 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 is also the primary site for gluconeogenesis. The glucose produced by either gluconeogenesis or obtained by glycogenolysis 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 in the bloodstream and travel to other tissue. The nervous system can acquire the ability to use ketone bodies during 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 by glycolysis. 
Regulation of Energy Metabolism
     The cells of the body depend upon molecular switches to convert between absorptive and post-absorptive metabolism. The pancreatic hormones are what primarily turn these switches on or off. 
Role of Insulin
     The metabolic adjustments from the post-absorptive to the absorptive state is triggered by insulin. Insulin is secreted by the beta cells of the pancreatic islets (a.k.a. islets of Langerhans) of the pancreas. Insulin promotes 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 acids
3. parasympathetic nervous system activity
4. 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 epinephrine secretion. 
  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 muscle
3. proteins in most tissues.
     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 by stimulating uptake of amino acids and glucose. Glucose uptake is enhanced by increasing the number of glucose transporters 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 glucose transporters 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. It promotes 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 plasma epinephrine concentration.
   Actions of Glucagon
     The overall effect of glucagon is to draw on the basic fuel molecules, glucose and ketone bodies, from energy reserves. Glucagon accomplishes this by promoting catabolic reactions that include:
    
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 acids and 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 synthesis
3. Protein synthesis
     Finally, to make more fuel molecules available glucagon promotes gluconeogenesis and ketone body synthesis. 
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 60 mg/dL is hypoglycemia.
   Increased blood glucose stimulates increased insulin secretion and inhibits glucagon secretion. 
   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 increases blood 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 source to 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 glucose levels to decrease. By stimulating glucagon secretion glucose levels are kept from falling. When amino acids are absorbed with glucose, insulin secretion is greater than glucagon secretion because both glucose and amino acids 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 nervous system and stimulates sympathetic activity including secretion of epinephrine by the adrenal medulla. Sympathetic activation increases glycogenolysis and gluconeogenesis in the liver and lipolysis in adipose tissue. Epinephrine also increases glycogenolysis in the skeletal muscle. 
   The sympathetic nervous system influence is most important during stress. When the body is challenged the sympathetic activity increases levels of plasma glucose and fatty acids. The extra availability of fuel enables the 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 with increases in the size of the bones, particularly in the length of long bones and in the size and number of cells in soft tissue. 
   Growth Hormone (GH) has an important influence on the changes associated with growth. Other hormones that 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 also stimulates 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. 
   Growth hormone needs to be associated with adequate diet to promote growth. An adequate diet has sufficient quantities of essential nutrients such as essential amino acids, minerals such as calcium for bone growth, and calories to provide energy for growth. 
   GH promotes growth to a large degree by the actions of intermediary chemical messengers. GH promotes the production of somatomedins by the liver and in some other target tissues. Somatomedins are also called insulin-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 hormone inhibiting hormone (GHIH, a.k.a. somatostatin) which are both released by the hypothalamus. GHRH is probably 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 secretion
decreased plasma fatty acids increase secretion
increased plasma amino acids increase secretion
2. Sleep, exercise or stress increases secretion
3. 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 due to the presence of osteoblasts which build up bone in the process of deposition and osteoclasts that tear down bone tissue in the process of resorption
     Osteoblasts lays down osteoid (the organic component of bone) which becomes calcified by the deposition of calcium crystals (hydroxyapatite). When osteoblasts become surrounded by bone tissue they are called osteocytes. Osteocytes remain in contact with each other and osteoblasts by processes that extend through channels called canaliculi. 
     Osteoclasts resorb bone by secreting acids that dissolve the calcium and phosphate crystals and enzymes that breakdown the osteiod. 
     Growth hormone increases the circumference of the bone by increasing the activity of the osteoblasts on the outer surface. This increase in the deposition of bone on the outer surface is associated with resorption of bone on 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 at either 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 making a 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 receptors
b. insufficient production of somatomedin
c. 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 Growth
Thyroid 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 follicles lined by a single layer of follicular cells. Thyroid hormones are stored within the colloid contained within the follicles in the form of a protein called thyroglobulin. Also, contained within the colloid are enzymes needed for thyroid hormone synthesis, and iodide (ionized form of iodine).
   Steps of Thyroid Hormone Synthesis
1. 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 MIT and 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 the enzymes 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 then transported in the blood by protein carriers. 
    Thyroid hormone secretion is maintained at a constant level by negative feedback. Thyroid hormone released 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. The primary action is to raise the body's metabolic rate. Oxygen consumption increases and heat generation also increases.
     Thyroid hormone increases the metabolic rate and one way this is accomplished is by increasing the activity of the sodium/potassium pump in the cells. This is associated with an increased consumption of ATP which necessitates that more ATP is produced. The fuel oxidized to produce ATP causes heat production. Thyroid hormone also promotes an increase in the numbers of mitochondria and in the concentrations of enzymes involved in oxidative phosphorylation.
      Thyroid hormone at higher than normal concentrations promote glycogenolysis, breakdown of muscle proteins, lipolysis, gluconeogenesis and ketone synthesis. Lower than normal concentrations cause glycogenesis 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 respond to 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 and growth is stunted.
Glucocorticoids
     Glucocorticoids at normal concentrations are needed for maintenance of a variety of essential body functions. At high concentrations, glucocorticoids assist in activating the bodies stress response. 
  Factors Affecting Secretion
     Secretion of glucocorticoids by the adrenal cortex is stimulated by adrenocorticotropic hormone whose own secretion is stimulated by corticotropin releasing hormone. Cortisol is the primary glucocorticoid. It is normally secreted 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 the catabolism of proteins, fats and glycogen and the conversion of amino acids into glucose in the liver. Glucocorticoids are necessary for survival  during prolonged fasting.
     Glucocorticoids are required for growth hormone secretion in association with thyroid hormone, maintain the vasoconstrictive response of blood vessels to hormones, and have a variety of effects on the functions of the immune 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 use with 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 and hormones 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. Hyperglycemia
2. Protein depletion
a. muscle wasting
b. breakdown of connective tissue
c. easy bruising
3. Lipolysis
4. Redistribution of adipocytes
a. hump back
b. pot belly
c. moon face
     Hyposecretion is known as Addison's Disease. Signs include:
1. Hypoglycemia
2. Poor stress tolerance
3. Hyponatrium
4. Hyperkalemia