Integration of Metabolism

1.

Interconnection of pathways

2.

Metabolic profile of organs

3.

Food intake, starvation and obesity

4.

Fuel choice during exercise

5.

Ethanol alters energy metabolism

6.

Hormonal regulation of metabolism

Connection of Pathways
1.

ATP is the universal currency of energy

2.

ATP is generated by oxidation of glucose, fatty acids, and amino acids ; common
intermediate -> acetyl CoA ; electron carrier -> NADH and FADH 2

3.

NADPH is major electron donor in reductive biosynthesis

4.

Biomolecules are constructed from a small set of building blocks

5.

Synthesis and degradation pathways almost always separated -> Compartmentation !!!

Key Junctions between Pathways

Metabolic Profile of Organs

1. Metabolic Profile of Brain

Glucose is fuel for human brain -> consumes 120g/day -> 60-70 % of utilization of glucose
in starvation -> ketone bodies can replace glucose

2. Metabolic Profile of Muscles

Major fuels are glucose, fatty acids, and ketone bodies

-> has a large storage of glycogen -> about of all glycogen
stored in muscles
-> glucose is preferred fuel for burst of activity -> production
of lactate (anaerobe)
-> fatty acid major fuel in resting muscles and in heart muscle
(aerobe)

3. Metabolic Profile of Adiposite tissue

Triacylglycerols are stored in tissue ->

enormous reservoir of metabolic fuel
-> needs glucose to synthesis TAG;
-> glucose level determines if fatty acids
are released into blood

4. Metabolic Profile of Kidney

Production of urine -> secretion of waste products

Blood plasma is filtered (60 X per day) -> water and glucose reabsorbed
-> during starvation -> important site of gluconeogenesis (1/2 of blood
glucose)

5. Metabolic Profile of the Liver (Glucose)

Essential for providing fuel to brain,

muscle, other organs
-> most compounds absorpt by diet
-> pass through liver -> regulates
metabolites in blood

Metabolic Activities of the Liver (Amino Acids)

-Ketoacids (derived from

amino acid degradation)
-> livers own fuel

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Metabolic Activities of the Liver (Fatty Acids)

cannot use acetoacetate

as fuel -> almost no
transferase to generate
acetyl-CoA

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Food Intake, Starvation, and Obesity

Normal Starved-Fed Cycle:

1.

Postabsorptive state -> after a meal

2.

Early fasting state -> during the night

3.

Refed state -> after breakfast

-> Major goal is to maintain blood-glucose level!

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Blood-Glucose

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1. Postabsorptive state

Glucose + Amino acids -> transport from intestine to blood

Dietary lipids transported -> lymphatic system -> blood
Glucose stimulates -> secretion of insulin
Insulin:
-> signals fed state
-> stimulates storage of fuels and synthesis of proteins
-> high level -> glucose enters muscle + adipose tissue (synthesis of TAG)
-> stimulates glycogen synthesis in muscle + liver
-> suppresses gluconeogenesis by the liver
-> accelerates glycolysis in liver -> increases synthesis of fatty acids
-> accelerates uptake of blood glucose into liver -> glucose 6-phosphate more
rapidly formed than level of blood glucose rises -> built up of glycogen stores

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Insulin Secretion Stimulated by Glucose Uptake

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Postabsorptive State -> after a Meal

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2. Early Fasting State

Blood-glucose level drops after several hours after the meal -> decrease
in insulin secretion -> rise in glucagon secretion
Low blood-glucose level -> stimulates glucagon secretion of -cells of the
pancreas
Glucagon:
-> signals starved state
-> mobilizes glycogen stores (break down)
-> inhibits glycogen synthesis
-> main target organ is liver
-> inhibits fatty acid synthesis
-> stimulates gluconeogenesis in liver
-> large amount of glucose in liver released to blood stream -> maintain
blood-glucose level
Muscle + Liver use fatty acids as fuel when blood-glucose level drops

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Early Fasting State -> During the Night

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3. Refed State

Fat is processed in same way as normal fed state

First -> Liver does not absorb glucose from blood (diet)
Liver still synthesizes glucose to refill livers glycogen stores
When liver has refilled glycogen stores + blood-glucose level still rises ->
liver synthesizes fatty acids from excess glucose

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Prolonged Starvation
Well-fed 70 kg human -> fuel reserves about 161,000 kcal
-> energy needed for a 24 h period -> 1600 kcal - 6000 kcal
-> sufficient reserves for starvation up to 1 3 months
-> however glucose reserves are exhausted in 1 day
Even under starvation -> blood-glucose level must be above 40 mg/100 ml

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Prolonged Starvation
First priority -> provide sufficient glucose to brain and other tissues that are dependent on it
Second priority -> preserve protein -> shift from utilization of glucose to utilization of fatty acids +
ketone bodies
-> mobilization of TAG in adipose tissues + gluconeogenesis by liver -> muscle shift from glucose to
fatty acids as fuel
After 3 days of starvation -> liver forms large amounts of ketone bodies (shortage of oxaloacetate) ->
released into blood -> brain and heart start to use ketone bodies as fuel
After several weeks of starvation -> ketone bodies major fuel of brain
After depletion of TAG stores -> proteins degradation accelerates -> death due to loss of heart, liver,
and kidney function

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Mobilization at Starvation
Also at not
treated
diabetes

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Diabetes Mellitus Insulin Insufficiency

Characterized by: -> high blood-glucose level
-> Glucose overproduced by liver
-> glucose underutilized by other organs
-> shift in fuel usage from carbohydrates to fats -> keton bodies (shortage of
oxaloacetate)
-> high level of keton bodies -> kidney cannot balance pH any more -> lowered pH in
blood and dehydration -> coma
Type I diabetes: insulin-dependent diabetes (requires insulin to live)
caused by autoimmune destruction of -cells
begins before age 20
-> insulin absent -> glycagon present
-> person in biochemical starvation mode + high blood-glucose level
-> entry of glucose into cells is blocked
-> glucose excreted into urine -> also water excreted -> feel hungry + thirsty
Type II diabetes: insulin-independent diabetes
have a normal-high level of insulin in blood -> unresponsive to hormone
develops in middle-aged, obese people

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Obesity

Mouse lacking leptin

or Leptin receptor

In the U. S. -> about 70% of adults are suffering from obesity (2009)
Risk factor for: Diabetes + Cardiovascular diseases
Cause of Obesity -> more food consumed than needed -> storage of energy as fat
Two important signals for caloric homeostasis and appetite control -> insulin + leptin

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The Role of Leptin and Insulin on Weight Control

Leptin is a hormone
that is produced in
direct proportion
to fat mass
(adipocytes)

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High Levels of Leptin and Insulin are a Signal for caloric homeostasis

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Obese People Produce More Heat

Body can deal with excess calories:

1.

Storage

2.

Extra exercise

3.

Production of heat
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Fuel Choice During Exercise

Fuels used are different in:

-> sprinting -> anaerobic exercise -> lactate
-> distance running -> aerobic exercise -> CO2
ATP directly powers myosin -> responsible for muscle contraction -> movement
-> amount of ATP in muscle is small
-> velocity depended on rate of ATP production
-> creatine phosphate generates ATP under intense muscle contractions for 5-6 s
Sprint: powered by ATP, creatine phosphate, and anaerobic glycolysis of glycogen -> lactate
Medium length sprint: complete oxidation of muscle glycogen -> CO2 (production slower) -> velocity lower
Marathon: complete oxidation of muscle and liver glycogen -> CO2
and complete oxidation of fatty acids from adipose tissues -> CO2 (ATP is generated even slower)
Low blood-glucose level -> high glucagon/insulin ratio -> mobilization of fatty
30 acids

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Ethanol Alters Energy Metabolism in Liver

Consumption of EtOH in excess -> number of health problems
EtOH has to be metabolised:
1.

EtOH + NAD+ ->

Acetaldehyde + NADH

(alcohol dehydrogenase, in cytoplasm)

2.

Acetaldehyde + NAD+ -> Acetate + NADH (aldehyde dehydrogenase, in mitochondria)

-> EtOH consumption leads to accumulation of NADH

High level NADH causes:
-> inhibition of gluconeogenesis (prevent oxidation of lactate to pyruvate) -> lactate accumulates
-> inhibits fatty acid oxidation -> stimulates fatty acid synthesis in liver -> TAG accumulates -> fatty liver
-> inhibition of citric acid cycle
Ethanol inducible microsomal ethanol-oxidizing system (MEOS) -> P450 dependent pathway -> generates free
oxygen radicals -> damages tissues
Acetate is converted into Acetyl CoA -> processing of Acetyl CoA by citric acid cycle is blocked by high
amounts of NADH -> Ketone bodies are generated and released into the blood -> further drop of pH
Processing of acetate in liver inefficient -> high level of acetaldehyde in liver -> reacts with proteins -> become
inactive -> damage liver -> cell death
Liver damage in 3 stages: Development of Fatty Liver -> alcoholic hepatitis (groups of cells die) -> cirrhosis (no
convertion of Ammonium -> urea)

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Hormonal Regulation of Metabolism

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Action of Different Hormones

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Hormone signals and their target tissues

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Cascade of Hormone Release Following

Central Nervous System Input to the
Hypothalamus

Cortisol:
-

Signals stress !!!

signals low blood glucose -> counterbalances insulin

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Epinephrine -> Signals Stress -> requires activity -> Fighting or Fleeing
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