Chapter 19 Regulation of Metabolism. Copyright © The McGraw-Hill Companies, Inc. Permission...

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 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.


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.


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.


Aerobic Requirements (continued)

Catabolism: Hydrolysis (break down monomers

down to C02 and H20.): Hydrolysis reactions and cellular

respiration. Gluconeogenesis. Glycogenolysis. Lipolysis.


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.


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:

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


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 Ca2+ balance.


The Major Vitamins


Minerals

Needed as cofactors for specific enzymes and other critical functions.

Trace elements: Required in small amounts from 50 g

to 18 mg/day.


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.


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.


Reactive Oxygen Species

Insert fig. 19.1


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


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.


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 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.


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.


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.


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.


Calorie Expenditures

3 components: Basal metabolic rate (BMR):

60% total calorie expenditure. Adaptive thermogenesis:

10% total calorie expenditure. Physical activity:

Contribution variable.


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.


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


Energy Regulation of Pancreas

Islets of Langerhans contain 3 distinct cell types: cells

Secreteglucagon. cells

Secreteinsulin. cells

Secrete somatostatin.


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.


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.


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


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.


Regulation of Insulin and Glucagon Secretion (continued)


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.


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.


Insert fig. 19.10

Effect of Feeding and Fasting on Metabolism


Diabetes Mellitus

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

Type I: insulin dependent diabetes (IDDM).

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


Comparison of Type I and Type II Diabetes Mellitus

Insert table 19.6


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.


Consequences of Uncorrected Deficiency in Type I Diabetes Mellitus

Insert fig. 19.11


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


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.


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


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.


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.


Metabolic Effects of Catecholamines (continued)


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.


Thyroxine

Active form is T3. 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.


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.


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].


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.


Progression of Acromegaly


Bone Deposition and Resorption

Ca2+ and phosphate concentrations are affected by: Bone formation and resorption. Intestinal absorption of Ca2+ and P04

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.


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 P04

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-/HC03

- pump.


Bone Deposition and Resorption (continued)


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 P04

3-. Promotes formation of 1,25 vitamin D3. Many cancers secrete PTH-related protein

that interacts with PTH receptors. Produce hypercalcemia.


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.


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.


Production of 1,25 dihydroxyvitamin D3

Insert fig. 19.20


1,25 dihydroxyvitamin D3 (continued)

Directly stimulates intestinal absorption of Ca2+ and P04

3-. When Ca2+ intake is inadequate, directly

stimulates bone reabsorption. Stimulates reabsorption of Ca2+ and P04

3-

by the kidney. Simultaneously raising Ca2+ and P04

3- results in increased tendency of these 2 ions to precipitate as hydroxyapatite crystals.

Stimulated by PTH.


Negative Feedback Control

Insert fig. 19.23

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Chapter 19 Regulation of Metabolism. Copyright © The McGraw-Hill Companies, Inc. Permission...

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