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Regulation Of Metabolism

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  • 1. Chapter 19 Regulation of Metabolism www.freelivedoctor.com
  • 2. 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.
    www.freelivedoctor.com
  • 3. 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.
    www.freelivedoctor.com
  • 4. 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.
    www.freelivedoctor.com
  • 5. Aerobic Requirements (continued)
    • Catabolism:
      • Hydrolysis (break down monomers down to C0 2 and H 2 0.):
        • Hydrolysis reactions and cellular respiration.
        • Gluconeogenesis.
        • Glycogenolysis.
        • Lipolysis.
    www.freelivedoctor.com
  • 6. 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.
    www.freelivedoctor.com
  • 7. 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.
    www.freelivedoctor.com
  • 8. 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.
    www.freelivedoctor.com
  • 9. The Major Vitamins www.freelivedoctor.com
  • 10. Minerals
    • Needed as cofactors for specific enzymes and other critical functions.
    • Trace elements:
      • Required in small amounts from 50  g to 18 mg/day.
    www.freelivedoctor.com
  • 11. 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.
    www.freelivedoctor.com
  • 12. 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.
    www.freelivedoctor.com
  • 13. Reactive Oxygen Species
    • Insert fig. 19.1
    www.freelivedoctor.com
  • 14. 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 www.freelivedoctor.com
  • 15. 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.
    www.freelivedoctor.com
  • 16. 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.
    www.freelivedoctor.com
  • 17. 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.
    www.freelivedoctor.com
  • 18. 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.
    www.freelivedoctor.com
  • 19. 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.
    www.freelivedoctor.com
  • 20. Calorie Expenditures
    • 3 components:
      • Basal metabolic rate (BMR):
        • 60% total calorie expenditure.
      • Adaptive thermogenesis:
        • 10% total calorie expenditure.
      • Physical activity:
        • Contribution variable.
    www.freelivedoctor.com
  • 21. 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.
    www.freelivedoctor.com
  • 22. 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 www.freelivedoctor.com
  • 23. Energy Regulation of Pancreas
    • Islets of Langerhans contain 3 distinct cell types:
      •  cells 
        • Secrete  glucagon.
      •  cells 
        • Secrete  insulin.
      •  cells 
        • Secrete somatostatin. 
    • 
    www.freelivedoctor.com
  • 24. 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.
    www.freelivedoctor.com
  • 25. 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.
    www.freelivedoctor.com
  • 26. 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 www.freelivedoctor.com
  • 27. 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.
    www.freelivedoctor.com
  • 28. Regulation of Insulin and Glucagon Secretion (continued) www.freelivedoctor.com
  • 29. 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.
    www.freelivedoctor.com
  • 30. 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.
    www.freelivedoctor.com
  • 31. Effect of Feeding and Fasting on Metabolism Insert fig. 19.10 www.freelivedoctor.com
  • 32. Diabetes Mellitus
    • Chronic high blood [glucose].
    • 2 forms of diabetes mellitus:
      • Type I: insulin dependent diabetes (IDDM).
      • Type II: non-insulin dependent diabetes (NIDDM).
    www.freelivedoctor.com
  • 33. Comparison of Type I and Type II Diabetes Mellitus Insert table 19.6 www.freelivedoctor.com
  • 34. 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.
    www.freelivedoctor.com
  • 35. Consequences of Uncorrected Deficiency in Type I Diabetes Mellitus Insert fig. 19.11 www.freelivedoctor.com
  • 36. 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. 19.12 www.freelivedoctor.com
  • 37. 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.
    www.freelivedoctor.com
  • 38. 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. 19.13 www.freelivedoctor.com
  • 39. 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.
    www.freelivedoctor.com
  • 40. 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.
    www.freelivedoctor.com
  • 41. Metabolic Effects of Catecholamines (continued) www.freelivedoctor.com
  • 42. 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.
    www.freelivedoctor.com
  • 43. 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.
    www.freelivedoctor.com
  • 44. 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.
    www.freelivedoctor.com
  • 45. 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].
    www.freelivedoctor.com
  • 46. 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.
    www.freelivedoctor.com
  • 47. Progression of Acromegaly www.freelivedoctor.com
  • 48. Bone Deposition and Resorption
    • Ca 2+ and phosphate concentrations are affected by:
      • Bone formation and resorption.
      • Intestinal absorption of Ca 2+ and P0 4 3- .
      • 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.
    www.freelivedoctor.com
  • 49. 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 P0 4 3- ; 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.
    www.freelivedoctor.com
  • 50. Bone Deposition and Resorption (continued) www.freelivedoctor.com
  • 51. 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 P0 4 3- .
    • Promotes formation of 1,25 vitamin D 3 .
    • Many cancers secrete PTH-related protein that interacts with PTH receptors.
      • Produce hypercalcemia.
    www.freelivedoctor.com
  • 52. 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 P0 4 3- by inhibiting reabsorption.
    • Physiological significance in adults is questionable.
    www.freelivedoctor.com
  • 53. 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.
    www.freelivedoctor.com
  • 54. Production of 1,25 dihydroxyvitamin D 3 Insert fig. 19.20 www.freelivedoctor.com
  • 55. 1,25 dihydroxyvitamin D 3 (continued)
    • Directly stimulates intestinal absorption of Ca 2+ and P0 4 3- .
    • When Ca 2+ intake is inadequate, directly stimulates bone reabsorption.
    • Stimulates reabsorption of Ca 2+ and P0 4 3- by the kidney.
      • Simultaneously raising Ca 2+ and P0 4 3- results in increased tendency of these 2 ions to precipitate as hydroxyapatite crystals.
    • Stimulated by PTH.
    www.freelivedoctor.com
  • 56. Negative Feedback Control Insert fig. 19.23 www.freelivedoctor.com