Integration of Metabolism

(Metabolisme energi otot & organ penting)

Abdul Salam M. Sofro

Faculty of Medicine YARSI University
 Learning objectives

• By the end of the lecture, it is expected that

students would :
– realize that human body is an integrated
system of organs, each with its own
requirements for nourishment & energy
utilization
– understand the use of fuels under different
metabolic conditions
Metabolism of major foodstuffs
 Food Digestion Simpler Absorption Amphibolic
Molecules Molecules Pathways

Anabolic pathways
2H

O2
~P
CO2 + H2O Proteins,
Carbohydrates.
Lipids,
Metabolic pathways: Nucleic acids etc.
(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 Protein Fat

------------------------------ Digestion and absorption ----------------------------

Simple sugars Fatty acids +

(mainly glucose) Amino acids glycerol

---------------------------------------- catabolism -----------------------------------

Acetyl-CoA

Citric
acid
cycle
2H ATP

2 CO2
• 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
spared 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 Specialization
– Compartmentalization 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
 Use of Fuels (1)
The fed state (resting)
Glucose Liver Storage (as Glycogen)
triglyceride synthesis (excess)
Other tissues
Brain & Kidney Energy production (ATP)

Muscle Storage predominantly (as Glycogen)

Amino acid Liver Energy production (ATP)

and protein synthesis

Other tissues protein synthesis

Fatty acid Adipose Tissue Storage (Triglycerides)

Muscles Energy production (ATP)

Small amount
• 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 State
Use of Fuels (2)

Glycogen (liver) Glucose-6-phosphate Glucose Brain & Muscle

Glycogen (muscle) Glucose-6-phosphate Energy production

(ATP)

Amino acids (liver) Glucose Brain

(via glukoneogenesis)

Triglycerides (Adipose tissue) Fatty acids

basal
Liver Muscle
rate

Energy production
(ATP)
Keton bodies
• 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 (several days)
Use of fuels (3)

Amino acids (liver) Glucose Brain

(via glukoneogenesis)

Triglycerides (Adipose tissue) Fatty acids

Liver high
Muscle
rate

Energy production
(ATP) Keton bodies

Brain

N.B. Glycogen reserves have been exhausted quickly

• 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
Use of fuels (4)

Liver Glucose 6-phosphate Glucose

Glucose 1-phosphate Gluconeogenesis

Glycogen

Liver Keton bodies Muscle

Supply of exogeneous fuels to muscle

Adipose Triglyserides Fatty acids

Tissue
• 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
Tambahan pada Diabetes Mellitus
http://www.medbio.info/Horn/Time 3-4/homeostasis_2.htm#Tissue distribution of glucose after a meal
http://www.medbio.info/Horn/Time 3-4/homeostasis_2.htm#Tissue distribution of glucose after a meal