The Integration of Metabolism
Week 13 & 14
Tissue-Specific Metabolism
Each tissue of the
human body has a
specialized
function, reflected
in its anatomy and
metabolic activity
The liver is the central distributing and processing organ for nutrients.
Sugars produced in digestion cross the intestinal epithelium and enter
the blood, which carries them to the liver
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Glucose 6-phosphate is the key
intermediate in carbohydrate
metabolism.
It may be polymerized into
glycogen, dephosphorylated to
blood glucose, or converted to
fatty acids via acetyl-CoA.
It may undergo oxidation by
glycolysis, the citric acid cycle, and
respiratory chain to yield ATP.
or enter the pentose phosphate
pathway to yield pentoses and
NADPH.
Amino acids produced in digestion cross the intestinal
epithelium and enter the blood, which carries them to the
liver
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Amino acids are used to
synthesize liver and plasma
proteins, or their carbon
skeletons are converted to
glucose and glycogen by
gluconeogenesis; the ammonia
formed by deamination is
converted to urea.
Some triacylglycerols derived from ingested lipids also make their way
to the liver, where the constituent fatty acids are used in a variety of
processes
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The liver converts fatty acids to
triacylglycerols, phospholipids,
or cholesterol and its esters, for
transport as plasma lipoproteins
to adipose tissue for storage.
Fatty acids can also be oxidized
to yield ATP or to form ketone
bodies, which are circulated to
other tissues.
Skeletal muscle is specialized to produce and use ATP for
mechanical work.
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During strenuous muscular
activity, glycogen is the ultimate
fuel, supplying ATP through
lactic acid fermentation.
During recovery, the lactate is
reconverted (through
gluconeogenesis) to glycogen
and glucose in the liver.
Phosphocreatine is an
immediate source of ATP
during active contraction
Heart muscle obtains nearly all its ATP from oxidative
phosphorylation
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Extremely active muscles use
glycogen as energy source,
generating lactate via glycolysis.
During recovery, some of this
lactate is transported to the liver
and converted to glucose via
gluconeogenesis.
This glucose is released to the
blood and returned to the muscles
to replenish their glycogen stores.
The overall pathway (glucose →
lactate → glucose) constitutes the
Cori cycle
The neurons of the brain use only glucose and β-hydroxybutyrate as
fuels, the latter being important during fasting or starvation.
The brain uses most of its ATP for the active transport of Na and K
and maintenance of the electrical potential across the neuronal
membrane.
The blood carries nutrients, waste products, and hormonal
signals among the organs.
Food intake and starvation induce
metabolic changes
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Starved-fed cycle
Nightly starved-fed cycle has 3 stages:
• Postabsorbtive state
• Early fasting during the night
• The refed state after breakfast
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Main goal is to maintain glc homeostasis!
The well-fed state
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After the consumption
Glc, aa’s and lipids are transported to the blood
The fed state The secretion of insulin increases.
Insulin increases the uptake of Glc into the liver by
GLUT2
Insulin also increases the uptake of Glc by muscle
and adipose tissue
The electron micrograph shows the release
of insulin from a pancreatic b cell.
One secretory granule is on the verge of
fusing with the plasma membrane and
releasing insulin into the extracellular
space, and the other has already released
the hormone
Early fasting state
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The blood Glc decreases several hors after a meal
Insulin decreases and glucagon increases
So, glucagon signals the starved state
It mobilizes the glycogen by cAMP pathway
Target liver
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Net result: Increase glucose in blood
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The refed state
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Fat process same as fed state
The liver does not initially absorb glc from the blood,
but rather leaves it for the peripheral tissues
Liver stays in gluconeogenic mode
Newly made Glc is used to make glycogen
As blood Glc increases the liver completes the
replenishment of its glycogen stores
Metabolic adaptation in prolonged starvation
minimize protein degradation
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What are the adaptations if fasting is prolonged to the
point of starvation?
– 70 kg man has fuel reserve ~ 161,000 kcal
– The energy need for a 24 hr cycle 1600-6000 kcal
– So, fuels are ok for 1-3 months!
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The very first priority of metabolism in starvation
– Providing Glc to the brain and other tissues
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The second priority of metabolism in starvation is to
preserve protein, which is accomplished by shifting
from glc to fa’s
Fuel metabolism in the liver during
prolonged starvation
Fuel Choice During Starvation.
The plasma levels of fatty acids and ketone bodies increase in
starvation, whereas that of glucose decreases.
• Plasma concentrations of
fatty acids, glucose, and
ketone bodies during the
first week of starvation.
• Despite the hormonal
mechanisms for
maintaining the level of
glucose in blood, glucose
begins to diminish after 2
days of fasting.
• The level of ketone
bodies, almost
unmeasurable before the
fast, rises dramatically
after 2 to 4 days of fasting.
These water-soluble ketones, acetoacetate and β-hydroxybutyrate, supplement
glucose as an energy source during a long fast. Fatty acids cannot serve as a
fuel for the brain; they do not cross the blood-brain barrier.
After 3 days of starvation
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Liver forms keton bodies
Their synthesis from AcetylCoA is increased because
TCA is not running(gluconeogenesis depletes the
supply of oxaloacetate)
So, liver makes lots of KBs
The brain begins to use acetoacetate
After 3 days, 1/3 of the energy comes from KBs for the
brain
The heart also uses KBs
Regulation of blood glucose by insulin and
glucagon