Metabolism in Wellfed and Starvation States

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Metabolism in Well-fed and Starvation States

• December 4, 2003
• Ichiro Matsumura

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How is metabolism controlled in different states?
Well fed Starvation
Synthesis of Glycogen Triacylglycerol Protein
Degradation of Glycogen Triacylglycerol Protein
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Control of Metabolism

• Availability of substrates
• Allosteric activation/inhibition
• Covalent modification of enzymes
• Synthesis of enzymes

Glucose Acetyl CoA
Phosphorylation of lipase
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How do individual tissues utilize nutrients in
the well-fed state?
Brain
Carbohydrates Fats Amino Acids
Stomach
Carbohydrates Amino Acids Fats
Intestines
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Liver Metabolism of Carbohydrates

• 60 of carbs retained in the liver
• Increased blood glucose levels
• Allows high Km glucokinase to phosphorylate
  glucose
• Increase glycogen synthesis
• Activate glycogen synthase
• Inactive glycogen phosphorylase
• Increased glycolysis
• Increased insulin activates PFK1 and pyruvate
  kinase
• Decreased gluconeogenesis
• Decreased activity of fructose 1, 6
  bisphosphatase

Carbohydrates
Glucose/Carbs
LIVER
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Liver metabolism of fat

• Increased fatty acid synthesis
• Increased substrates acetyl coA
• Activation of acetyl coA carboxylase
• Increase in triacylglycerol synthesis
• High FAcoA
• High glycerol3phosphate (glycolysis)

Fat
fatty acids
Acetyl CoA
triacylglycerol
VLDL
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Liver metabolism of amino acids
Amino Acid

• Production of energy
• Pyruvate, TCA intermediates, acetyl coA
• Increased protein synthesis
• Amino acids cannot be stored, except as protein

aa
Protein synthesis
pyruvate
Acetyl CoA
TCA
Energy
LIVER
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Liver metabolism in well-fed state

• Carbohydrates are used to raise blood glucose, as
  storage in glycogen, and for energy
• Lipids are used to synthesize fatty acids and
  triacylglycerol
• Amino acids can be converted to energy or used
  for protein synthesis

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Adipose tissue metabolismof carbohydrates
store energy
Carbohydrates
glucose
Glucose-6-P glycolysis
pentose phosphate shunt
triacylglycerol
Glyceraldehyde 3 P
ADIPOSE
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Adipose tissue metabolism of fats
Chylomicron
Fats
Chylomicron
1. Lipoprotein lipase
FA
triacylglycerol
2. Hormone Sensitive lipase
energy
LIVER
ADIPOSE
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Adipose tissue in the well-fed state

• Stores energy as fat
• Carbohydrates are converted to FA
• Lipids are stored and not broken down
• Protein metabolism not significant for adipose
  tissue

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Skeletal muscle and carbohydrate metabolism
Carbohydrates
Insulin-dependent Glucose transporter
Glycogenesis
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Skeletal muscle and amino acid metabolism
Amino Acids
Amino Acids
MUSCLE
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Skeletal muscle in the well-fed state

• Carbohydrates are used for energy and for
  glycogen storage
• Lipid metabolism is not significant
• Amino acids are used for protein synthesis to
  replace damaged proteins

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Brain and carbohydrate metabolism

• Brain requires glucose for energy
• Brain cannot store glycogen
• Brain uses 140g glucose/day

Carbohydrates
Glucose
Glycolysis
Energy
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Brain and lipid metabolism(or lack thereof)

• Lipids do not pass the blood/brain barrier
• (epithilial cell layer)

Fat
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How is metabolism controlled in different states?
Well fed Starvation
Synthesis of Glycogen Triacylglycerol Protein
Degradation of Glycogen Triacylglycerol Protein
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Hunger remains a problem

• Global
• wealthiest 20 consumes 86 of goods and services
• 800 million people go hungry (200 million are
  children)
• United States
• 33 million people (including 13 million children
  and 20 of elderly) experience hunger or are at
  risk
• Georgia
• 12.9 of Georgians live in poverty
• one in six children is food insecure

UN report on hunger 2003, Bread for the World
2002, U.S. census
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Prolonged starvation
Glucose Proteins Fats Insulin Glucagon
Catabolic State Degradation of Glycogen,
Triacylglycerol, and Proteins
Blood Glucose
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Metabolism in Starvation State

• How do the individual tissues survive without
  nutrients?
• Liver
• Adipose Tissue
• Skeletal Muscle
• Brain

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LIVER in Starved State
Production of glucose for the tissues
Glycogen
Glucose
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LIVER in Starved State
Production of energy for itself and brain
Amino Acids Glycerol Lactate
FA
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Adipose in Starved State
Release of energy for other tissues
Ephinephrine
Glucagon
Triacylglycerol
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Adipose in Starved State
Production of energy for itself
Ephinephrine
Glucagon
Triacylglycerol
Hormone-sensitive lipase
Fatty acid glycerol
Pyruvate
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Skeletal Muscle in Starved State
TCA
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Brain in the starved state

• Requires more than 1/2 of glucose produced by the
  liver (ketone bodies)
• Glucose depletion leads to loss of mental
  function, consciousness, and can cause
  neurological damage

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Metabolism in Starved State

• Liver produces glucose for other tissues
• Adipose tissue produces FA to be used for energy
• Skeletal muscle produces amino acids for energy

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Time line for metabolism in starvation

• Free glucose must be replaced every 2 hours
• After 12-24 hours of fasting, release of FA from
  stores and amino acids from muscle
• 2-3 days of fasting, glucose is synthesized from
  glycerol, amino acids, lactate and pyruvate
• 1 week, psychological changesmood and
  depression, decrease in basal metabolic rate,
  increase in uric acid in urine, and the loss of
  calcium

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Water Deprivation

• Fluid Deprivation
• Na and water deplete the extracellular volume
• First sign is thirst
• Elderly patients do not have thirst reactions as
  well as young patients
• Weight loss, poor skin turgor, dry mucous
  membranes

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Starvation in the clinic

• Trauma
• Surgery, injury, etc
• Cancer and other disease states
• Eating disorders
• Anorexia nervosa and bulimia nervosa

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Symptoms of starvation

• Fluid and electrolyte imbalance
• Alteration in hypothalamic-pituitary function
• Amenorrhea and infertility
• Reduction in pulse rates, respiratory rate, blood
  pressure, O consumption, cardiac output
• Cold intolerance, dry skin, dry hair,
  constipation
• Ketone Bodies Acetoacetic Acid and B
  hyroxybutyrate ? acetone
• B oxidation of FA

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Refeeding syndrome

• During first week of nutritional replacement
• Expansion of extracellular fluid
• Edema (fluid overload)
• Increase in sodium uptake
• Increased carbohydrate consumption
• Vitamin depletion
• Heart failure
• Increase in intravascular volume and vitamin
  deficits

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What do you feed a starved individual?

• Normalize fluid and electrolyte parameters
• Mixed diet
• Maintain energy levels
• Avoid phosphate deficit--milk
• Accelerate protein accretion--rebuild lean body
  mass
• Reverse hypometabolism

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Two types of diabetes
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Insulin-dependent diabetes is an autoimmune
disease
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Hyperglycemia and ketoacidosis lead to
complications
premature atherosclerosis retinopathy nephropathy
neuropathy
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Intensive vs.conventionalinsulin therapy
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Non-insulin-dependent diabetes

• Caused by
• Insulin-resistance in peripheral tissues
• Inadequate insulin secretion from b cells
• Treatment
• Weight reduction and dietary modification
• Sulfonylurea drugs (hypoglycemic agents)
• Insulin therapy

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What did we learn today?

• How each organ metabolizes macromolecules during
  well fed state
• How each organ survives during starvation
• Eating disorders as an example of starvation that
  you will see in the clinic
• Treatment of starving patients
• diabetes