INTEGRATION OF

METABOLISM
Abdul Salam M. Sofro
Faculty of Medicine
YARSI University Jakarta
Learning objectives
By the end of the lecture, students :
will realize that human body is an integrated
system of organs, each with its own
requirements for nourishment & energy
utilization
will understand the use of fuels under different
metabolic conditions
Metabolism of major foodstuffs
Food
Molecules
Simpler
Molecules
Amphibolic
Pathways
Digestion Absorption
A
n
a
b
o
l
i
c

p
a
t
h
w
a
y
s

CO2 + H2O
O2
Proteins,
Carbohydrates.
Lipids,
Nucleic acids etc.
2H
~
P
Metabolic pathways:
(i) Anabolic pathways
(ii) Catabolic pathways
(iii) Amphibolic pathways
Products of digestion:
Carbohydrate : glucose
Lipid : fatty acid & glycerol acetyl-CoA
Protein : amino acid
In Ruminants:
Cellulose is digested by symbiotic
microorganisms to lower fatty acids
(acetic, propionic, butyric) acetyl-CoA
Carbohydrate Fat Protein
Simple sugars
(mainly glucose)
Amino acids
Fatty acids +
glycerol
Digestion and absorption
------------------------------ ----------------------------
catabolism
----------------------------------- ----------------------------------------
Acetyl-CoA
Citric
acid
cycle
2 CO2
2H ATP
Many of the major foodstuffs are
inconvertible :
carbohydrate (glucose) is converted to
FA via pyruvate dehydrogenase reaction
which is essentially irreversible, so the
opposite process can not take place
No net conversion of acetyl-CoA to
glucose via Cyclic acid cycle (CA cycle)
Many carbon skeletons of non-essential
amino acids can be produced from
carbohydrate via CA cycle &
transamination
Reversal of this process allows glucogenic
amino acids to enter the pathway of
gluconeogenesis
During starvation, FFA & ketone bodies are
oxidized in preference to glucose which is
spares for tissues such as brain &
erythrocyte that require glucose at all times
Ketosis is a metabolic adaptation to
starvation and it is exacerbated in
pathologic conditions such as DM &
ruminant ketosis
Overview of Metabolism
Some important points can be made
about this summary diagram
These pathways are integrated - they do not
operate in isolation. Early parts of the
pathways are reversible
this is important for the storage and
mobilization of fuels within the body as
dietary supply and the body's need for fuel
changes
ATP is produced from the catabolic
pathways - fuels are oxidized to products
ATP is consumed in anabolic pathways -
synthesis of storage forms of fuels
Acetyl CoA is a central focus of
metabolism
it is formed from all three groups of fuel
molecules and acts as a carrier of acetyl
groups into the TCA cycle for their final
oxidation to carbon dioxide
it is also the starting point for important
syntheses
it is the starting point for fatty acids synthesis
it can be converted to ketone bodies (not
shown on this diagram) when required


Notes:
Under positive caloric balance, a
significant proportion of the total energy
intake is stored as either glycogen or fat
If the diet is mainly carbohydrate, glucose
will be the principal fuel of the tissue.
However, in some tissues (even under fed
conditions) fatty acid (FA) are oxidized in
preference to glucose, but particularly
under conditions of caloric deficit or
starvation
The economics of carbohydrate & lipid
metabolism
Glucose is a metabolic necessity for the
brain & erythrocytes in all nutritional states
gluconeogenesis is particularly important
A minimal supply of glucose is probably
necessary in extrahepatic tissues to
maintain oxaloacetate concentrations & the
integrity of the CA cycle
Glucose is also the main source of glycerol-
3-P in tissues devoid of glicerol kinase such
as adipose tissue
minimal & obligatory rate of glucose
utilization under all conditions
Large quantities of glucose are also
necessity for fetal nutrition & the synthesis
of lactose in milk
Preferencial utilization of ketone bodies &
FFA spares glucose for its essential
functions by:
Impairing its entry into cell
Its phosphorylation by hexokinase &
phosphofructokinase
Its oxidative decarboxylation to pyruvate
Turning Metabolism Off and On.
Insulin Affects both Glucose and Lipid
Metabolism.
http://www.medbio.info/Horn/IntMet/integration_of_metabolism%20v2.htm
Notes:
Muscle tissue & liver not just take up
glucose but they have glycogen
reserves will be filled up when
glucose is taken up
Skeletal muscle which makes up more
than 50% of the body will use glucose
as a substrate for aerobic glycolysis
Increased glucose levels stimulate
pancreatic secretion of insulin the
immediate effects :
Increased skeletal muscle glucose
uptake
Inhibition of hepatic gluconeogenesis &
glycogenolysis and stimulation of
glucose uptake in the liver (not shown)
Inhibition of lipolysis in fat tissue
The rates of flux through the various
metabolic pathways are finely controlled in
the healthy individual.
There are a number of strategies used by
the organism to achieve this
regulation. These methods include:
Organ Specialisation
Compartmentalisation of metabolic pathways
Allosteric control of enzymes
Covalent modification of enzymes
Levels of Enzymes

Use of Fuels Under Different Metabolic
Conditions
Different tissues are highly inter-dependent
for appropriate supply of metabolic fuels
under differing metabolic conditions.
The diagrams below illustrate the use of
fuels under four distinct metabolic
scenarios :
the fed state at rest
the fasting state between meals
starvation of several days duration
sustained heavy exercise

http://www.unisanet.unisa.edu.au/10921/metab.htm
THE FED STATE
Ingested food is digested to its
monomeric units and absorbed from the
gut. At rest most metabolic activity is
directed towards storage -
carbohydrate as glycogen
fatty acids as triglyceride
amino acids as protein
Some energy (ATP) must be synthesized
to power these anabolic reactions so
relatively small amounts of amino acids
and fatty acids are used in this way. Brain,
kidney and involuntary muscle have a
continuous need for ATP synthesis and all
rely on glucose supplied readily in the diet
in the fed
FASTING
During a period of fasting such as occurs
between meals metabolic pathways are
reversed and activity is now directed to
maintaining fuels supplies for catabolic
pathways to those tissues with higher
needs.
glycogen stored in the liver is mobilised
(glucagon stimulates) to supply brain and
muscle
glycogen stored in muscle is mobilized
(adrenaline stimulates) and is used ONLY
within the muscle (remember : muscle
lacks glucose 6-phosphatase)
amino acids are used by the liver for
gluconeogenesis to maintain adequate
circulating blood glucose particularly for
the brain
a small amount of mobilization of
triglycerides occurs and the released fatty
acids can be used directly by muscle and
liver for catabolism while a small amount is
converted to ketone bodies for use by
muscle


STARVATION
During extended starvation the metabolic
pathways utilized change again.
Glycogen reserves have been exhausted
quickly - a short a period as 36h will
significantly deplete glycogen stores. The
body then relies primarily on stored
triglycerides (in adipose tissue) to supply
the fuel requirements of muscle and
other tissues.
The brain uses glucose produced by
gluconeogenesis in the liver, but ultimately
will switch to using the polar ketone bodies
which can cross the blood-brain barrier.
Ketone body production by the liver
increases significantly with longer periods
of starvation.
HEAVY EXERCISE
During extended exercise the aim of these
metabolic pathways is to supply muscle with
sufficient fuel for sustained muscle
contraction.
Glycogen stores in the liver are mobilized as
are triglycerides from adipose tissue. The
former supplies glucose and the latter
supplies fatty acids, either directly or as
ketone bodies (after they are synthesized
from fatty acids in the liver).
Muscle uses its own glycogen reserves,
primarily via glycolysis and then aerobic
oxidation of pyruvate via the TCA cycle.
Muscle has the capacity to rely solely on
glycolysis in the absence of oxygen for a
short period. Anaerobic glycolysis can be
regarded as an emergency pathway and is
only capable of supplying sufficient ATP
for 1 - 2 minutes.
Ketosis
Is a metabolic adaptation to starvation & fat
feeding is relatively mild compared with the
condition encountered in uncontrolled Diabetes
Mellitus
Arises as a result of a deficiency in available
carbohydrate (glucose) & causes an imbalance
between esterification & lipolysis in adipose
tissue as a result of lower insulin levels release
of FFA into the circulation (metabolic or
endocrine factor affect the release of FFA from
adipose tissue)
Ketone bodies are utilized by extrahepatic tissues
in proportion to their concentration in blood
http://www.medbio.info/Horn/Time 3-4/homeostasis_2.htm#Tissue distribution of glucose after a meal