Chapter 19

Regulation of Metabolism

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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 cm3 of H20 from 14.5o to 15.5o C.

The amount of energy released as heat when food is combusted in vitro = amount of energy released within cells through aerobic respiration.

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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. Oxygen consumption of an awake relaxed person 1214 hours after eating and at a comfortable temperature. Age. Gender.

BMR:

BMR determined by:

Body surface area. Thyroid secretion.

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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.

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Aerobic Requirements

(continued)

Catabolism:

Hydrolysis (break down monomers down to C02 and H20.):

Hydrolysis reactions and cellular respiration. Gluconeogenesis. Glycogenolysis. Lipolysis.

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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.

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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. B1, B2, B3, B6, B12, pantothenic acid, biotin, folic acid, and vitamin C.

Water-soluble:

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Vitamins

Water-soluble vitamins:

Serve as coenzymes in the metabolism of carbohydrates, lipids, and proteins. May serve as antioxidants. Bind to nuclear receptors. Serve as antioxidants. Assist in regulation of fetal development. Regulate Ca2+ balance.

Fat-soluble vitamins:

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The Major Vitamins

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Minerals

Needed as cofactors for specific enzymes and other critical functions. Trace elements:

Required in small amounts from 50 mg to 18 mg/day.

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Free Radicals and Antioxidants

Electrons are located in orbitals.

Each orbital contains a maximum of 2 electrons. When an orbital has an unpaired electron. Highly reactive in the body. Oxidize or reduce other atoms.

Free radical:

Major free radicals called:

Reactive oxygen or nitrogen species:

Oxygen or nitrogen as unpaired electron.

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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.
Can react with free radicals by picking up unpaired electrons.

Protective mechanism against oxidative stress.

Glutathione, vitamin C, and vitamin E.

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Reactive Oxygen Species

Insert fig. 19.1

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Regulation of Energy Metabolism

Energy reserves:

Molecules that can be oxidized for energy are derived from storage molecules (glycogen, protein, and fat).

Insert fig. 19.2

Circulating substrates:

Molecules absorbed through small intestine and carried to the cell for use in cell respiration.

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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.

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Regulatory Functions of Adipose Tissue

Adipostat regulatory system (negative feedback loops) to defend amount of adipose tissue.

Differentiation of adipocytes require nuclear receptor protein (PPARg) which is activated when bound to 15-D PGJ2:

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.

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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.

TNFa:

Acts to reduce the sensitivity of cells to insulin.

Increased in obesity.

May contribute to insulin resistance.

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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.

PYY3-36:

Acts within the hypothalamus.

Decreases neuropeptide Y.

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Obesity

Obesity is often diagnosed by using using a body mass index (BMI). BMI = w h2

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.

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Calorie Expenditures

3 components:

Basal metabolic rate (BMR):

60% total calorie expenditure. 10% total calorie expenditure. Contribution variable.

Adaptive thermogenesis:

Physical activity:

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Hormonal Regulation of Metabolism

Absorptive state:

Absorption of energy. 4 hour period after eating. Increase in insulin secretion. Fasting state. At least 4 hours after the meal. Increase in glucagon secretion.

Postabsorptive state:

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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, T3, cortisol, and Epi balance anabolism and catabolism.

Insert fig. 19.4

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Energy Regulation of Pancreas

Islets of Langerhans contain 3 distinct cell types:

a cells:

Secrete glucagon.
Secrete insulin. Secrete somatostatin.

b cells:

D cells:

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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 65105 mg/dl.

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Regulation of Insulin and Glucagon

(continued)

When blood [glucose] increases:

Glucose binds to GLUT2 receptor protein in b cells, stimulating the production and release of insulin. Stimulates skeletal muscle cells and adipocytes to incorporate GLUT4 (glucose facilitated diffusion carrier) into plasma membranes.

Insulin:

Promotes anabolism.

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Oral Glucose Tolerance Test

Measurement of the ability of b cells to secrete insulin. Ability of insulin to lower blood glucose. Normal persons rise in blood [glucose] after drinking solution is reversed to normal in 2 hrs.

Insert fig. 19.8

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Regulation of Insulin and Glucagon

Parasympathetic nervous system:

Stimulates insulin secretion.

Stimulates glucagon secretion. Stimulates insulin secretion. Stimulates insulin secretion. Stimulates insulin secretion.

Sympathetic nervous system:

GIP:

GLP-1:

CCK:

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Regulation of Insulin and Glucagon Secretion

(continued)

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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.

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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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Effect of Feeding and Fasting on Metabolism

Insert fig. 19.10

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Diabetes Mellitus

Chronic high blood [glucose]. 2 forms of diabetes mellitus:

Type I: insulin dependent diabetes (IDDM). Type II: non-insulin dependent diabetes (NIDDM).

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Comparison of Type I and Type II Diabetes Mellitus

Insert table 19.6

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Type I Diabetes Mellitus

b 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 b cells. Rate of fat synthesis lags behind the rate of lipolysis.

Glucose cannot enter the adipose cells.

Fatty acids converted to ketone bodies, producing ketoacidosis.

Increased blood [glucagon].

Stimulates glycogenolysis in liver.

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Consequences of Uncorrected Deficiency in Type I Diabetes Mellitus

Insert fig. 19.11

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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.

Insert fig. 19.12

Obesity.

Do not usually develop ketoacidosis. May have high blood [insulin] or normal [insulin].

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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.

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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

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Metabolic Regulation

Anabolic effects of insulin are antagonized by the hormones of the adrenals, thyroid, and anterior pituitary.

Insulin, T3, and GH can act synergistically to stimulate protein synthesis.

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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. Contains uncoupling protein that dissociates electron transport from ATP production.

NE stimulates b3 receptors in brown fat.

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Metabolic Effects of Catecholamines

(continued)

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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.

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Thyroxine

Active form is T3. Stimulates cellular respiration by:

Production of uncoupling proteins. Lowers cellular [ATP].

Stimulation of active transport Na+/K+ pumps:

Increases metabolic heat. Increases metabolic rate. Contributes to proper growth and development of CNS in children.

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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.

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Growth Hormone

(continued)

IGF-1:

Liver produces and secretes IGF-1 in response to GH. Stimulates cell division and growth of cartilage.
Has more insulin-like actions. Stimulates cellular uptake of amino acids and protein synthesis. Decreases glucose utilization by the tissues.

IGF-2:

Promotes anabolism and catabolism.

Raises blood [glucose].

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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. Elongation of jaw, deformities in hands, feet, and bones of face.

Growth of soft tissue.

Dwarfism:

Inadequate secretion of GH during childhood.

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Progression of Acromegaly

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Bone Deposition and Resorption

Ca2+ and phosphate concentrations are affected by: Bone formation and resorption. 2+ and P0 3-. Intestinal absorption of Ca 4 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.

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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 Ca2+ and P043- ; 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. Cytoplasm prevented from becoming to basic by a Cl-/HC03pump.

Protein matrix digested by cathepsin K.

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Bone Deposition and Resorption

(continued)

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Parathyroid Hormone (PTH)

Single most important hormone in the control of blood [Ca2+].

Stimulated by decreased blood [Ca2+].

Stimulates osteoclasts to reabsorb bone. Stimulates kidneys to reabsorb Ca2+ from glomerular filtrate, and inhibit reabsorption of P043-. Promotes formation of 1,25 vitamin D3. Many cancers secrete PTH-related protein that interacts with PTH receptors.

Produce hypercalcemia.

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Calcitonin

Works with PTH and 1,25 vitamin D3 to regulate blood [Ca2+]. Stimulated by increased plasma [Ca2+]. Inhibits the activity of osteoclasts. Stimulates urinary excretion of Ca2+ and P043- by inhibiting reabsorption. Physiological significance in adults is questionable.

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1,25 Vitamin D3

Pre-vitamin D3 is synthesized in the skin when exposed to mid-ultraviolet waves.

Pre-vitamin D3 isomerized to vitamin D3 (cholecalciferol).

Cholecalciferol is hydroxylated in liver to form 25 hydroxycholecalciferol. In proximal convoluted tubule is hydroxylated to 1,25 dihydroxycholecalciferol (active vitamin D3).

Stimulated by PTH.

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Production of 1,25 dihydroxyvitamin D3

Insert fig. 19.20

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1,25 dihydroxyvitamin D3

(continued)

Directly stimulates intestinal absorption of Ca2+ and P043-. When Ca2+ intake is inadequate, directly stimulates bone reabsorption. Stimulates reabsorption of Ca2+ and P043- by the kidney.

Simultaneously raising Ca2+ and P043- results in increased tendency of these 2 ions to precipitate as hydroxyapatite crystals.

Stimulated by PTH.

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Negative Feedback Control

Insert fig. 19.23