Chapter 19 Regulation of Metabolism

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Nutritional Requirements Living tissue is maintained by constant expenditure of energy (ATP). Indirectly from glucose, fatty acids, ketones, amino acids, and other organic molecules. Energy of food is commonly measured in kilocalories. One kilocalorie is = 1000 calories. One calorie = amount of heat required to raise the temperature of 1 cm 3 of H 2 0 from 14.5 o to 15.5 o C. The amount of energy released as heat when food is combusted in vitro = amount of energy released within cells through aerobic respiration.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Metabolic Rate and Caloric Requirements Metabolic rate is the total rate of body metabolism. Metabolic rate measured by the amount of oxygen consumed by the body/min. BMR: Oxygen consumption of an awake relaxed person 12–14 hours after eating and at a comfortable temperature. BMR determined by: Age. Gender. Body surface area. Thyroid secretion.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Anabolic Requirements Anabolism: Food supplies raw materials for synthesis reactions. Synthesize: DNA and RNA. Proteins. Triglycerides. Glycogen. Must occur constantly to replace molecules that are hydrolyzed.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Aerobic Requirements (continued) Catabolism: Hydrolysis (break down monomers down to C0 2 and H 2 0.): Hydrolysis reactions and cellular respiration. Gluconeogenesis. Glycogenolysis. Lipolysis.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Turnover Rate Rate at which a molecule is broken down and resynthesized. Average daily turnover for carbohydrates is 250 g/day. Some glucose is reused to form glycogen. Only need about 150 g/day. Average daily turnover for protein is 150 g/day. Some protein may be reused for protein synthesis. Only need 35 g/day. 9 essential amino acids. Average daily turnover for fats is 100 g/day. Little is actually required in the diet. Fat can be produced from excess carbohydrates. Essential fatty acids: Linoleic and linolenic acids.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Vitamins and Minerals Vitamins: Small organic molecules that serve as coenzymes in metabolic reactions or have highly specific functions. Must be obtained from the diet because the body does not produce them, or does so in insufficient amounts. 2 classes of vitamins: Fat-soluble: A,D, E, and K. Water-soluble: B 1, B 2, B 3, B 6, B 12, pantothenic acid, biotin, folic acid, and vitamin C.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Vitamins Water-soluble vitamins: Serve as coenzymes in the metabolism of carbohydrates, lipids, and proteins. May serve as antioxidants. Fat-soluble vitamins: Bind to nuclear receptors. Serve as antioxidants. Assist in regulation of fetal development. Regulate Ca 2+ balance.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. The Major Vitamins

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Minerals Needed as cofactors for specific enzymes and other critical functions. Trace elements: Required in small amounts from 50  g to 18 mg/day.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Free Radicals and Antioxidants Electrons are located in orbitals. Each orbital contains a maximum of 2 electrons. Free radical: When an orbital has an unpaired electron. Highly reactive in the body. Oxidize or reduce other atoms. Major free radicals called: Reactive oxygen or nitrogen species: Oxygen or nitrogen as unpaired electron.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Free Radicals and Antioxidants (continued) Functions of free radicals: Help to destroy bacteria. Produce vasodilation. NO radical, superoxide radical, and hydroxy radical. Exert oxidative stress contributing to disease states. Excess production of free radicals can damage lipids, proteins, and DNA. Promotes apoptosis, contributes to aging, inflammatory disease, heart disease, CVA, HTN, and degenerative disease. Promotes malignant growth. Protective mechanism against oxidative stress. Can react with free radicals by picking up unpaired electrons. Glutathione, vitamin C, and vitamin E.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Reactive Oxygen Species Insert fig. 19.1

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Regulation of Energy Metabolism Energy reserves: Molecules that can be oxidized for energy are derived from storage molecules (glycogen, protein, and fat). Circulating substrates: Molecules absorbed through small intestine and carried to the cell for use in cell respiration. Insert fig. 19.2

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Eating Eating behaviors partially controlled by hypothalamus. Lesions in vetromedial area produce hyperphagia (obesity). Lesions in lateral hypothalamus produces hypophagia (weight loss). Endorphins, NE, serotonin, and CCK affect hunger and satiety.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Regulatory Functions of Adipose Tissue Adipostat regulatory system (negative feedback loops) to defend amount of adipose tissue. Differentiation of adipocytes require nuclear receptor protein (PPAR  which is activated when bound to 15-D PGJ 2: Stimulates adipogenesis by promoting development of preadipocytes into mature adipocytes. Number of adipocytes increase after birth. Differentiation promoted by high [fatty acids]. Adipocytes store fat within large vacuoles. May secrete hormones involved in regulation of metabolism.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Regulatory Functions of Adipose Tissue (continued) Leptin: Hormone that signals the hypothalamus to indicate the level of fat storage. Involved in long-term regulation of eating. Satiety factor in obese have decreased sensitivity to leptin in the brain. Neuropeptide Y: Potent stimulator of appetite. Functions as a NT within the hypothalamus. These neurons are inhibited by leptin. TNF  Acts to reduce the sensitivity of cells to insulin. Increased in obesity. May contribute to insulin resistance.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Regulation of Hunger Adipose tissue secrete satiety factor: Acts through its regulation of hunger centers in hypothalamus. Ghrelin: Secreted by stomach. Secretions rise between meals and stimulate hunger. CCK: Secretions rise during and immediately after a meal. Produce satiety. PYY 3-36 : Acts within the hypothalamus. Decreases neuropeptide Y.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Obesity Obesity is often diagnosed by using using a body mass index (BMI). BMI = w h 2 w = weight in kilograms h = height in meters Healthy weight as BMI between 19 – 25. Obesity defined as BMI > 30. Obesity in childhood is due to an increase in both the size and the # of adipocytes. Weight gains in adulthood is due to increase in adipocyte size in intra-abdominal fat.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Calorie Expenditures 3 components: Basal metabolic rate (BMR): 60% total calorie expenditure. Adaptive thermogenesis: 10% total calorie expenditure. Physical activity: Contribution variable.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Hormonal Regulation of Metabolism Absorptive state: Absorption of energy. 4 hour period after eating. Increase in insulin secretion. Postabsorptive state: Fasting state. At least 4 hours after the meal. Increase in glucagon secretion.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Balance Between Anabolism and Catabolism The rate of deposit and withdrawal of energy substrates, and the conversion of 1 type of energy substrate into another; are regulated by hormones. Antagonistic effects of insulin, glucagon, GH, T 3, cortisol, and Epi balance anabolism and catabolism. Insert fig. 19.4

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Energy Regulation of Pancreas Islets of Langerhans contain 3 distinct cell types:  cells  Secrete  glucagon.  cells  Secrete  insulin.  cells  Secrete somatostatin.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Regulation of Insulin and Glucagon Mainly regulated by blood [glucose]. Lesser effect: blood [amino acid]. Regulated by negative feedback. Glucose enters the brain by facilitated diffusion. Normal fasting [glucose] is 65–105 mg/dl.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Regulation of Insulin and Glucagon (continued) When blood [glucose] increases: Glucose binds to GLUT2 receptor protein in  cells, stimulating the production and release of insulin. Insulin: Stimulates skeletal muscle cells and adipocytes to incorporate GLUT4 (glucose facilitated diffusion carrier) into plasma membranes. Promotes anabolism.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Oral Glucose Tolerance Test Measurement of the ability of  cells to secrete insulin. Ability of insulin to lower blood glucose. Normal person’s rise in blood [glucose] after drinking solution is reversed to normal in 2 hrs. Insert fig. 19.8

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Regulation of Insulin and Glucagon Parasympathetic nervous system: Stimulates insulin secretion. Sympathetic nervous system: Stimulates glucagon secretion. GIP: Stimulates insulin secretion. GLP-1: Stimulates insulin secretion. CCK: Stimulates insulin secretion.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Regulation of Insulin and Glucagon Secretion (continued)

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Absorptive State Insulin is the major hormone that promotes anabolism in the body. When blood [insulin] increases: Promotes cellular uptake of glucose. Stimulates glycogen storage in the liver and muscles. Stimulates triglyceride storage in adipose cells. Promotes cellular uptake of amino acids and synthesis of proteins.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Postabsorptive State Maintains blood glucose concentration. When blood [glucagon] increased: Stimulates glycogenolysis in the liver (glucose-6-phosphatase). Stimulates gluconeogenesis. Skeletal muscle, heart, liver, and kidneys use fatty acids as major source of fuel (hormone-sensitive lipase). Stimulates lipolysis and ketogenesis.

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Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Diabetes Mellitus Chronic high blood [glucose]. 2 forms of diabetes mellitus: Type I: insulin dependent diabetes (IDDM). Type II: non-insulin dependent diabetes (NIDDM).

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Comparison of Type I and Type II Diabetes Mellitus Insert table 19.6

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Type I Diabetes Mellitus  cells of the islets of Langerhans are destroyed by autoimmune attack which may be provoked by environmental agent. Killer T cells target glutamate decarboxylase in the  cells. Glucose cannot enter the adipose cells. Rate of fat synthesis lags behind the rate of lipolysis. Fatty acids converted to ketone bodies, producing ketoacidosis. Increased blood [glucagon]. Stimulates glycogenolysis in liver.

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Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Type II Diabetes Mellitus Slow to develop. Genetic factors are significant. Occurs most often in people who are overweight. Decreased sensitivity to insulin or an insulin resistance. Obesity. Do not usually develop ketoacidosis. May have high blood [insulin] or normal [insulin]. Insert fig

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Treatment in Diabetes Change in lifestyle: Increase exercise: Increases the amount of membrane GLUT-4 carriers in the skeletal muscle cells. Weight reduction. Increased fiber in diet. Reduce saturated fat.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Hypoglycemia Over secretion of insulin. Reactive hypoglycemia: Caused by an exaggerated response to a rise in blood glucose. Occurs in people who are genetically predisposed to type II diabetes. Insert fig

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Metabolic Regulation Anabolic effects of insulin are antagonized by the hormones of the adrenals, thyroid, and anterior pituitary. Insulin, T 3, and GH can act synergistically to stimulate protein synthesis.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Metabolic Effects of Catecholamines Metabolic effects similar to glucagon. Stimulate glycogenolysis. Stimulate release of glucose from the liver. Stimulate lipolysis and release of fatty acids. NE stimulates  3 receptors in brown fat. Contains uncoupling protein that dissociates electron transport from ATP production.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Metabolic Effects of Catecholamines (continued)

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Metabolic Effects of Glucocorticoids Glucocorticoids secreted in response to release of ACTH. Support the effects of increased glucagon. Promote lipolysis and ketogenesis. Promote protein breakdown in the muscles. Increases blood [amino acids]. Promote liver gluconeogenesis.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Thyroxine Active form is T 3. Stimulates cellular respiration by: Production of uncoupling proteins. Stimulation of active transport Na + /K + pumps: Lowers cellular [ATP]. Increases metabolic heat. Increases metabolic rate. Contributes to proper growth and development of CNS in children.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Growth Hormone (Somatotropin) Inhibited by somatostatin. Stimulates growth in children and adolescents. Stimulated by: GHRH. Increase in blood [amino acids]. Decrease in blood [glucose]. Pulsatile, increasing during sleep, decreasing during day.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Growth Hormone (continued) IGF-1: Liver produces and secretes IGF-1 in response to GH. Stimulates cell division and growth of cartilage. IGF-2: Has more insulin-like actions. Promotes anabolism and catabolism. Stimulates cellular uptake of amino acids and protein synthesis. Decreases glucose utilization by the tissues. Raises blood [glucose].

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Effects of Growth Hormone on Body Growth Gigantism: Excess GH secretion in children. Maintain normal body proportions. Acromegaly: Excess GH secretion in adults after the epiphyseal discs are sealed. No increase in height. Growth of soft tissue. Elongation of jaw, deformities in hands, feet, and bones of face. Dwarfism: Inadequate secretion of GH during childhood.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Progression of Acromegaly

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Bone Deposition and Resorption Ca 2+ and phosphate concentrations are affected by: Bone formation and resorption. Intestinal absorption of Ca 2+ and P Urinary excretion. Osteoblasts: Secrete an organic matrix of collagen proteins. Deposit hydroxyapatite crystals. Osteoclasts: Secrete enzymes to dissolve hydroxyapatite. Formation and resorption of bone occur constantly at rates determined by osteoblasts and osteoclasts.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Bone Deposition and Resorption (continued) Bone resorption occurs when an osteoclast attaches to the bone matrix and forms ruffled membrane. Osteoclast secretes products that dissolve both Ca 2+ and P ; and digest the matrix. Transport of H + by H + ATPase pump in ruffled border. Cl - channel allows Cl - to flow to H + to maintain electrical neutrality. Protein matrix digested by cathepsin K. Cytoplasm prevented from becoming to basic by a Cl - /HC0 3 - pump.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Bone Deposition and Resorption (continued)

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Parathyroid Hormone (PTH) Single most important hormone in the control of blood [Ca 2+ ]. Stimulated by decreased blood [Ca 2+ ]. Stimulates osteoclasts to reabsorb bone. Stimulates kidneys to reabsorb Ca 2+ from glomerular filtrate, and inhibit reabsorption of P Promotes formation of 1,25 vitamin D 3. Many cancers secrete PTH-related protein that interacts with PTH receptors. Produce hypercalcemia.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Calcitonin Works with PTH and 1,25 vitamin D 3 to regulate blood [Ca 2+ ]. Stimulated by increased plasma [Ca 2+ ]. Inhibits the activity of osteoclasts. Stimulates urinary excretion of Ca 2+ and P by inhibiting reabsorption. Physiological significance in adults is questionable.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1,25 Vitamin D 3 Pre-vitamin D 3 is synthesized in the skin when exposed to mid-ultraviolet waves. Pre-vitamin D 3 isomerized to vitamin D 3 (cholecalciferol). Cholecalciferol is hydroxylated in liver to form 25 hydroxycholecalciferol. In proximal convoluted tubule is hydroxylated to 1,25 dihydroxycholecalciferol (active vitamin D 3 ). Stimulated by PTH.

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Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1,25 dihydroxyvitamin D 3 (continued) Directly stimulates intestinal absorption of Ca 2+ and P When Ca 2+ intake is inadequate, directly stimulates bone reabsorption. Stimulates reabsorption of Ca 2+ and P by the kidney. Simultaneously raising Ca 2+ and P results in increased tendency of these 2 ions to precipitate as hydroxyapatite crystals. Stimulated by PTH.

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Negative Feedback Control Insert fig