Gastrointestinal 3
(Metabolism)
NROSCI-BIOSC 1070
Human Physiology
November 30, 2015
Metabolism
Definition: all the chemical reactions in all the cells of the body
Quantification: heat production by the body
★
Defined as the quantity of heat required to raise 1 gram of
water by 1°C, and abbreviated by “c” (lower case)
★
Since this value is so small, the Kilocalorie (1000 calories) is
used as a base. The Kilocalorie is defined by “C” (upper
case)
★
2000 Calories (typical daily intake)=enough heat to raise
2,000 Kg (2,000 L) of water by 1°C
Measurement: direct calorimetry (direct
measurement of heat production)
Subject in insulated, air-filled chamber
Heat from subject’s body warms air
Air pumped through pipes in cool water
bath
Rate of heat gain by water = rate of
heat liberation of body (~ metabolic
rate)
Indirect Calorimetry
Defined by rate of oxygen utilization
> 95% of energy expended in body is derived from reactions
involving oxygen
Good approximation of metabolic rate
Amount of energy released when 1 L of O2 reacts with…
-
Glucose = 5.01 Calories of energy
-
Starches = 5.06 Calories of energy
-
Fat = 4.70 Calories of energy
-
Protein = 4.60 Calories
-
Average = 4.825 Calories/L O2
Caloric Utilization
Average man who lays in bed all day
uses ~1650 Calories of energy
If the man lies in bed but eats, he
utilizes ~1850 Calories of energy
Up to 3000 Calories per day can be
utilized if an individual is involved in
strenuous activity
Basal Metabolic Rate
Minimal energy required to exist –
processes to “just keep you alive”
Highly variable depending on sex, age,
body size, etc.
Skeletal muscle accounts for ~20-30% of
BMR (might help explain above)
Most of BMR: accounted for by CNS,
heart, kidney, and other organ functions
BMR
Decline of BMR with age:
decreased muscle mass,
increased adipose tissue
(lower rate of
metabolism)
Lower BMR in females:
generally lower muscle
mass
Thyroid and growth
hormones also affect
BMR
93% of secreted thyroid hormone
is thyroxine (T4)
TSH from anterior pituitary
T4
T3
Over several days: almost all T4 is
converted to T3
T4
Deiodination of T4 in tissues
T3
Thyroid Hormone(s)
Are both hormones the same in their
actions? – yes, but they act with
different efficacy
Differ in rapidity and intensity of
action
T3 is ~4 times as potent as T4
T3 – lower plasma concentration,
shorter half life
Anatomy of the
Thyroid Gland
Cuboidal epithelial cells
secrete colloid into the middle
of a division of the thyroid
gland, which is called a
follicle.
The major constituent of
colloid is the thyroid
hormones, which can be
stored for a considerable
period of time.
When needed, the hormones
are absorbed from the center
of the follicle by the cuboidal
epithelial cells, and then
secreted into the blood.
Anatomy of the Thyroid Gland
Normal thyroid
gland
Histological section
Synthesis of Thyroid Hormone
T3 and T4 are unusual
molecules, as they contain
iodine.
About 1 mg of iodine must
be consumed per week in
order for adequate
quantities of T3 and T4 to be
produced.
To insure that iodine
deficiencies are not
common, table salt is
typically iodized with one
part sodium iodide to every
100,000 parts sodium
chloride.
Question for
Discussion
Why were
iodine tablets given to
Japanese citizens after
the recent nuclear
power plant disaster?
Transport of Thyroid
Hormone
T3 and T4 must bind to a carrier protein in the blood to be
transported.
The carrier is made in the liver, and is typically thyroxinebinding globulin.
As noted above, T4 is typically deiodinated to form T3 as
it circulates.
Once T3 is released from the carrier, it passes into target
cells by simple diffusion and binds to specific intracellular
receptors that are bound to chromatin.
By binding to these receptors, T3 affects the expression of
specific genes.
Half-Life of Thyroid Hormone
After secretion of
T3 and T4 it can
take a long time for
the effects of the
hormones to
become apparent.
This is best demonstrated in the case of an individual whose
thyroid gland has been removed, and is injected with a single
dose of thyroxine.
Essentially no effects can be discerned for 2-3 days, and
maximal effects do not occur until about 10 days after injection.
Effects of Thyroid Hormones
Growth and Development
✴ Thyroid
hormone plays an important role in stimulating
growth.
✴ Essential
for proper nervous system development
Carbohydrate Metabolism
✴ Thyroid
hormone stimulates almost all aspects of
carbohydrate metabolism, including rapid uptake of glucose
by cells, enhanced glycolysis, enhanced gluconeogenesis,
increased rate of absorption of sugar from the GI tract, and
even greater insulin secretion.
✴ These
effects are due to a generalized increase in the
production of cellular metabolic enzymes.
Effects of Thyroid Hormones
Fat Metabolism
✴ Almost
all aspects of fat metabolism are also enhanced by
thyroid hormone, including mobilization of lipids from fat
tissue and acceleration of oxidation of free fatty acids by
cells.
✴ Thus,
fat stores of the body are rapidly depleted when thyroid
hormone secretion is high.
Vitamin Requirements
✴ Because
thyroid hormone increases the levels of many
enzymes in the body and thus enhances enzymatic reactions,
the demands for cofactors for those reactions is increased.
✴ Thus,
an otherwise normal consumption of vitamins may be
insufficient in a hyperthyroid patient.
Effects of Thyroid Hormone
Because thyroid hormone
increases metabolism in
almost every cell of the
body,excessive quantities of
the hormone vastly increase
BMR.
In fact, BMR can double with
extremely high levels of
thyroid hormone.
Effects of Thyroid Hormone
Body Weight
✴Typically,
high levels of metabolism
associated with high levels of thyroid
hormone result in a drop in body weight.
✴This
does not always occur, however, as
appetite and food intake also increase
when thyroid hormone levels are raised.
Effects of Thyroid Hormone
Cardiovascular System Physiology
✴ Increased
metabolic rate in almost every body tissue results
in an increased oxygen usage and the formation of high
levels of metabolic wastes.
✴ These
agents serve as paracrine factors that increase blood
flow to a region. Blood flow to the skin becomes especially
high with high levels of thyroid hormone, as body heat
increases and must be dissipated.
✴ The
lowered peripheral resistance in almost every tissue
demands that cardiac output must increase tremendously.
✴ Thyroid
hormone affects the rate of enzymatic reactions in
the myocardial muscle itself. These effects coupled with
excessive work can lead to cardiac failure in the chronic
hyperthyroid patient.
Effects of Thyroid Hormone
Respiratory System Physiology
✴ Because
of the enhanced levels of aerobic metabolism
in hyperthyroid patients, oxygen demands of the body
rise. This triggers an increase in both the rate and depth
of respiration.
Gastrointestinal Physiology
✴ Increased
levels of thyroid hormone are typically
associated with increased food consumption, which
obviously affects the gastrointestinal system.
✴ Furthermore,
thyroid hormone directly stimulates
increased gastrointestinal secretion and motility. As a
result, a common complaint of hyperthyroid patients is
diarrhea.
Effects of Thyroid Hormone
Nervous System Physiology
✴ In
general, neuronal excitability is increased as levels of
thyroid hormones rise.
✴ This
can result in a wide range of neurological and psychiatric
problems, including tremor, psychoneurotic tendencies,
anxiety, and even paranoia.
✴ In
addition, hyperthyroid patients have great trouble in
sleeping, despite the fact that their high level of metabolic
activity leaves them feeling very tired.
Effects of Thyroid Hormone
Muscle Physiology
✴ Slight
increases in the level of thyroid hormone results in a
small increase in muscle strength and reactivity because of
the generalized acceleration of metabolism.
✴ However,
very high levels of thyroid hormone can result in
protein catabolism and muscle weakness.
Control of Thyroid Hormone
Secretion: TSH
Effects of TSH:
Increased release of T3 and T4 via proteolysis of
thyroglobulin
Increased rate of iodide trapping
Increased iodination of tyrosine
Thyroid gland hyperplasia, increased secretion, and overall
hypertrophy
TSH does this by binding to receptors on basal membrane of
follicular cells – cAMP second messenger
What Controls TSH
Secretion?
TRH (thryotropin-releasing hormone)
from the hypothalamus. Temperature
plays a primary role in controlling the
secretion of TRH into the portal blood
system.
Feedback on anterior pituitary and
hypothalamus by T3 and T4
Hypothalamus
+
TRH
+
-
Anterior Pituitary
T3 and T4
Temperature
(low body temp)
TSH
+
Thyroid
Gland
T3 and T4
+
Nuclear Receptors
Diseases Affecting Thyroid
Hormone Secretion
Autoimmune diseases affecting the
thyroid gland
Can cause both hypo- and
hyperthyroidism
Cancer in thyroid gland or anterior
pituitary
Iodide deficiency
Hyperthyroidism
Thyroid gland increased to two to three times normal size
– hyperplasia; also greatly increased secretion of thyroid
hormone
Plasma TSH less than normal in nearly all patients
Immunoglobulin antibodies that bind to TSH receptors on
membranes of cuboidal thyroid follicular cells; TSH
agonists
Cause: excess of thyroid antigens released – formation of
antibodies against thyroid gland
Continual activation of cAMP system of cells
Hyperthyroidism
Hypothalamus
-
Anterior Pituitary
+
T3 and T4
Thyroid
Gland
T3 and T4
B cells producing antibodies
That bind to TSH receptors
+
Nuclear Receptors
Hyperthyroidism – note apparent hyperplasia and
infolding of thyroid epithelium
Note enlarged right lobe
Hyperthyroidism
Symptoms easily predicted by considering
what excess thyroid hormone would do
Also – exophthalamos (protrusion of the
eyeballs) in the most common form of the
disease (Grave’s disease)
Protrusion caused by antibodies attacking
extraocular muscles
Treatment: surgical resection of gland or
delivery of radioactive iodide
Hypothyroidism
Commonly, again, autoimmunity
develops against the thyroid gland
Now, autoimmunity destroys glandular
tissue
Deterioration/fibrosis of gland
Decreased secretion of thyroid
hormone
Hypothyroidism
Hypothalamus
+
TRH
+
Anterior Pituitary
Temperature
(low body temp)
TSH
+
-
Thyroid
Gland
T3 and T4
B cells producing antibodies
That destroy Thyroid
Nuclear Receptors
Hypothyroidism
Note lymphoid tissue,
small follicles
Goiter: a hallmark of some types of
hypothyroidism
2 Types of Goiters in
Hypothyroidism
Endemic goiter – due to lack of iodide in the diet – low
production of thyroid hormone – increased TSH
secretion – increased stimulation of thyroid gland
Idiopathic nontoxic colloid goiter – same situation as
above, but cause of low thyroid hormone production is
unknown
“Hypo” thus refers to gland secretions and not size
Clinical Implications
(Hypothyroidism)
Symptoms easily predicted from consideration of a low
level of thyroid hormone
Treatment often involves oral ingestion of thyroid
hormone
If pathology occurs early in development – cretinsim –
marked by failure of body growth and mental retardation
Growth Hormone
Peptide released from anterior
pituitary
Bound in plasma by GH binding
protein
Stimulates protein synthesis, fat
breakdown, hepatic glucose output,
and bone/cartilage growth
Glucocorticoids
Steroid hormones secreted by the adrenal cortex
Most predominant hormone is cortisol
Effects:
Raise blood glucose levels
Stimulate gluconeogenesis in liver, breakdown of
skeletal muscle proteins, fat breakdown
Plays an important role in protecting the body against
hypoglycemia
Adrenal Cortex
Fasciculata: glucocorticoids
glomerulosa
fasciculata
reticularis
Hypothalamus
CRH
+
+
Anterior Pituitary
Note similarities to T3T4 secretion;
Same general pattern,
Also “independent”
Stimulus for release
-
Cortisol
ACTH
Adrenal
Cortex
+
Cortisol
+
Low plasma
glucose
Nuclear Receptors
Other Actions of
Glucocorticoids
Besides essentially combating
hypoglycemia, these steroids are
involved in response to stressful
situations
Cortisol also has an anti-inflammatory
effect (inhibits T-cell proliferation)
May contribute to “flash bulb memories”
Applications
Before development of nonsteroidal antiinflammatory drugs, cortisol metabolites
(i.e. cortisone) prescribed for swelling
Topical creams (i.e. Cortaid) and
injectable glucocorticoids (i.e.
dexamethasone) are available
Prednisone is a commonly-prescribed
cortisol analog
Side Effects of Glucocorticoid
Therapy
Difficulty sleeping
Increased appetite
Increased sweating
Indigestion
Mood changes
Nervousness
Addison’s Disease
Autoimmune disease attacking the adrenal
gland
Loss of cortisol secretion – impossible to
maintain normal blood glucose levels between
meals
Reduced mobilization of proteins and fats from
tissues – decrease in several metabolic
functions
High ACTH levels – darkening of skin
(stimulation of melanocytes and deposition of
melanin)
Question for
Discussion
Which Presidential
candidate benefited
from Addison’s
disease?
Cushing’s Syndrome
Produced by an ACTH secreting
tumor
Results in elevated blood glucose as
well as muscle weakness
Question for
Discussion
Why does prolonged
glucocorticoid
therapy lead to water
retention?