1. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Chapter 19 Regulation of Metabolism 19-1

2. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Nutritional Requirements  Living tissue is maintained by constant expenditure of energy (ATP)  ATP derived from glucose, fatty acids, ketones, amino acids, and others  Energy of food is commonly measured in kilocalories (1 kcal = 1000 calories)  Carbohydrates and proteins yield 4kcal/gm; fats-9kcal/gm 19-4

3. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Metabolic Rate and Caloric Requirements  Metabolic rate (MR) is total rate of body metabolism  = amount of O 2 consumed by body/min  Basal metabolic rate (BMR) is MR of awake relaxed person 12–14 hrs after eating and at a comfortable temperature  BMR depends on age, sex, body surface area, activity level, and thyroid hormone levels  Hyperthyroids have high BMR; hypothyroids have low BMR 19-5

4. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Metabolism  Is all chemical reactions in body  Includes synthesis and energy storage reactions (anabolism); and energy liberating reactions (catabolism) 19-6

5. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Anabolic Requirements  Anabolic reactions synthesize DNA and RNA, proteins, fats, and carbohydrates  Must occur constantly to replace molecules that are hydrolyzed in catabolic reactions 19-7

6. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Turnover Rate  Is rate at which a molecule is broken down and resynthesized  Average turnover for Carbs is 250 g/day  Some glucose is reused so net need ~150 g/day  Average turnover for protein is 150 g/day  Some is reused for protein synthesis so net need ~35 g/day  9 essential amino acids must be supplied in diet because can't be synthesized 19-8

7. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Turnover Rate continued  Average turnover for fats is 100 g/day  Little is required in diet because can be synthesized from Carbs  2 essential fatty acids must be supplied in diet 19-9

8. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Vitamins  Are small organic molecules that serve as coenzymes in metabolism or have highly specific functions  Must be obtained in diet because body does not produce them, or does so in insufficient amounts  Can be placed in 2 classes  Fat-solubles include A, D, E, and K  Water-solubles include B 1, B 2, B 3, B 6, B 12, pantothenic acid, biotin, folic acid, and vitamin C  Serve as coenzymes in metabolism 19-10

9. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 19-11

10. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Minerals (Elements)  Are needed as cofactors for specific enzymes and other critical functions  Sodium, potassium, magnesium, calcium, phosphate, and chloride are needed daily in large amounts  Iron, zinc, manganese, fluorine, copper, molybdenum, chromium, and selenium are trace elements required in small amounts/day 19-12

11. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Free Radicals  Are highly reactive and oxidize or reduce other atoms  Because have an unpaired electron in their outer orbital  The major free radicals are reactive oxygen or reactive nitrogen species  Because contain oxygen or nitrogen with unpaired electron  Include NO radical, superoxide radical, and hydroxyl radical 19-13

12. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.  Serve important physiological functions  Help to destroy bacteria  Can produce vasodilation  Can stimulate cell proliferation Free Radicals continued 19-14

13. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.  In excess can exert oxidative stress contributing to disease states  Can damage lipids, proteins, and DNA  Promote apoptosis, aging, inflammatory disease, degenerative, and other diseases and malignant growth  Underlying cause is widespread production of superoxide radicals by mitochondria Free Radicals continued 19-15

14. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 19-17

15. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Control of Adipose Tissue Levels  Body appears to have negative feedback loops (an adipostat) to defend maintenance of a certain amount of adipose tissue  Adipose cells (adipocytes) store and release fat under hormonal control  And may release their own hormone(s) to influence metabolism 19-20

16. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.  Adipocytes secrete regulatory hormones called adipokines when their PPARg receptors are activated  Regulate hunger, metabolism, and insulin sensitivity  E.g., cause muscle to become more responsive to insulin  Include adiponectin, leptin, resistin, TNF , and retinol BP4 Endocrine Functions of Adipocytes 19-22

17. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.  The adipocyte hormones TNFa, resistin, retinol BP4, and leptin are increased in obesity and Type II diabetes  All appear to reduce sensitivity of muscle to insulin (insulin resistance)  Leptin signals the hypothalamus on how much fat is stored, thereby regulating hunger and food intake  Adiponectin is decreased in obesity and Type II diabetes  has an insulin-sensitizing, antidiabetic effect Endocrine Functions of Adipocytes cont. 19-23

18. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Low Adiposity: Starvation  Starvation and malnutrition diminish immune function  Low adipose levels cause low leptin levels  Helper T cells have leptin receptors  Thus, low leptin can lead to diminished immune function  Leptin may play role in timing of puberty and in the amenorrhea of underweight women 19-24

19. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Obesity  Childhood obesity involves increases in both size and number of adipocytes  Weight gain in adulthood is due mainly to increase in adipocyte size 19-25

20. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Obesity continued  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 is BMI between 19 – 25  Obesity defined as BMI > 30  60% of pop in US is either overweight (BMI>25) or obese (BMI>30) 19-26

21. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Regulation of Hunger  Is at least partially controlled by hypothalamus  Lesions in ventromedial area produce hyperphagia and obesity in animals  Lesions in lateral area produce hypophagia  Involves a number of NTs: endorphins (promote overeating), Norepi (promotes overeating), serotonin (suppresses overeating)  Very successful diet pills Redux and fen-phen worked by elevating brain serotonin  (Now banned because of heart valve side effects) 19-27

22. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Regulation of Hunger: Signals from Stomach and SI  Involves polypeptide hormones secreted by the stomach and SI  Ghrelin stimulates hunger via effect in arcuate  Secreted by stomach at high levels when stomach is empty and low levels when full  CCK from SI promotes satiety  Released during digestion  Levels rise during and immediately after a meal  Ghrelin and CCK regulate hunger on short-term, meal-to- meal basis 19-29

23. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Regulation of Hunger continued  Is influenced by leptin--a satiety factor secreted by adipocytes and involved in long-term regulation  Secretion increases as stored fat increases  Signals body's level of adiposity  Acts in arcuate to suppress Neuropep Y and agouti- related peptide; and stimulate MSH  Insulin may play role in satiety  Suppresses Neuropep Y 19-31

24. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Calorie Expenditure of Body  Has 3 components:  Number of calories used at the BMR make up 60% of total  Number used in response to temperature changes and during digestion/absorption (adaptive thermogenesis) make-up 10% of total  Starvation can lower MR 40%; eating raises MR 25- 40% (thermic effect of food)  Number used during physical activity depends on type and intensity 19-33

25. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Hormonal Regulation of Metabolism  Balance between anabolism and catabolism depends on levels of insulin, glucagon, GH, thyroxine, and others 19-35

26. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 19-36

27. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Pancreatic Islets of Langerhans  Contain 2 cell types involved in energy homeostasis:  α cells secrete glucagon when glucose levels are low  Which causes increased glucose by stimulating glycogenolysis in liver  β cells secrete insulin when glucose levels are high  Which reduces blood glucose by promoting its uptake by tissues 19-39

28. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Insulin and Glucagon Secretion  Normal fasting glucose level is 65–105 mg/dl  Insulin and glucagon normally prevent levels from rising above 170mg/dl after meals or falling below 50mg/dl between meals 19-40

29. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Insulin  Overall effect is to promote anabolism  Promotes storage of digestion products  Inhibits breakdown of fat and protein  Inhibits secretion of glucagon  Stimulates insertion of GLUT4 transporters in cell membrane of skeletal muscle, liver, and fat  Transports by facilitated diffusion 19-41

30. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Glucagon  Maintains blood glucose concentration above 50mg/dl  Stimulates glycogenolysis in liver  Stimulates gluconeogenesis, lipolysis, and ketogenesis  Skeletal muscle, heart, liver, and kidneys use fatty acids for energy 19-43

31. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Effects of ANS on Insulin and Glucagon  ANS innervates islets  Activation of Parasymp NS stimulates insulin secretion  Activation of Symp NS stimulates glucagon and inhibits insulin  This can cause "stress hyperglycemia" 19-45

32. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Diabetes Mellitus  Characterized by chronic high blood glucose levels (hyperglycemia)  Type I (insulin dependent or IDDM) is due to insufficient insulin secretion  5% of diabetics are this type  Type II (insulin independent or NIDDM) is due to lack of effect of insulin  95% of diabetics are this type 19-49

33. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Type I Diabetes  β cells of islets are progressively destroyed by autoimmune attack by killer T lymphocytes  Glucose is unable to enter resting muscle or adipose cells  Rate of fat synthesis lags behind rate of lipolysis  Fatty acids are converted to ketone bodies, producing ketoacidosis  Increased glucagon levels stimulate glycogenolysis in liver 19-51

34. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Effects of Uncontrolled Type I Diabetes 19-52

35. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Metabolic Effects of Cortisol  Cortisol is secreted in response to ACTH  Which is often released in response to stress, including fasting and exercise  Where it supports effects of glucagon  Promotes lipolysis, ketogenesis, and protein breakdown  Protein breakdown increases amino acid levels for use in gluconeogenesis in liver 19-58

36. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Metabolic Effects of Cortisol continued 19-59

37. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 19-63

38. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Growth Hormone and Body Growth  Growth of skeleton occurs first as growth of cartilage at epiphyseal discs which then become converted to bone  Mediated by IGF-1 and 2 which stimulate chondrocytes to divide and secrete more cartilaginous matrix  Growth stops when epiphyseal discs are ossified  Gigantism produced by excess GH secretion in children  Dwarfism caused by inadequate secretion of GH during childhood 19-64

39. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1,25 Vitamin D 3  Synthesis begins in skin when cholesterol derivative is converted to Vit D 3 by sunlight 19-75

40. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1,25 Vitamin D 3 continued  Directly stimulates intestinal absorption of Ca 2+ and PO 4 3-  Directly stimulates bone reabsorption by promoting formation of osteoclasts  Stimulates kidney to reabsorb Ca 2+ and PO 4 3  Simultaneously raising Ca 2+ and PO 4 3- results in increased tendency of these to precipitate as hydroxyapatite  Stimulated by PTH  Inadequate Vit D in diet and body causes osteomalacia and rickets (loss of bone calcification) 19-76