FEED FAST CYCLE DETAILS. METABOLISM IN WEL FED AND FASTING STATE

Metabolic
Interrelationship
Dr. Apeksha Niraula
Assistant Professor
Department of Clinical
Biochemistry
IOM
TUTH

Objectives
 Metabolic Interrelationship
 Well fed state, early fasting state, early re-fed state, caloric
homeostasis, energy requirements and reserves
 Five phases of glucose homeostasis and complete starvation
cycle
 Mechanism involved in switching the metabolism of the liver
between the well-fed state and the starved state

Absorptive (fed) state
 Absorptive state: 2 – 4 hours period after ingestion of a normal
meal
 Transient increase in plasma glucose, amino acids &
triacylglycerols (main nutrients) occur
 Insulin secretion is increasedfrom the pancreas & glucagon
secretion is decreased
 Elevated insulin/glucagon ratio : Increased synthesis of
triacylglycerol & glycogen to be stored (anabolicperiod)
 During the absorptive period: all tissues use glucose as a fuel
 Metabolic responses of the body is dominated by alterations of the
metabolism of 4 organs , liver, adipose tissue, muscle & brain

Enzyme changes in the fed state
 Flow of intermediates through metabolic pathways is controlled by:
1. Availability of substrates (within minutes)
2. Allosteric regulation of enzymes (within minutes)
3. Covalent modification of enzymes (within minutes to hours)
4. Induction-repression of enzyme synthesis (within hours to days)
 Each mechanism operates on a different time-scale (i.e. response
occurs within minutes, minutes to hours or hours to days)
 In fed state, these regulatory mechanisms ensure that available nutrients
of food (in abundance) are directed to be stored as glycogen,
triacylglycerol & protein

Organs Involved
 Liver
 Adipose Tissue
 Brain
 Skeletal Muscle
 Kidneys

Liver: Nutrient distribution center
These nutrients are metabolized
or: stored
or: routed to other tissues
 Venous drainage of gut & pancreas passes through the hepatic
portal vein (to liver cells) before entry into the general
circulation
 Thus, after a meal, liver receives blood containing absorbed
nutrients (mainly glucose, amino acids & fatty acids) &
elevated levels of insulin secreted by the pancreas
 During the absorptive period, the liver takes up nutrients which
are carbohydrates, lipids & most amino acids.

Carbohydrate metabolism:
 After a meal containing carbohydrate, liver consumes about 60% of glucose
from portal circulation
 Increased entry of glucose is not insulin dependent: as GLUT-2 of liver is not
influenced by insulin
 Liver metabolism of glucose is increased by:
1- Increased phosphorylation of glucose (i.e. glucose 6-phosphate by
glucokinase)
2- Increased glycolysis of glucose (with production of acetyl CoA)
3- Increased glycogen synthesis glucose stored
fatty acids)
or: energy
4 Increased activity of pentose phosphate pathway of glucose (to provide
NADPH)
5 Decreased gluconeogenesis (synthesis of glucose from non-carbohydrate
sources)

Fat metabolism:
1. Increased fatty acid synthesis:
Favored by :
-Availability of substrates (acetyl CoA & NADPH from glucose metabolism)
-Activation of acetyl CoA carboxylase (enzyme of the rate-limiting step in fatty
acid synthesis)
2. Increased triacylglycerol (TAG)synthesis:
Favored by:
- Fatty acid is provided from de novo synthesis from acetyl CoA & chylomicron
remnants taken by the liver.
- Glycerol 3-phosphate is provided by glucose metabolism (glycolysis).
 Liver packages TAGinto very-low density lipoproteins (VLDL) that are secreted into
blood for use by extrahepatic tissues (particularly adipose & muscle)

Amino acid metabolism:
1. Increased protein synthesis:
 Increase in synthesis of liver proteins to replace any degraded proteins during
fast period
2. Increased amino acid degradation:
 In the absorptive state, more amino acids are present than the liver can use
for synthesis of proteins (i.e. more than liver capacity to synthesize proteins)
 Excess amino acids are not stored in any form BUT, they are released to blood
to other tissues for protein synthesis or, deaminated in liver into carbon
skeleton & ammonia
 Carbon skeleton can be catabolized for energy production or used for fatty acid
synthesis

Liver
in the
absorptive
state

Adipose tissue: Energy storage depot
1. Increased glucose transport:
 GLUT-4 of adipocytes are insulin-sensitive
 In the absorptive state, insulin conc. is elevated resulting in increased influx of
glucose into adipocytes
2. Increased glycolysis:
 Due to increased intracellular levels of glucose
 Glycolysis provides glycerol 3-phosphate for triacylglycerol synthesis
3. Increased activity of pentose phosphate pathway(PPP)
 Increased PPP results in increased formation of NADPH essential for fatty acid
synthesis

Fat metabolism:
1. Increased synthesis of fatty acids (NOT A MAJOR PATHWAY):
 Fatty acid synthesis in adipose tissue is not a major pathway
 Instead, most fatty acids added to adipose tissues are provided by diet
 Fat (in chylomicrons) with a lesser amount supplied by VLDL of liver
2. Increased triacylglycerol synthesis:
 Exogenous fatty acids (from diet fat: chylomicrons & liver fat: VLDL) & glycerol
3 phosphate (from glycolysis of glucose) are used for synthesis of triacylglycerol
in adipose tissue
 Thus, in well-fed state (absorptive state), storage of triacylglycerol (fat)
in adipose tissue is favored

Adipose tissue in
the absorptive
state

Overview:
 Skeletal muscle is able to respond to changes in demand for ATP that
accompanies muscle contraction
 At rest, muscle account for about 30% of oxygen consumption of the body
 During vigorous exercise, muscles account for up to 90% of total oxygen
consumption
 Skeletal muscle depends on aerobic & anaerobic glycolysis metabolism for getting
energy (while heart muscle depends on aerobic metabolism only)
 Skeletal muscles have stores for energy in the form of glycogen & lipids, (while
heart muscle does not have these stores)
Resting skeletal muscle

1. Increased glucose transport:
 GLUT-4 of skeletal muscles cells are insulin-sensitive
 In the absorptive state (after a carbohydrate rich meal), insulin conc. is elevated
resulting in increased influx of glucose into skeletal muscle cells
 Glucose provides energy to muscles during the fed state (in contrast to the fasting
state in which ketone bodies & fatty acids are the major fuels of resting
muscles)
2. Increased glycogen synthesis:
 During absorptive period, glucose (which is abundant after a carbohydrate rich meal),
is stored in the form of glycogen in skeletal muscles

Amino acid metabolism:
1. Increased protein synthesis:
 During the absorptive period, amino acid uptake & protein synthesis is
increased to replace degraded protein since the previous meal
2. Increased uptake of branched-chain amino acids
(Leucine, isoleucine & valine)
 These amino acids escape metabolism by the liver & are taken up by muscle

Skeletal muscles in the
absorptive state

 Brain accounts for 20% of basal oxygen consumption of body at rest (although
it is only 2% of adult weight)
 Brain uses energy at a constant rate
 Brain is vital for proper functioning of all organs of the body & so, special priority
is given to its energy needs
 Glucose normally serves as the primary fuel as the concentration of ketone
bodies in the fed state is too low to serve as an alternate energy source.
 If blood glucose falls to below 30 mg/100 ml (Normal: 70 – 90 mg/100ml),
cerebral functions are impaired
 If hypoglycemia occurs for even a short time, severe & irreversible brain
damage may occur
 During fast, ketone bodies play a significant roles
Brain

 In the fed (absorptive) state, the brain uses
glucose exclusively as a fuel
 (140 grams/day is oxidized to carbon
dioxide & water)
 Excess glucose is not stored (no
glycogen stores)
 Accordingly, the brain is completely
dependent on availability of blood glucose
Brain

Organ map during the absorptive state
showing inter-tissue relationship

Fasting may result from:
-Inability to obtain food
-Desire to lose weight rapidly
-Clinical situations in which an individual cannot eat (trauma,
surgery , etc..)
- Ramadan fasting for Muslims
 Plasma levels of glucose, amino acids & triacylglycerol (main
nutrients) fall with a resulting decline in insulin secretion &
increase in glucagon release
 The decreased insulin/glucagon ratio & decreased availability of
circulating substrates, favors a catabolic period in which
degradation of triacylglycerol, glycogen & protein is characteristic
Fasting

Exchange of substrates between liver, adipose tissue, muscle &
brain is guided by two priorities:
1. Need to maintain adequate plasma levels of glucose to secure
energy metabolism to brain, RBCs & other tissues utilizing
glucose as sole fuel
2. Need to mobilize fatty acids from adipose tissue, synthesis &
release of ketone bodies to supply energy to other tissues

 For a normal 70 kg man at the beginning of a fast:
Fuel stores at the beginning of fasting
 Only 1/3 of body`s protein can be used for energy production without
fatally compromising vitalfunction

Liver in fasting
 The primary role of liver in energy metabolism during
fasting is maintaining of blood glucose through
production & release ofenergy molecules for use by
other organs

Liver in fasting
 Carbohydrate metabolism:
 In liver during fasting, glycogen is degraded first (10-18 hrs of
fasting) & then gluconeogenesis (after 18 hrs to secure
glucose to brain & other tissues utilizing glucose as a sole fuel).
1. Increased glycogen degradation (glycogenolysis) to produce glucose to
blood: exhausted after 10 – 18 hours of fasting (early fasting).
2. Increased gluconeogenesis:
 Gluconeogenesis is the synthesis of glucose from non-carbohydrate sources:
amino acids & lactate from muscles & glycerol from adipose fat
 Gluconeogenesis plays an essential role during overnight & prolonged fasting.
Gluconeogenesis begins 4 - 6 hours after the last meal & becomes fully active
when stores of glycogen are depleted (after about 18 hours)

Liver in fasting
Fat metabolism:
1. Increased fatty acid oxidation:
 Fatty acids obtained from adipose tissue is the major source
of energy to liver during the fasting state
2. Increased synthesis of ketone bodies:
 The liver can synthesize & release ketone bodies from fatty
acids to tissues for use as a fuel. (BUT: liver cannot use ketone
bodies as a fuel)

 Ketone bodies formation is favored by the
availability of fatty acids obtained from adipose
tissue (fatty acids are degraded to acetyl CoA, the
precursor of ketone bodies) [Acetyl CoA produced from
fatty acids exceeds the capacity of citric acidcycle]
 Significant synthesis of ketone bodies starts during the first
days of fasting
 Ketone bodies (unlike FA) are water-soluble & appears in blood
& urine by the second day of a fast

Liver in fasting
Liver
in the fasting
state

Adipose tissue in fasting
Fat metabolism:
1 Increased degradation of triacylglycerols:
 Activation of hormone-sensitive lipase(+Glucagon, Epinephrine) with subsequent
hydrolysis of stored triacylglycerol are enhanced by elevated catecholamines
(epinephrine & norepinephrine) released from sympathetic nerve endings in adipose
tissue
2 Increased release of fatty acids from adipose tissue:
 Fatty acids produced from hydrolysis of triacylglycerol are released to blood &
are transported to tissues to be utilized as a source of energy.
 Fatty acids are also transported to liver to be converted to ketone bodies
 Glycerol produced from hydrolysis of triacylglycerol in adipose tissue is taken by
the liver & is converted to glucose (gluconeogenesis).
 So, fat is a source of glucose (carbohydrate) in fasting state

Resting skeletal muscle in fasting
 Resting muscle uses fatty acids as its major fuel source
 By contrast, exercising muscle initially uses its glycogen stores as a source of energy.
 Carbohydrate metabolism:
 Because of low levels of insulin, glucose transport & glucose metabolism are depressed
 Lipid metabolism:
 During first 2 weeks of fasting , muscle uses fatty acids from adipose tissues &
ketone bodies from liver as sources of energy
 After 3 weeks, muscles depend only on fatty acids

 Protein metabolism:
 During the first few days of fasting, there is a rapid
breakdown of muscle proteins, providing amino acids
that are used by the liver for gluconeogenesis
 After several weeks of fasting, rate of proteolysis is decrease as
there is a decline in need for glucose as a fuel for the brain
(which begins use ketone bodies as a source of energy)

Resting skeletal muscle in fasting

 During the first few days of fasting, the brain continues to use
glucoseonly as a source of energy.
 In prolonged fasting (more than 2 -3 weeks), plasma ketone
bodies reach elevated levels & are used in addition to glucose
in as a source of energy the brain
 This reduces the need for protein degradation for
gluconeogenesis
Brain in fasting

 Renal cortex: expresses the enzymes of gluconeogenesis, including
glucose 6-phosphatase, and, in late fasting, ~50% of gluconeogenesis
occurs here
 Kidneys: provides compensation for the acidosis that accompanies the
increased production of ketone bodies (organic acids)
 Glutamine released from the muscle’s metabolism of BCAA is taken up by the
kidney and acted upon by renal glutaminase and glutamate dehydrogenase,
producing α- ketoglutarate, which can be used as a substrate for
gluconeogenesis, plus ammonia (NH3)
KIDNEYS IN LONG-TERM FASTING

 The NH3 picks up protons from ketone body dissociation
and is excreted in the urine as ammonium (NH4
+), thereby
decreasing the acid load in the body
 Therefore, in long-term fasting, there is a switch from
nitrogen disposal in the form of urea to disposal in the
form of NH4
+

Organ map during the fasting state
showing inter-tissue relationship

Phases of Glucose Homeostasis
 Five Phases
 Well-Fed State (Phase I)
 In Fasting:
 Phase II (Glycogenolysis)
 Phase III (Gluconeogenesis)
 Phase IV ( Glucose, Ketone Bodies Oxidation)
 Phase V (Fatty acid, Ketone Body Oxidation)

FEED FAST CYCLE DETAILS. METABOLISM IN WEL FED AND FASTING STATE

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Editor's Notes