Integration of Metabolism and Hormone Action

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Integration of Metabolism and Hormone Action

• Metabolic process in single cells
• Whole organism
• Hormonal signals integrate and coordinate the
  metabolic activities of different tissues and
  bring about optimal ALLOCATION of fuels and
  precursors to each organ.
• Our focus
• The specialized metabolism of major organs
• Some tissues are energy suppliers, others are
  energy consumers, and some are both.
• Q How do these tissues communicate to each
  other?
• A Hormones.

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Metabolism has highly interconnected pathways

• Central themes
• ATP is universal currency of energy
• ATP is made by the oxidation of Glc, fas and
  aas
• The common intermediate is AcetylCoA
• NADPH is the major electron donor in reductive
  biosynthesis
• Biomolecules are made from building blocks.
• Biosynthetic and degradative pathways are almost
  always distinct!
• They could be easily controlled
• They become thermodynamically favorable at all
  times

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Regulation of blood glucose by insulin and
glucagon
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Recurring motifs in regulation

• 1. Allosteric interaction
• 2. Covalent modification
• 3. Enzyme levels
• 4. Compartmentation
• 5. Metabolic specializations of organs

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Major metabolic pathways and control sites

• Glycolysis
• PFK is the most important control point
• In the liver, the most important regulator is
  F-2,6 BiP
• When blood Glc goes down, glucagon triggerred
  pathway increases phosphatase, decreases kinase
  (making F-2,6BiP)
• Therefore, F-2,6BiP decreases
• PFK decreases
• Glycolysis slows down

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TCA cycle and Ox-Plation

• Mitochondria
• ATP controls it
• High ATP levels decrease the activities of 2
  enzymes
• Isocitrate dehydrogenase
• Alpha ketoglutarate dehydrogenase

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Pentose phosphate pathway

• Takes place in the cytosol in two stages
• Oxidative decarboxylation of G-6-Phosphate
• Nonoxidative reversible metabolism of 5C phospho
  sugars into phospharylated 3C and 6C glycolitic
  intermediates

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Gluconeogenesis

• Glc can be made by the liver from
  noncarbohydrates
• The major entry point of this pathway is pyruvate
  which is carboxylated to OAA in mitochondria.
• Gloconeogenesis and glycolysis are usually
  reciprocally regulated so one pathway is not
  active while the other one is active.
• If F-2,6BiP increases, gluconeogenesis is
  inhibited and glycolysis is activated.

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Glycogen synthesis and degradation

• Glycogen synthesis and degradation are
  coordinately controlled by a hormone-triggered
  cascade so there is no misunderstanding
• Enzymes to remember
• Phosphorylase
• Glycogen synthase

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Fa synthesis and degradation

• Fas are made in the cytosol
• 2C donor MalonylCoA
• Acetyl groups are carried from mitochondria to
  the cytosol as CITRATE
• Citrate increases the activity of acetylCoA
  carboxylase which increases fa synthesis
• Beta oxidation is in mitochondria
• Acylcarnitine formation is important
• ATP need is important
• If there is too much malonyl CoA, fa degradation
  is inhibited.

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Key junctions

• There are 3 metabolic junctions
• Glc-6-P
• Pyruvate
• AcetylCoA

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Metabolic pathways for G-6-P in the liver
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Metabolism of amino acids in the liver
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Metabolism of fatty acids in the liver
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Each organ has a unique metabolic profile

• Brain
• Muscle
• Adipose tissue
• The kidney
• Liver

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Brain

• Glc is virtually the sole fuel for the human
  brain, except during prolonged starvation
• It consumes 120 g glc per day
• No glycogen strores in the brain
• During prolonged starvation acetaacetate is used
• Fas do not serve as fuel in the brain because
• They are bound to albumin in plasma, therefore
  they cannot pass the blood brain barrier.
• In essence, ketone bodies are transported
  equivalents of fas

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Muscle

• Muscle differs from brain in having a large store
  of glycogen
• 75 of glycogen is in muscle.
• The energy consumption increases with muscle
  activity
• In actively contracting skeletal muscle, the rate
  of glycolysis far exceeds that of the citric acid
  cycle, and much of the pyruvate -------gt lactate
  then.
• Lactate goes to liver and it is converted to glc
  again
• CORI cycle

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Heart muscle

• For reasons that are not clear, the heart relies
  mainly on fatty acids.
• Fatty acid supply is more reliable than the
  fluctuating carbohydrate supply?
• Most organisms have a very extensive supply of
  fas thus the functioning of the heart muscle is
  protected

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Adipose tissue

• The TAGs are stored here.
• They are enormous reservoir of fuel.
• Adipose cells need glucose for the synthesis of
  TAGs
• The glucose level inside adipose cells is a major
  factor in determining whether fatty acids are
  released into the blood
• Adipose tissue If too much food ? FFA stored.
• If Glc and glycogen are NOT enough,
• TAG? FFA? Liver

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The kidney

• Major role to make urine
• The blood plasma is filtered nearly 60 times each
  day in the renal tubules.
• During starvation the kidney becomes an important
  site of gluconeogenesis and may contribute as
  much as half of the blood glucose!

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Liver

• The liver serves as the bodys distribution
  center, detoxification center, and central
  clearing house.
• Metabolic hub
• The liver plays an essential role in the
  integration of metabolism.
• Liver removes 2/3 of the glucose from the blood.
• Glc------gt G-6-P
• G-6-P has many fates
• Fa, cholesterol or bile synthesis
• Glycogen synthesis
• PPP

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liver

• When fuels are increased, fas are derived from
  the diet or synthesized by the liver as TAGs
• They are secreted into the blood in the form of
  VLDL
• During fasting, the liver converts fas into
  ketone bodies
• The liver also plays an essential role in amino
  acid metabolism
• It secretes 20-30 g urea/day
• Liver meets its own energy by using alpha
  ketoacids

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Food intake and starvation induce metabolic
changes

• Starved-fed cycle
• Nightly starved-fed cycle has 3 stages
• Postabsorbtive state
• Early fasting during the night
• The refed state after breakfast
• Main goal is to maintain glc homeostasis!

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The well-fed state

• After the consumption
• Glc, aas 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

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Early fasting state

• 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
• Net result Increase glucose in blood

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The refed state

• 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

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Metabolic adaptation in prolonged starvation
minimize protein degradation

• 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!
• The very first priority of metabolism in
  starvation
• Providing Glc to the brain and other tissues
• The second priority of metabolism in starvation
  is to preserve protein, which is accomplished by
  shifting from glc to fas

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Fuel metabolism in the liver during prolonged
starvation
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After 3 days of starvation

• 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

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Diabetes

• Incidence 5 of the population
• Most common metabolic disorder
• Type I(IDDM)---no insulin
• Type II (NIDDM)---insulin is normal
• Biochemical starvation is made despite of a high
  concentration of blood glucose, because insulin
  deficient and the entry is impaired.

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Obesity

• It is an epidemic
• 20 adults are obese in the US
• It is a risk factor for
• Diabetes
• Hypertension
• Cardiovascular diseases
• Cause is simple
• More food taken than needed
• Two important signal molecules
• Insulin
• leptin

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Metabolic changes during exercise

• Sprinting and marathon running are powered by
  different fuels to maximize power output
• A 100 meter sprinter uses
• Stored ATP
• CP
• Anaerobic glycolysis of muscle glycogen
• A 1000 meter runner
• Oxidative phosphorylation starts.
• Marathon requires a different selection of fuels
• A nice cooperation between muscle, liver and
  adipose tissue
• Total glycogen stores (103 mol of ATP) are
  insufficient to provide 150 mol of ATP.
• Fat breakdown is needed.

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Ethanol alters energy metabolism in the liver

• EtOH causes many health problems
• Liver damage takes place in 3 stages
• Fatty liver
• Alcoholic hepatitis
• Cirrhosis (fibrous structure and scar tissue
  around dead cells)