The integration of intermediaryThe integration of intermediary
metabolism of nutrientsmetabolism of nutrients
at the tissue and organ level
Biochemistry II
Lecture 3 2007 (J.S.)
Nutrients – dietary fuels
Saccharides are the most universal nutrients –
the overdose is transformed in the fat stores,
Nutrients – dietary fuels
the overdose is transformed in the fat stores,
carbon skeleton of non-essential amino acids may originate
from saccharides.from saccharides.
Triacylglycerols exhibit the highest energetic yield –
but fatty acids cannot convert into saccharides or thebut fatty acids cannot convert into saccharides or the
skeleton of amino acids.
Amino acids in the form of proteins represent the unique,Amino acids in the form of proteins represent the unique,
precious source of nitrogen for proteosynthesis. They can
be used as a fuel rather when the body is lacking in otherbe used as a fuel rather when the body is lacking in other
nutrients – during starving, a disease, or injury.
Glucogenic amino acids can convert into glucose.Glucogenic amino acids can convert into glucose.
An overdose of diet protein may be transformed into fat
stores. 2
stores.
Fuel reserves in a typical 70-kg man
Nutrient mass and available energy
Total energy stores of the body equal about 700 MJ, most of that as the fat storesTotal energy stores of the body equal about 700 MJ, most of that as the fat stores
(total body fat represents approximately 10 - 25 % body weight.
Glycogen in the liver is not very large, it is exhausted, without refilling, less than 24 h.
Muscle glycogen can be utilized only within muscles, because there is no glucose-6-Muscle glycogen can be utilized only within muscles, because there is no glucose-6phosphatase
activity to release free glucose.
Proteins have essential roles other than providing energy. Muscle protein may supply amino
acids for gluconeogenesis, but only limited amounts (not more than approximately ⅓ of muscle
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acids for gluconeogenesis, but only limited amounts (not more than approximately ⅓ of muscle
protein) can be oxidized for energy to preserve the vital functions of the tissue.
Synthesis and mobilization of TG stores in adipose tissueSynthesis and mobilization of TG stores in adipose tissue
stimulation of the enzyme is
mediated by GLUCAGON
Hormone-sensitive lipase
mediated by GLUCAGON
or adrenaline (in stress)
inhibition
mediated by INSULINmediated by INSULIN
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Basal metabolic rate (BMR)Basal metabolic rate (BMR)
Rough estimate: 100 kJ / d per l kg body weight
Harris and Benedict equations (BMR in kcal / kg):
BMRwomen = 655 + (9.6 × w) + (1.8 × h) – (4.7 × a)
× × ×
w – weight in kg
h – height in cm
a – age in years
BMRmen = 6.6 + (13.7 × w) + (5 × h) – (6.8 × a)
1 kcal = 4.2 kJ
a – age in years
Basal metabolic rate depends on
- gender (women about 10 % lower than men),- gender (women about 10 % lower than men),
- body temperature (increase by 12 % at 1 °C body temperature increment),
- environmental temperature (increased in cold climates),- environmental temperature (increased in cold climates),
- thyroid status (increased in hyperthyroidism),
- pregnancy and lactation (increased),
- long-term low-energy intake (low-calory diets, anorexia nervosa,- long-term low-energy intake (low-calory diets, anorexia nervosa,
- age (increased in childhood).
Under basal conditions, muscle spends about 30 % BMR,Under basal conditions, muscle spends about 30 % BMR,
nervous system (namely central) 20 %,
myocard 11 %, and
the kidney up to 10 %.
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the kidney up to 10 %.
Energetic content of dietary componentsEnergetic content of dietary components
corresponds to the heat of combustion of a nutrient:
Saccharides 17 kJ / gSaccharides 17 kJ / g
Fats 38 kJ / g
Protein *) 17 kJ / gProtein *) 17 kJ / g
*) the biological value, final catabolites of proteins in human bodies
are CO2, H2O a urea CO(NH2)2.
Notice the energetic content of alcohol, which equals 30 kJ / g.
are CO2, H2O a urea CO(NH2)2.
Recommended ratio of nutrients in the human dietRecommended ratio of nutrients in the human diet
for individuals performing light to moderate physical activity:
Saccharides 50 - 55 % of energy intake (predominantly polysaccharides),
fat 25 - 30 % (essential fatty acids should account for about
10 % of total intake, saturated less than 10 %),10 % of total intake, saturated less than 10 %),
proteins 10 - 15 % (0.7 g / kg ideal body weight per day, containing
satisfactory amounts of essential amino acids).
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satisfactory amounts of essential amino acids).
Body mass index (BMI)Body mass index (BMI)
extreme undenourishment
underweight
< 16
16-20
BMI
underweight
"ideal" body mass
overweight
16-20
20-25
25-30 overweight
obesity
extreme obesity
25-30
30-40
> 40
Daily energy expenditure (kJ / d)
BMRwomen
BMR
6000 - 7000
7000 - 8000
(kJ / d)
BMRmen
Very light activity
7000 - 8000
8000 - 11000
Light to moderate activity
Heavy work
11000 - 14000
14000 - 18000
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14000 - 18000
Relationships among the major energy metabolism pathways
GLYCOGEN STORES FAT STORES
TRIACYLGLYCEROLS
MONOSACCHARIDES
TRIACYLGLYCEROLS
FATTY ACIDSGlycerol FATTY ACIDSGlycerol
Pyruvate
×PROTEINS
Glucogenic AA (non-essent.) ×
×
×
Glucogenic AA (essential)
Ketogenic AA (essential) ACETYL-CoA
×
ACETYL-CoA
Citrate cycleKETONE BODIES
× ×
Citrate cycle
OXIDATIVE PHOSPHORYLATION
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OXIDATIVE PHOSPHORYLATION
ATP
Tissues differ in the ability to utilize nutrients
due to their enzyme equipment:due to their enzyme equipment:
Pathway Liver Kidney Muscle CNS RBC
Adipose
Pathway Liver Kidney Muscle CNS RBC
Adipose
tissue
Glycolysis + + + + + +Glycolysis + + + + + +
FA β-oxidation + + + 0 0 0FA β-oxidation + + + 0 0 0
Utilization of
ketone bodies 0 + + (+) 0 +
ketone bodies
Ketogenesis + 0 0 0 0 0
Gluconeogenesis + + 0 0 0 0
FA synthesis + ± ± ± 0 +
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The metabolism of nutrients is sophistically controlledThe metabolism of nutrients is sophistically controlled
through different mechanisms in
the fed state (absorptive phase),
the early fasting state (post-absorptive phase), and inthe early fasting state (post-absorptive phase), and in
the metabolic adaptation in prolonged starvation..
During physical activity, the nutrient sources for muscle contractionDuring physical activity, the nutrient sources for muscle contraction
are determined by intensity and duration of activity. There are
differences in the selection of fuels between anaerobic musculardifferences in the selection of fuels between anaerobic muscular
work and prolonged aerobic work (e.g. sprinting and dostance
running).running).
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The absorptive (fed, postprandial) state
After a typical high-saccharide meal, glucose leaves the intestine in high
concentrations.
The absorptive (fed, postprandial) state
concentrations.
Hyperglycaemia stimulates the pancreas to release insulin,
glucagon release isglucagon release is
inhibited.
A part of nutrient is oxidized to meet the immediate energy needs,A part of nutrient is oxidized to meet the immediate energy needs,
excessive nutrients are stored
– as glycogen in liver and muscle, and mainly
– as triacylglycerols in adipose tissue.– as triacylglycerols in adipose tissue.
Insulin secretion from the B cells of Langerhans islets of the pancreas:Insulin secretion from the B cells of Langerhans islets of the pancreas:
Basal secretion is very low, glucose levels below 4.5 – 5,5 mmol/l don't stimulate insulin
release. During the hyperglycaemia, transporters GLUT 2 more effectively facilitates diffusion
of glucose into the B cells. ATP produces by glycolysis closes the ATP-dependent K+-channel;of glucose into the B cells. ATP produces by glycolysis closes the ATP-dependent K+-channel;
the resulting depolarization of the plasma membrane opens the voltage-operated Ca2+channels,
and increase in intracellular Ca2+ is followed by the exocytosis of secretion granules
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containing insulin.
Insulin
is an anabolic hormone. Itis an anabolic hormone. It
– inhibits the secretion of glucagon from the pancreatic A cells
(paracrine effect),(paracrine effect),
– supports the entry of glucose into skeletal muscle and adipocytes by
translocation of GLUT4 transporters to the cell membrane,translocation of GLUT4 transporters to the cell membrane,
– promotes glycogen synthesis and storage in the liver and muscle
(at the same time inhibits glycogen breakdown through
dephosphorylation of the key enzymes),dephosphorylation of the key enzymes),
– stimulates glycolysis (at the same time inhibits gluconeogenesis)
through its effects on glycolytic enzymes and induction ofthrough its effects on glycolytic enzymes and induction of
synthesis of those enzymes,
– intensifies triacylglycerol synthesis in the liver (secretion of VLDL)
and in adipose tissue (induces the production of lipoprotein
lipase in vascular beds and inhibits hormone-sensitive lipase),
– promotes synthesis of proteins in muscle by increasing amino acid– promotes synthesis of proteins in muscle by increasing amino acid
transport as well as by stimulating ribosomal proteosynthesis.
The mentioned effects result in the hypoglycaemic effect.
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The mentioned effects result in the hypoglycaemic effect.
Saccharides in the absorptive state
The LIVER
ADIPOSE TISSUE
The LIVER
GLYCOGEN TG
Food intake:
GLUCOSE FATTY ACIDS glycerol 3-P
glucose
VLDLNADPH
MUSCLE
high blood GLUCOSE
INSULINMUSCLE
Erc
INSULIN
glucose
lactate
HEART
GLYCOGEN
Glc
CO
CNS
(prefer FA from LDL)
HEART
KIDNEY
Glc
CO
CO2
(FA from LDL preferred)
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(prefer FA from LDL)
CO2
ADIPOSE TISSUE
The LIVER
Triacylglycerols in the absorptive state
The LIVER
TRIACYLGLYCEROLS
FA
TRIACYLGLYCEROLS
glycerol 3-P
FATTY ACIDS
Food intake:
TG in VLDL
FAglycerol 3-P
MUSCLE
Chylomicrons
TRIACYLGLYCEROLS
glycerol
TG in CM, VLDL and LDL
LPL
MUSCLE
Erc
TG in CM, VLDL and LDL
glycerol
HEART
FA
LPL
CNS
HEART
KIDNEY
FACO2 CO2
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FACO2 CO2
The postabsorptive phase – early fasting
is the time period from the first feeling of hunger (few hours after a meal),
which doesn't last usually more than 10 -12 h (e.g. during the nightly
The postabsorptive phase – early fasting
which doesn't last usually more than 10 -12 h (e.g. during the nightly
starved-fed cycle, till the refed state is reached again after breakfast)
Within about one hour after a meal, blood glucose concentrationWithin about one hour after a meal, blood glucose concentration
begins to decline. As a consequence, release of glucagon from
the A cells begins, the stimulation of insulin discontinues.
– stimulates the liver glycogenolysis (inhibits glycogenesis),
the A cells begins, the stimulation of insulin discontinues.
Glucagon antagonizes the effect of insulin:
– stimulates the liver glycogenolysis (inhibits glycogenesis),
– activates mobilization of fat stores (fatty acid release from adipocytes),
– supports gluconeogenesis from lactate, glycerol, and amino acids in the– supports gluconeogenesis from lactate, glycerol, and amino acids in the
liver and kidney, and induces the synthesis of key-enzymes of
gluconeogenesis
All these effects result in maintaining fuel availability in the absence
of dietary glucose.
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Glucagon has no influence on skeletal muscles metabolism.
The LIVER
ADIPOSE TISSUESaccharides in the postabsorptive state
The LIVER
Glycogenolysis
Gluconeogenesis
Glucose
glycerol
90 %
glycerol
MUSCLE
low blood GLUCOSE
GLUCAGONMUSCLE
Erc
GLUCAGON
lactate
Glycogenolysis
KIDNEY
lactate
alanine
GlcGlc-6-P
Pyruvate KIDNEY
CNS
Glc
CO
Gluconeogenesis
10 %
Pyruvate
CO2
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Glc
CO2
CO2
For example, glucagon turns the glycolysis to gluconeogenesis
through the decrease in the concentration of fructose 2,6-bisphosphatethrough the decrease in the concentration of fructose 2,6-bisphosphate
(Fru-2,6-P2), which acts as one of the allosteric activators of phosphofructo-1-kinase
as well as an allosteric inhibitor of fructose 1-bisphosphatase.as well as an allosteric inhibitor of fructose 1-bisphosphatase.
The concentration of Fru-2,6-P2 controlled by a bifunctional enzyme:
Its phosphofructo-2-kinase activity catalyzes the phosphorylation of Fru-6-P to Fru-
2,6-P2, the fructose 2-bisphosphatase activity of the same protein molecule, but
another domain, catalyzes dephosphorylation of Fru-2,6-P2 to Fru-6-P.
The phosphorylated form of the enzyme exhibits the phosphatase activity (it depends
on glucagon, reversal of glycolysis to gluconeogenesis), the dephosphorylated form
of the enzyme (controlled by insulin) catalyzes the formation of Fru-2,6-P .
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of the enzyme (controlled by insulin) catalyzes the formation of Fru-2,6-P2.
Control of the Fru-2,6-P concentration by phosphorylation andControl of the Fru-2,6-P2 concentration by phosphorylation and
dephosphorylation of the bifunctional enzyme:
GLUCAGON
INSULIN
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INSULIN
The LIVER
ADIPOSE TISSUETriacylglycerols in the postabsorptive state
The LIVER Hydrolysis of
TRIACYLGLYCEROLS
Hormone-sensitive lipase
KETOGENESIS FATTY ACIDS
Hormone-sensitive lipase
KETOGENESIS
glycerol
FATTY ACIDS
MUSCLE
low blood GLUCOSE
GLUCAGON
FATTY ACIDS
MUSCLE
Erc
KETONE BODIES
Ketone bodies
HEART
Ketone bodies
Fatty acids
CNS
HEART
KIDNEYCO2
CO
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CO2
Adrenaline (as well as noradrenaline) in the state of acute stress,
acute exposure to danger, initiates the alarm reaction
("fight or flight"). The adaptation syndrome follows, in which("fight or flight"). The adaptation syndrome follows, in which
the fuel metabolism is maintained by the action of cortisol.
The actions of adrenaline on fuel metabolism
are similar to those of glucagon.are similar to those of glucagon.
In addition, adrenaline stimulates glycogenolysis in skeletal muscles.
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Prolonged fasting - starvationProlonged fasting - starvation
During prolonged fasting, changes in utilization of nutrients occur.
A major goal is to spare glucose: tissues use less glucose than
they use during a brief fast and use predominantly triacylglycerols
and ketone bodies. After several days of starvation, the brain also
begins to consume appreciable amounts of acetoacetatebegins to consume appreciable amounts of acetoacetate
(30 – 60 %) in place of glucose.
The second priority is to spare proteins.
ketone bodies
The second priority is to spare proteins.
ketone bodies
glucoseglucose
free fatty acidsfree fatty acids
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The LIVER ADIPOSE TISSUE
Metabolism of nutrients in prolonged starvation (approx. 3 – 4 weeks)
The LIVER ADIPOSE TISSUE
TRIACYLGLYCEROLS
(No glycogen)
GLUCONEOGENESIS (90%)
KETOGENESIS
TRIACYLGLYCEROLS
FATTY ACIDS
GLUCONEOGENESIS (90%)
80 g/d 180 g/d
KETOGENESIS
glycerol
FATTY ACIDS
100 g/d
MUSCLE
Erc
low GLUCOSE
FATTY ACIDS
MUSCLE
Erc
KETONE BODIES
(No glycogen)
Proteolysis
alanine
20 g/d
lactate
Glc
KETONE BODIES
20 g/d
Acetyl-CoA
CNS KIDNEY
CO2
COCO
Glc Proteolysis
Gluconeogenesis (10 %)
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CO2CO2
Glc
Gluconeogenesis (10 %)
Nutrient consumption / production
Amount in grams per day
Nutrient consumption / production
Amount in grams per day
3rd day 40th day
Glucose needed for the brain 100 40
Ketone bodies needed for the brain 50 100
All other use of glucose 50 40
Glucose output of the liver 150 80Glucose output of the liver 150 80
Ketone bodies output 150 150
Triacylglycerols mobilized 180 180Triacylglycerols mobilized 180 180
Muscle proteins degraded 75 20
Amount of glucose consumpted in erythrocytes (about 30 g/d) remains the same,
it can reach up to 50 % of glucose production in starvation.
Utilization of ketone bodies on muscles is stopped, ketone bodies are sparedUtilization of ketone bodies on muscles is stopped, ketone bodies are spared
for the brain.
Proteolysis increases in the course of several days of starving temporarily, in theProteolysis increases in the course of several days of starving temporarily, in the
earliest weeks, after that it diminishes to spare proteins; 20 g degraded protein
represent approx. 12 g glucose. Initial sources of proteins are proteins of
intestinal epithelium, digestive enzymes, some of the liver enzymes, and in skeletal
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intestinal epithelium, digestive enzymes, some of the liver enzymes, and in skeletal
muscles, contractile proteins and enzymes of the glycolytic pathway.
Fuels consumption in muscles
Anaerobic phases of physical exercise
or muscular work with maximal intensity
Initially, exercising muscle uses endogenous fuels, from its own stores).
or muscular work with maximal intensity
Initially, exercising muscle uses endogenous fuels, from its own stores).
ATP (5 mmol/l), ATP regenerated from phosphocreatine (9 mmol/l), and muscle
glycogen. The decrease in ATP concentration as well as appearance of AMP
initiates breakdown of glycogen and stimulates glycolysis.initiates breakdown of glycogen and stimulates glycolysis.
ATP and phosphocreatine can sustain exercise for only a few seconds.
Glycogen stores in muscle are adequate to support an exercise with maximal outputGlycogen stores in muscle are adequate to support an exercise with maximal output
intensity for only a limited period of time, not longer than 1 - 2 minutes, because of
lactate accumulation. The limited supply of O2 disables aerobic glycolysis and
fatty acid oxidation.fatty acid oxidation.
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Aerobic phase of physical exercise –
prolonged exercise with sufficiently low energy expenditureprolonged exercise with sufficiently low energy expenditure
In initial 3 - 30 minutes, utilization of saccharides prevails (liver glycogen,
gluconeogenesis from lactate and alanine – the Cori and the glucose-alanine
cycles, later on also from glycerol – product of lipolysis).
After approximately 1 hour of exercise, fatty acid oxidation is the major sourceAfter approximately 1 hour of exercise, fatty acid oxidation is the major source
of ATP generation. Glucose is spared so that a sufficient amount of glucose is
available to supply oxaloacetate for the citrate cycle.
The Cori cycle and the glucose-alanine cycle
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