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Chapter 19
Regulation of Metabolism
19-1
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Chapter 19 Outline
Nutrition & Metabolism
Regulation of Metabolism & Hunger
Energy Regulation by Islets of Langerhans
Diabetes Mellitus & Hypoglycemia
Metabolic Regulation by Adrenal Hormones,
Thyroxine, & GH
Regulation of Calcium & Phosphate Balance
19-2
Nutrition & Metabolism
19-3
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Nutritional Requirements
Living
tissue is maintained by constant expenditure of
energy (ATP)
ATP derived from glucose, fatty acids, ketones,
amino acids, & others
Energy of food is commonly measured in kilocalories
(1 kcal = 1000 calories)
Carbohydrates & proteins yield 4kcal/gm; fats9kcal/gm
19-4
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Metabolic Rate & Caloric Requirements
Metabolic
rate (MR) is total rate of body metabolism
= amount of O2 consumed by body/min
Basal metabolic rate (BMR) is MR of awake relaxed
person 12–14 hrs after eating & at a comfortable
temperature
BMR depends on age, sex, body surface area, activity
level, & thyroid hormone levels
Hyperthyroids have high BMR; hypothyroids have
low BMR
19-5
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Metabolism
Is
all chemical reactions in body
Includes synthesis & energy storage reactions
(anabolism); & energy liberating reactions (catabolism)
19-6
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Anabolic Requirements
Anabolic
reactions synthesize DNA & RNA, proteins,
fats, & carbohydrates
Must occur constantly to replace molecules that are
hydrolyzed in catabolic reactions
19-7
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Turnover Rate
Is
rate at which a molecule is broken down &
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
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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
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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, & K
Water-solubles include B1, B2, B3, B6, B12,
pantothenic acid, biotin, folic acid, & vitamin C
Serve as coenzymes in metabolism
19-10
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19-11
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Minerals (Elements)
Are
needed as cofactors for specific enzymes & other
critical functions
Sodium, potassium, magnesium, calcium, phosphate,
& chloride are needed daily in large amounts
Iron, zinc, manganese, fluorine, copper, molybdenum,
chromium, & selenium are trace elements required in
small amounts/day
19-12
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Free Radicals
Are
highly reactive & 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, & hydroxyl
radical
19-13
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Free Radicals continued
Serve
important physiological functions
Help to destroy bacteria
Can produce vasodilation
Can stimulate cell proliferation
19-14
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Free Radicals continued
In
excess can exert oxidative stress contributing to
disease states
Can damage lipids, proteins, & DNA
Promotes apoptosis, aging, inflammatory disease,
degenerative, & other diseases & malignant growth
Underlying cause is widespread production of
superoxide radicals by mitochondria
19-15
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Free Radicals continued
Body
uses enzymatic & nonezymatic means to protect
itself against oxidative stress
Enzymes that neutralize free radicals include
superoxide dismutase (SOD), catalase, &
glutathione peroxidase
Nonenzymes that react with free radicals by picking
up unpaired electrons include glutathione, vitamin C,
& vitamin E
19-16
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Fig 19.1: Reactive Oxygen Species Balance
19-17
Regulation of Metabolism & Hunger
19-18
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Regulation of Energy Metabolism
 Blood
contains
glucose, fatty acids,
amino acids, & others
that can be used for
energy
 These can be
circulating energy
substrates from
digestion or energy
reserves (glycogen,
protein, or fat)
Fig 19.2
19-19
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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 & release fat under
hormonal control
And may release their own hormone(s) to influence
metabolism
19-20
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Development of Adipose Tissue
Number
of adipocytes increases greatly after birth
Due to mitosis & differentiation of preadipocytes into
adipocytes
Differentiation promoted by high levels of fatty
acids
 Requires nuclear receptor protein (PPARg) that
is activated when bound to a prostaglandin or
drugs
19-21
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Endocrine Functions of Adipocytes
Adipocytes
secrete regulatory factors when their
PPARg receptors are activated
Which cause muscle to become more responsive to
insulin
PPARg-activating drugs are used to treat Type II
diabetes
19-22
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Endocrine Functions of Adipocytes cont.
The
adipocyte hormones TNFa, resistin, & leptin are
increased in obesity & Type II diabetes
All appear to reduce sensitivity of muscle to insulin
(insulin resistance)
Leptin signals hypothalamus how much fat is stored,
regulating hunger & food intake
19-23
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Low Adiposity: Starvation
Starvation
& 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 & in
amenorrhea of underweight women
19-24
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Obesity
Childhood
obesity involves increases in both size &
number of adipocytes
Weight gain in adulthood is due mainly to increase in
adipocyte size
19-25
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Obesity continued
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 is BMI between 19 – 25
Obesity defined as BMI > 30
19-26
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Regulation of Hunger
Is
at least partially controlled by hypothalamus
Lesions in ventromedial area produce hyperphagia
& 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 & fen-phen worked
by elevating brain serotonin
(Now banned because of heart valve side effects)
19-27
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Regulation of Hunger continued
Involves
arcuate nucleus of hypothalamus
Its neurons send axons to paraventricular nucleus &
lateral hypothalamus
1 type of neurons produce MSH which suppresses
hunger
Another produces neuropeptide Y & agouti-related
peptide which increase hunger
19-28
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Regulation of Hunger continued
Involves
signals from stomach & SI
Ghrelin stimulates hunger via effect in arcuate
Secreted by stomach at high levels when
stomach is empty & low levels when full
CCK from SI promotes satiety
Levels rise during & immediately after a meal
Ghrelin & CCK regulate hunger on short-term, mealto-meal basis
19-29
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Regulation of Hunger continued
PYY
is secreted by SI in proportion to caloric content
of food
Decreases hunger by acting in arcuate to
decrease neuropeptide Y & stimulate MSH
Seems to serve intermediate level of control
because injections reduce appetite for 12 hrs
19-30
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Regulation of Hunger continued
Is
influenced by leptin--a satiety factor secreted by
adipocytes & involved in long-term regulation
Secretion increases as stored fat increases
Signals body's level of adiposity
Acts in arcuate to suppress Neuropep Y & agoutirelated peptide; & stimulate MSH
Insulin may play role in satiety
Suppresses Neuropep Y
19-31
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Fig 19.3
19-32
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Calorie Expenditure of Body
Has
3 components:
Number of calories used at BMR make up 60% of
total
Number used in response to temperature changes
& 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 & intensity
19-33
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Absorptive & Postabsorptive States
Absorptive
state is 4 hr period after eating
Energy substrates from digestion are used &
deposited in storage forms (anabolism)
Postabsorptive or fasting state follows absorptive state
Energy is withdrawn from storage (catabolism)
19-34
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Hormonal Regulation of Metabolism
 Balance
between
anabolism &
catabolism
depends on
levels of
insulin,
glucagon,
GH,
thyroxine, &
others
Fig19.5
19-35
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19-36
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Fig 19.6
19-37
Energy Regulation by Islets of
Langerhans
19-38
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Pancreatic Islets of Langerhans
Contain
2 cell types involved in energy homeostasis:
a cells secrete glucagon when glucose levels are
low
Which causes increased glucose by stimulating
glycogenolysis in liver
b cells secrete insulin when glucose levels are high
Which reduces blood glucose by promoting its
uptake by tissues
19-39
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Insulin & Glucagon Secretion
Normal
fasting
glucose level is 65–
105 mg/dl
Insulin & glucagon
normally prevent
levels from rising
above 170mg/dl
after meals or
falling below
50mg/dl between
meals
Fig 19.7
19-40
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Insulin
Overall
effect is to promote anabolism
Promotes storage of digestion products
Inhibits breakdown of fat & protein
Inhibits secretion of glucagon
Stimulates insertion of GLUT4 transporters in cell
membrane of skeletal muscle, liver, & fat
Transports by facilitated diffusion
19-41
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Oral Glucose Tolerance Test
 Measures
response
to drinking a glucose
solution
 Assesses ability of b
cells to secrete
insulin & insulin's
ability to lower blood
glucose
 In non-diabetics,
glucose levels return
to normal within 2
hrs
Insert fig. 19.8
Fig 19.9
19-42
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Glucagon
Maintains
blood glucose concentration above 50mg/dl
Stimulates glycogenolysis in liver
Stimulates gluconeogenesis, lipolysis, & ketogenesis
Skeletal muscle, heart, liver, & kidneys use fatty
acids for energy
19-43
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Fig 19.10
19-44
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Effects of ANS on Insulin & Glucagon
ANS
innervates islets
Activation of Parasymp NS stimulates insulin secretion
Activation of Symp NS stimulates glucagon & inhibits
insulin
This can cause "stress hyperglycemia"
19-45
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Effects of Intestinal Hormones
Insulin
levels increase more after glucose ingestion
than after intravenous glucose infusion
Due to hormones secreted by intestine during meals
"in anticipation" of glucose rise
GIP, GLP-1, & CCK all stimulate insulin secretion
19-46
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Effect of Feeding & Fasting on Metabolism
Fig 19.11
19-47
Diabetes Mellitus & Hypoglycemia
19-48
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Diabetes Mellitus
Characterized
by chronic high blood glucose levels
(hyperglycemia)
Type I (insulin dependent or IDDM) is due to
insufficient insulin secretion
Type II (insulin independent or NIDDM) is due to lack
of effect of insulin
19-49
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19-50
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Type I Diabetes
b
cells of islets are destroyed by autoimmune attack
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
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Effects of Uncontrolled Type I Diabetes
Fig 19.12
19-52
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Type II Diabetes
 Is
slow to develop
 Is hereditary
 Occurs most often in
overweight people
 Involves insulin resistance
 Usually accompanied by
normal-to-high insulin
levels
 Treatable by exercise &
diet
 Is not usually
accompanied by
ketoacidosis
Fig 19.13
19-53
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Hypoglycemia
 Reactive
hypoglycemia is oversecretion of insulin due to an
exaggerated response of b cells to a rise in glucose
 Occurs in people who are genetically predisposed to type II
diabetes
 Symptoms include tremors, hunger, weakness, blurred
vision, & confusion
Fig 19.14
19-54
Metabolic Regulation by Adrenal
Hormones, Thyroxine & GH
19-55
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Metabolic Regulation
Anabolic
effects of insulin are antagonized by
hormones of adrenals, thyroid, & anterior pituitary
Insulin, thyroxine, & GH can act synergistically to
stimulate protein synthesis
19-56
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Metabolic Effects of Epi & Norepi
 Are
similar to glucagon, stimulating glycogenolysis & lipolysis
Fig 19.15
19-57
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Metabolic Effects of Cortisol
Cortisol
is secreted in response to ACTH
Which is often released in response to stress,
including fasting & exercise
Where it supports effects of glucagon
Promotes lipolysis, ketogenesis, & protein
breakdown
 Protein breakdown increases amino acid
levels for use in gluconeogenesis in liver
19-58
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Metabolic Effects of Cortisol continued
Fig 19.16
19-59
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Thyroxine (T4)
Thyroid
secretes mostly tetraiodothyronine (thyroxine)
& a little triiodothyronine (T3)
Active form is T3
Is converted to T3 in target cells by deiodination
Sets BMR by regulating cell respiration
Is necessary for growth & development, especially of
CNS
Increases metabolic heat (calorigenic effect)
Is essential for cold adaptation
19-60
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Growth Hormone Secretion
Is
from anterior pituitary; stimulated by GHRH, &
inhibited by somatostatin, from hypothalamus
Follows a circadian pattern--is greater during sleep &
lower during waking hours
Stimulates growth in children & adolescents
Has important metabolic effects in adults
Is stimulated by increased blood amino acids &
decreased blood glucose
Is increased during fasting
Stimulates protein synthesis, fat breakdown, &
decreases glucose use by most tissues
19-61
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Insulin-like Growth Factors (IGFs)
Are
similar to pro-insulin; produced by many tissues
Are called somatomedins because mediate many of
GH's effects
Liver produces & secretes IGF-1 in response to GH
IGF-1 in turn stimulates cell division & growth of
cartilage
These actions are supported by IGF-2 which has
more insulin-like actions
Do not mediate effects of GH on lipolysis & glucose
sparing
19-62
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Fig 19.17
19-63
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Growth Hormone & Body Growth
Growth
of skeleton occurs first as growth of cartilage at
epiphyseal discs which then become converted to
bone
Mediated by IGF-1 & 2 which stimulate
chondrocytes to divide & 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
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Growth Hormone & Body Growth
 Excess
GH secretion in
adults, after epiphyseal
discs are ossified, results
in acromegaly
 There is no increase in
height
 However soft tissue
still grows
 Causing elongation
of jaw, deformities
in hands, feet, &
bones of face
Fig 19.18
19-65
Regulation of Calcium & Phosphate
Balance
19-66
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Endocrine Control of Ca2+ & PO43 Parathyroid
hormone, 1,25-dihydoxyVit D, & calcitonin control
Ca2+ and P043- levels & activities
 Via effects on bone formation & reabsorption, intestinal
absorption, & urinary excretion
19-67
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Bone Deposition & Reabsorption
Skeleton
is a storage reservoir for calcium &
phosphate
Bone is hardened with calcium phosphate crystals
(hydroxyapatite)
Osteoblasts make bone by 1st secreting a matrix of
collagen which becomes hardened by deposition of
hydroxyapatite
19-68
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Bone Deposition & Reabsorption continued
 Osteoclasts
reabsorb bone by
secreting enzymes
to dissolve matrix &
hydroxyapatite
Fig 19.19
19-69
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Bone Deposition & Reabsorption continued
Formation
& resorption of bone occur constantly at
rates determined by relative activities of osteoblasts &
osteoclasts
During skeletal growth phase, activity of osteoblasts
predominates
During osteoporosis activity of osteoclasts
predominates
Allows tooth position to be shifted by braces
19-70
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Parathyroid Hormone (PTH)
Secreted
by parathyroid glands
Is most important hormone in control of Ca2+ levels
Release is stimulated by low blood Ca2+ levels
Stimulates osteoclasts to reabsorb bone
Stimulates kidneys to reabsorb Ca2+ from filtrate, &
inhibits reabsorption of P043Promotes formation of 1,25 Vit D3
Many cancers secrete PTH-related protein that
interacts with PTH receptors producing hypercalcemia
19-71
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Calcitonin
Secreted
by C cells of thyroid gland
Works with PTH & 1,25 Vit D3 to regulate blood Ca2+
levels
Stimulated by increased plasma Ca2+
Inhibits activity of osteoclasts
Stimulates urinary excretion of Ca2+ & P043- by
inhibiting reabsorption
Physiological significance in adults is not understood
19-72
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Estrogen
Causes
epiphyseal discs (cartilaginous growth plates)
to seal (ossify) which stops growth
Is necessary for proper bone mineralization &
prevention of osteoporosis
Stimulates osteoblast activity & suppresses formation
of osteoclasts
19-73
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TSH & Thyroxine
Hyperthyroids
are more prone to osteoporosis
Not well understood, but osteoblasts & osteoclasts
have receptors for T3
19-74
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1,25 Vitamin D3
 Synthesis
begins in skin when cholesterol derivative is
converted to Vit D3 by sunlight
Fig 19.21
19-75
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1,25 Vitamin D3 continued
stimulates intestinal absorption of Ca2+ & P043When Ca2+ intake is inadequate, directly stimulates
bone reabsorption
Stimulates kidney to reabsorb Ca2+ and P043
Simultaneously raising Ca2+ & P043- results in
increased tendency of these to precipitate as
hydroxyapatite
Stimulated by PTH
Inadequate Vit D in diet & body causes osteomalacia &
rickets (loss of bone calcification)
Directly
19-76
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Overview of Hormonal Control of Ca2+
Fig 19.23
Fig 19.24
19-77