Integration of Metabolism in Fed state

Shahnawaz Alam
Dept of Biochemistry
Afsms&rc
 Competency BI 6.1

• Discuss the metabolic processes that take place

in specific organs in the body in the fed and
fasting states
 Food for thought?

• We consume food continuously but rather intermittently, every 4

Hours on an average.

• Still metabolic needs of body are maintained and homeostasis is

maintained.

• This is possible due to metabolic adaptations that occurs in body in

relation to food intake (Fed) or Fasting.

• This cycle of event is termed as FEED-FAST cycle or

• Starve-Feed Cycle.
 Specific learning Objectives

• Describe organ specialized integration of metabolism (liver,

adipose tissue, skeletal muscle & brain) in fed state.

• Describe interrelationships between the metabolic pathways of

carbohydrate, lipids & proteins in fed state
 Integration is coordinated

 The metabolic pathways of carbohydrate, lipids and proteins occur

simultaneously. The network of reactions in metabolism is coordinated.
 Each pathway is able to sense the status of the others to function
optimally to meet the needs of the body.
 All the major metabolic pathways do not operate in every tissue at any
given time. However, cells and organs cooperate for the common good
of the body.
 Together they control the everyday challenges of overeating, fasting
and muscular activity.
Metabolic interrelation
 Integration of Metabolism
Definition
The various anabolic and catabolic pathways by which
carbohydrates, lipids and proteins are processed for energy
supply or for the biosynthesis of compounds required by the cell
are closely co-ordinated.
This co-ordination between three metabolites is called
integration of metabolism.
Integration of metabolism is considered at two levels:
1. Cellular level
2. Tissue or organ level.
 Integration of Metabolism at Cellular Level

Integration of metabolism at cellular level includes the

different metabolic pathways of glucose, FA, glycerol & AA,
at the cellular level which results in:

1.Conversion of carbohydrates into fats and fats into

carbohydrates
2.Conversion of carbohydrates into proteins and proteins into
carbohydrates
3.Conversion of proteins into fats.
 Conversion of Carbohydrates into Fats and
Fats to Carbohydrate

 Carbohydrates (glucose) are metabolized to pyruvate and then pyruvate to acetyl-CoA

 Acetyl-CoA is the precursor for synthesis of fatty acids.

 Fatty acids, that are produced, combine with glycerol to form triacylglycerol.

Glycerol is supplied from the glucose

 Propionyl-CoA, odd carbon number fatty acid converted to succinyl-CoA, can be
converted to glucose

 The glycerol moiety of triacylglycerol is converted to glucose by gluconeogenesis.

 Conversion of Carbohydrates into Proteins and
Proteins into Carbohydrates

 Carbon skeletons of the non-essential amino acids can be

produced from carbohydrate via the intermediates of citric acid

cycle and transamination.

 By reversal of these processes, glucogenic amino acids yield

intermediates of the citric acid cycle. They are converted to

glucose by gluconeogenesis.
 Conversion of proteins into fats
& Conversion of fats into proteins

 Conversion of carbon skeletons of glucogenic amino acids to

fatty acids is possible either by formation of pyruvate and acetyl-
CoA.
 Generally, however, the net conversion of amino acids to fat is
not a significant process
 Conversion of fats into proteinsIt is not possible for a net
conversion of fatty acids to amino acids to take place.
 Integration of Metabolism at Tissue or Organ
Level

 Integration of metabolism at tissue or organ level includes the

inter-relationship of different tissues and organs to meet

metabolic demands for the whole body.

 Liver, skeletal muscle, Adipose tissue, Brain and heart are the

major organs involved .

 Significance of Integration of Metabolism

 Integration of metabolism ensures a supply of suitable fuel

for all tissues, at all times from the fully fed state to the
totally starved state.
 Under positive caloric balance, i.e. in well fed state, a
significant proportion of the food energy intake is stored as
either glycogen or fat.
 Under negative caloric balance, i.e. in starvation, fatty acids
are oxidized in preference to glucose, to spare glucose for
those tissues, (e.g. brain and erythrocytes) that require it
under all conditions
 Well fed state
• Well fed state or absorptive state constitutes the 2-4 hr period
following meal

• Fed state transiently raises blood glucose, amino acids and

triacylglycerol levels.

• Rise in blood glucose and AA induces the secretion of insulin from

pancreas.

• Insulin signals the fed state and stimulate the synthesis of glycogen
TAG and protein synthesis

• Synthesis of Glycogen in muscle and liver

• High insulin Promotes entry of Glucose into muscle and
adipose tissue via GLUT 4 glucose transporter

• All tissues use glucose as fuel. Insulin stimulates glycolysis

results in pyruvate and Acetyl CoA formation which enters
TCA cycle to release energy

• Glucose in adipose tissue provides Glycerol 3 phosphate for

synthesis of TAGs
• Insulin Promotes uptake of branched chain AA by muscles.

• Insulin has stimulating effect on protein synthesis, mucle

proteins (actin and myosin) inhibits degradation of proteins
• Metabolic responses of body in fed state occurs Mainly 4 organs
• Liver, adipose tissue, skeletal muscle and brain.
• Regulatory mechanisms
• 1. Availability of substrate,
• 2. Allosteric regulation of enzymes,
• 3.Covalent modifications of enzymes,
• 4. Induction repression of enzyme synthesis which ensures availability
of nutrients.

• Thus in FED state there is

• Increased glycolysis, glycogenesis, TGL Synthesis and protein synthesis
• Decreased gluconeogenesis
 Role of Liver
 Maintenance of blood glucose levels.

 During the fed state, the liver takes up excess glucose and stores it
as glycogen or converts it to fatty acids.
 During the fasting state, liver provides glucose for the body by the
glycogenolysis and gluconeogenesis.
 The liver synthesizes ketone bodies during starvation and supplies
to the peripheral tissues as a source of energy
 Liver & carbohydrate metabolism
• Liver is normally a glucose-producing rather than a glucose-using
tissue. However, after a meal containing carbohydrate, the liver
becomes a net consumer of glucose, retaining roughly 60 g of every
100 g of glucose presented by the portal system.

• Elevated levels of glucose within the hepatocyte (as a result of

elevated extracellular levels) allow glucokinase to phosphorylate
glucose to glucose 6-phosphate

• The conversion of glucose 6-phosphate to glycogen is favored by the

activation of glycogen synthase.

• The increased availability of glucose 6-phosphate in the absorptive

state, combined with the active use of NADPH in hepatic lipogenesis,
stimulate the HMP shunt
 Increased glycolysis

• In liver, glycolytic metabolism of glucose is significant only

during the absorptive period following a carbohydrate- rich meal.
The conversion of glucose to acetyl CoA is stimulated by the
elevated insulin to glucagon ratio that results in increased
activity (and amount) of the regulated enzymes of glycolysis, for
example, pyruvate kinase

Decreased gluconeogenesis
• Whereas glycolysis is stimulated in the absorptive state,
gluconeogenesis is decreased. Pyruvate carboxylase, which
catalyzes the first step in gluconeogenesis, is largely inactive due
to low levels of acetyl CoA—an allosteric effector essential for
enzyme activity
 Fat metabolism & Liver
• Increased fatty acid synthesis:
• Liver is the primary tissue for de novo synthesis of fatty acids.
• This pathway occurs in the absorptive period, when dietary caloric
intake exceeds energy expenditure by the body.
• Fatty acid synthesis is favored by the availability of substrates (acetyl
CoA and NADPH derived from the metabolism of glucose) and by the
activation of acetyl CoA carboxylase,

Increased TAG synthesis

• TAG synthesis is favored because fatty acyl CoA is available both
from de novo synthesis from acetyl CoA and from hydrolysis of the
TAG component of chylomicron remnants removed from the blood
by hepatocytes.
• Glycerol 3-phosphate, the backbone for TAG synthesis, is provided
by the glycolytic metabolism of glucose
 Amino acid metabolism:
Increased amino acid degradation:

• In the absorptive period, more amino acids are present than the
liver can use in the synthesis of proteins and other nitrogen-
containing molecules.

• The surplus amino acids are not stored, but are either released
into the blood for all tissues to use in protein synthesis or are
deaminated, with the resulting carbon skeletons being
degraded by the liver to pyruvate, acetyl CoA, or TCA cycle
intermediates.

• These metabolites can be oxidized for energy or used in fatty

acid synthesis
 These The liver has limited capacity to degrade the branched-
chain amino acids leucine, isoleucine, and valine. They pass
through the liver essentially unchanged and are preferentially
metabolized in muscle

 Increased protein synthesis: The body cannot store protein in

the same way that it maintains glycogen or TAG reserves However,
a transient increase in the synthesis of hepatic proteins does
occur in the absorptive state
 Role of Adipose Tissue

 During fed state, the adipose tissue synthesizes triacylglycerols

from glucose and free fatty acids
 During the fasting state, triacylglycerols are converted to
glycerol and fatty acids, which are exported to the liver and
other tissues
 Adipose tissue & Carbohydrate metabolism

 Increased glucose transport: Glucose transport by GLUT-4

into adipocytes is sensitive to the insulin concentration in the
blood. Circulating insulin levels are elevated in the absorptive
state, resulting in an influx of glucose into adipocytes.

 Increased glycolysis: The increased intracellular availability

of glucose results in an enhanced rate of glycolysis.

 Increased activity in the HMP: Adipose tissue can

metabolize glucose by means of the HMP, thereby producing
NADPH, which is essential for fat synthesis
 Adipose tissue & Fat metabolism

 Increased synthesis of fatty acids: De novo synthesis of fatty

acids from acetyl CoA in adipose tissue is low in humans.

 Increased TAG synthesis: After consumption of a lipid-

containing meal, hydrolysis of the TAG of chylomicrons (from
the intestine) and VLDL (from the liver) provides adipose tissue
with fatty acids .The fatty acids are released from lipoproteins by
the action of lipoprotein lipase.

 Decreased TAG degradation: Elevated insulin favors the

dephosphorylated (inactive) form of hormone-sensitive lipase,
TAG degradation is thus inhibited in the fed state.
 Role of Skeletal Muscle

 Skeletal muscle maintains large stores of glycogen, which

provide energy during exertion.
 During starvation, free fatty acids and ketone bodies supplied by
liver are oxidized in preference to glucose in muscle.
 The protein present in muscle may be used as a fuel source, if no
other fuel is available.
 Pyruvate, the product of glycolysis in the skeletal muscle, may
be converted to either lactate or alanine and transported to the
liver, where it is used to regenerate glucose via gluconeogenesis
 Skeletal muscle

• The energy metabolism of skeletal muscle is unique in being

able to respond to substantial changes in the demand for ATP
that accompanies muscle contraction.

• At rest, muscle accounts for approximately 30% of the oxygen

consumption of the body.

• whereas during vigorous exercise, it is responsible for up to 90%

of the total oxygen consumption.
 Carbohydrate and fat metaboilsm
1. Increased glucose transport: The transient increase in
plasma glucose and insulin after a carbohydrate-rich meal
leads to an increase in glucose transport into muscle cells by
GLUT-4 ,Glucose is phosphorylated to glucose 6- phosphate
by hexokinase, and metabolized to provide the energy.

2. Increased glycogen synthesis: The increased insulin to

glucagon ratio and the availability of glucose 6-phosphate
favor glycogen synthesis, particularly if glycogen stores have
been depleted as a result of exercise
Fat metabolism
 Fatty acids are released from chylomicrons and VLDL by the
action of lipoprotein lipase ,However, fatty acids are of
secondary importance as a fuel for muscle during the fed
state, in which glucose is the primary source of energy.
 Amino acid metabolism
 1. Increased protein synthesis:
A spurt in amino acid uptake and protein synthesis occurs in the
absorptive period after ingestion of a meal containing protein This
synthesis replaces protein degraded since the previous meal.

 2. Increased uptake of branched-chain amino acids:

Muscle is the principal site for degradation of branched-chain
amino acids because it contains the required transaminase.

The branched-chain amino acids, leucine, isoleucine, and valine,

escape metabolism by the liver, and are taken up by muscle,
where they are used for protein synthesis, and as sources of
energy.
 Role of Brain

 Brain tissue normally uses glucose as an exclusive fuel, except

during starvation, when it can adapt to use ketone bodies as an
energy source
 The brain contains essentially no fuel reserves and must be
continuously supplied with fuel from the liver.
 Although contributing only 2% of the adult weight, the brain
accounts for a consistent 20% of the basal oxygen consumption
of the body at rest.

 brain is vital to the proper functioning of all organs of the body,

special priority is given to its fuel needs.
 To provide energy, substrates must be able to cross the endothelial
cells that line the blood vessels in the brain (the “blood-brain
barrier”). Normally, glucose serves as the primary fuel for the
brain. [Note: If blood glucose levels fall below approximately 40
mg/100 ml (cerebral function is impaired.

 If the hypoglycemia occurs for even a short time, severe and

potentially irreversible brain damage may occur.

 During a fast, however, ketone bodies play a significant role as a

fuel for brain, reducing its dependence on glucose
 Brain & FED state
Carbohydrate metabolism
• In the fed state, the brain uses glucose exclusively as a fuel,
completely oxidizing approximately 140 g/day to CO2 and
H2O.
• The brain contains no significant stores of glycogen and is,
therefore, completely dependent on the availability of blood
glucose.
Fat metabolism
• The brain has no significant stores of TAG.
• Fatty acids circulating in the blood make little contribution to
energy production because fatty acids bound to albumin do not
efficiently cross the blood-brain barrier.
 Summary

• Describe organ specialized integration of

metabolism (liver, adipose tissue, skeletal
muscle & brain) in fed state
• Describe interrelationships between the
metabolic pathways of carbohydrate, lipids &
proteins in fed state
 Bibliography

1.Harper’s Illustrated Biochemistry, 8th Edi.

Murray & Bender
2.Biochemistry, 4th edition.
Satyanarayan, & Chakraborthy
3.Text Book of Biochemistry,6th edi
Vasudevan & Sreekumari S

4.Lippincott’s Biochemistry, 5th edi.

Harvey & Ferrier
5.Text Book of Biochemistry
Chatterjee & Ranashinde
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