1. Integration of body fuel metabolism
Atif Hassan Khirelsied, Ph.D
,
Department of Biochemistry
Faculty of Medicine
International University of Africa

2. Integration of Metabolism
1. Interconnection of pathways
2. Metabolic profile of organs
3.
3 Food intake starvation and obesity
intake,
4. Fuel choice during exercise
5. Hormonal regulation of metabolism
2

5. Connection of Pathways
1. ATP is generated by oxidation of
1 ATP is generated by oxidation of
glucose, fatty acids, and amino acids
; common intermediate ‐> acetyl
CoA ; electron carrier ‐> NADH and
FADH2
2. Synthesis and degradation pathways
almost always separated ‐>
Compartmentation !!!
5

9. Biosynthetic functions of glycolysis. Compounds
formed from intermediates of glycolysis are
shown in blue.

10. In the liver, TCA cycle intermediates are used for fatty acids synthesis, amino
y y y
acids synthesis, gluconeogenesis, and heme synthesis.
In the brain α ketoglutarate is converted to neurotransmitter glutamate and
brain, α-ketoglutarate neurotransmitter,
GABA.

11. The amphibolic role of
the TCA cycle.

12. Key Junctions between Pathways
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13. Key Junctions between Pathways
• G‐6‐P is a central in
carbohydrate metabolism
• It links PPP, glycogenesis,
glycogenolysis t l l i
l l i to glycolysis.

14. Key Junctions between Pathways
• Pyruvate is another important intermediate of carbohydrates and
amino acids metabolism
• It links gluconeogenesis and amino acids metaabolism to glycolysis.
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15. Acetyl‐CoA is derived from the oxidation of various fuels
Acetyl CoA

16. The central role of acetyl‐CoA in fuel metabolism

17. Metabolic Profile of Body Organs
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18. Metabolic Profile of Organs
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19. 1. Metabolic Profile of Brain
• Glucose is fuel for human brain ‐>
Glucose is fuel for human brain >
consumes 100‐120g/day ‐> 60‐70 %
of utilization of glucose.
• In starvation ‐> ketone bodies can
replace glucose.
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20. 1. Metabolic Profile of Muscles
• Major fuels are glucose, fatty acids, and ketone bodies
Major fuels are glucose fatty acids and ketone bodies
• Has a large storage of glycogen > about ¾ of all
Has a large storage of glycogen ‐> about ¾ of all
glycogen stored in muscles
• Glucose is preferred fuel for burst of activity ‐>
p oduc o o ac a e (a ae obe)
production of lactate (anaerobe)
• Fatty acid major fuel in resting muscles and in heart
y j g
muscle (aerobe)
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21. 2. Metabolic Profile of Muscles
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22. 3. Metabolic Profile of Adiposite tissue
• Triacylglycerols are stored in
tissue ‐> enormous reservoir of
metabolic fuel.
• Needs glucose to synthesis
TAG.
TAG
• Glucose level determines if
fatty acids are released into
blood.
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23. 4. Metabolic Profile of Kidney
4 M b li P fil f Kid
• 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,
produces ½ of blood glucose.
•
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24. 5. Metabolic Profile of
the Liver (Glucose)
the Liver (Glucose)
• Essential for providing
fuel to brain, muscle,
other organs
• Most compounds
absorpt by diet pass
by diet pass
through liver.
• It regulates the levels of
metabolites in blood.
e abo es b ood
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25. Metabolic Activities
of the Liver (Amino
(
Acids)
α‐Ketoacids (derived
from amino acid
degradation)
d d ti )
‐> liver’s own fuel
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26. Metabolic Activities
of the Liver (Fatty
( y
Acids)
• Cannot use
acetoacetate as fuel.
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27. Fuel Metabolism During Fed and
Fuel Metabolism During Fed and
Fast State Conditions
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28. Food Intake, Starvation, and Obesity
Normal Starved‐Fed Cycle:
1. Postabsorptive state ‐> after a meal
2. Early fasting state ‐> during the night
2 Early fasting state > during the night
3. Refed state ‐> after breakfast
4. Prolonged fasting ‐> 12 hrs.
5. Starvation ‐> days
‐> Major goal is to maintain blood‐glucose level!
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29. 1.Postabsorptive state
• Glucose + Amino acids ‐> transport from intestine to
blood
bl d
• Dietary lipids transported ‐> lymphatic system ‐>
blood.
bl d
• Glucose stimulates ‐> secretion of insulin.
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30. 1.Postabsorptive state
Insulin:
l
‐> signals fed state
g
‐> 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
> 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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31. Insulin Secretion –Stimulated by Glucose Uptake
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32. Insulin Secretion –
Stimulated by Glucose
Uptake
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33. Postabsorptive
State -> after a
Meal
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34. 2. Early Fasting State
2 E l F i S
• Blood‐glucose level drops after several hours after
Bl d l l ld ft lh ft
the meal ‐> decrease in insulin secretion ‐> rise in
glucagon secretion
l ti
• Low blood‐glucose level ‐> stimulates glucagon
secretion of α‐cells of the pancreas
p
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35. 2. Early Fasting State
Glucagon:
‐> signals starved state
‐> mobilizes glycogen stores (break down)
‐> inhibits glycogen synthesis
> inhibits glycogen synthesis
‐> main target organ is liver
‐> inhibits fatty acid synthesis
‐> stimulates gluconeogenesis in liver
> stimulates gluconeogenesis in liver
‐> large amount of glucose in liver released to blood stream ‐>
maintain blood‐glucose level
y g
Muscle + Liver use fatty acids as fuel when blood‐glucose level
drops
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36. Early Fasting State ‐> During the Night
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37. 3. Refed State
•Fat is processed in same way as normal fed state
•First > Liver does not absorb glucose from blood (diet)
•First ‐> Liver does not absorb glucose from blood (diet)
y g gy g
•Liver still synthesizes glucose to refill liver’s glycogen
stores
•When liver has refilled glycogen stores + blood‐glucose
level still rises ‐> liver synthesizes fatty acids from excess
glucose
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38. Prolonged fasting, 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
ffi i t f t ti t 1 3 months
th
‐> 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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39. Prolonged fasting, Starvation
First priority ‐> provide sufficient glucose to brain and
p y p g
other tissues that are dependent on it.
Second priority ‐> preserve protein ‐> shift from
p y p p
utilization of glucose to utilization of fatty acids + ketone
bodies.
‐> mobilization of TAG in adipose tissues +
g
gluconeogenesis by liver ‐> muscle shift from glucose to
g y g
fatty acids as fuel.
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40. Prolonged fasting, Starvation
• 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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41. Prolonged fasting, Starvation
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