The Fed/Fast Cycle

The absorptive fed state is the 2-4h period after ingestion of

a meal during which theres an increase in plasma blood
glucose, amino acids & TAG. Consequently, the islet cells
increase insulin secretion and decrease glucagon secretion
=> increase synthesis of glycogen, protein, TAG anabolism
Enzymatic changes in the absorptive state:
The flow of intermediates through metabolic pathways is
controlled by:
1. Availability of the substrates
2. Allosteric effects: involve rate-limiting reactions
e.g. in the liver during the absorptive state, fructose 2,6
bisphosphate allosterically activates PFK-1( glycolysis) and
allosterically inhibits fructose 1,6 bisphosphatase
( gluconeogenesis)
3. Covalent modification regulates enzymes by addition or
removal of phosphate from serine, threonine or tyrosine residue of
the protein.
e.g. in the absorptive state, most enzymes are dephosphorylated
and active except glycogen phosphorylase kinase, glycogen
phosphorylase, hormone sensitive lipase ( inactive in the
dephosphorylated form).
4. induction and repression of enzyme synthesis:
This Changes the total number of active site rather than enzyme
efficiency. E.g, increase synthesis of acetyl CoA carboxylase, 3hydroxy-3-methyl-glutaryl-CoA reductase in the fed state.
Adipose tissue: energy storage depot
A. CHO metabolism:
1. Increased glucose transport into adipocyte by insulinsensitive GLUT-4.
2. Increased glycolysis( increased IC glucose) which
provides glycerol phosphate for TAG synthesis.

The Fed/Fast Cycle

3. Increased activity in HMP which provides NADPH,
important for fatty acid synthesis.
B. Fat metabolism:
1. Increased synthesis of fatty acids: De novo synthesis of
FAs from acetyl CoA is low except when re-feeding a
previously fasted individual.
2. Increased TAG synthesis:
- FAs are provided from hydrolysis of TAG of
chylomicrons(from the intestine) and VLDL(from the liver)
released by lipoprotein lipase.
- Glycerol 3-phosphate comes from glucose metabolism
because adipocytes lack glycerol kinase.
3. Decreased TAG degradation by dephosphorylation
(inactive) of hormone-sensitive lipase by elevated
levels of insulin.
Resting skeletal muscle:
Its energy metabolism changes according to ATP demands
accompanied by muscle contraction( accounts for 30% of
oxygen consumption at rest vs 90% with vigorous exercise.
A. CHO metabolism:
1. Increased glucose transport by GLUT-4 due to
increased. Glucose is phsophorylated by hexokinase
and metabolized to provide energy needs.
2. Increased glycogen synthesis due to increased insulin
to glucagon ratio and availability of glucose 6phosphate.
B. Fat metabolism:
FAs are relased from chylomicrons and VLDL by lipoprotein
lipase.( FAs and ketone bodies are the major source fuels
of resting muscle in the fasted state)
C. Amino acids metabolism:
1. Increased protein synthesis by uptake of amino acids.
2. Increased uptake of branched-chain amino acids:

The Fed/Fast Cycle

Branched chain AAs; leucine, isoleucine, valine escape
liver metabolism and are taken by muscle to be
degraded by transaminase for protein synthesis.

Brain:
- Accounts for 20% of oxygen consumption at rest.
A. CHO metabolism:
Exclusively uses glucose in the fed state. No glycogen
stores.
B. Fat metabolism:
No TAG stores. Circulating FAs are bound to albumin and
cant efficiently cross the blood-brain barrier.
Liver: nutrient distribution center (venous drainage of the
gut rich in absorbed nutrients and insulin passes through
hepatic portal vein before entering general circulation)
A. CHO metabolism:( glucose transported through noninsulin sensitive GLUT-2).
Only after a meal the liver becomes a net consumer of
glucose(retains 60g of every 100g of glucose in the portal
system), why?
1. Increased phosphorylatoin of glucose by glucokinase
due to elevated levels of glucose within the
hepatocyte(low affinity for glucose)
2. Increased glycogen synthesis by
dephosphorylation(activation) of glycogen synthase and
increased availability of glucose-6P (allosteric effector).
3. Increased activity of hexose monophosphate pathway:
increased availability of glucose6P and use of NADPH in
hepatic lipogenesis.
4. Increased glycolysis: due to high insulin/glucagon,
acetyl CoA is produced and used for FA synthesis or
provding energy (TCA cycle)
5. Decreased gluconeogenesis: due to inactivation of
pyruvate carboxylase (low acetyl CoA, used in FA

The Fed/Fast Cycle

synthesis)& high insulin to glucagon ratio which
inactivates other enzymes in gluconeogenesis.
6. Decreased glycogenolysis
B. Fat metabolism:
1. Increased FA synthesis: (liver is the primary tissue for
de novo synthesis of FAs ) due to increased availability
of substrates acetyl CoA and NADPH+ activation of
acetyl CoA carboxylase by dephosphorylation and
citrate => malonyl CoA formed(rate-limiting step ,
inhibits FA oxidation).
2. Increased TAG synthesis:
- Fatty acyl CoA from de novo synthesis & hydrolysis of TAG of
chylomicrons.
- Glycer3P from glycolysis
- TAG packaged in VLDL, secreted into the blood for
extrahepatic tissue use.
C. Amino acid metabolism:
1. Increased amino acid degradation:
AA in the liver exceed the ability of liver to synthesize
proteins => AA released into blood for protein
synthesis in other tissue/ deaminated and degraded to
pyruvate, acetyl CoA ..=> energy /FA synthesis.
2. Increased protein synthesis
Overview of fasting:
- Begins if no food is ingested after the absorptive period
caused by inability to obtain food, desire to lose weight,
trauma, cancer, burn, surgery
- Plasma glucose, AAs, TAG decrease => decrease
insulin/glucagon=>degradation of TAG, proteins,
glycogencatabolism
Exchange of substrates between adipose tissue, brain,
muscle and brain
1.maintain adequate plasma glucose for glucose requiring
tissue

The Fed/Fast Cycle

3. Mobilize FAs from adipose tissue+ ketone body

synthesis and release
A. Fuel stores:
Enormous caloric stores in TAG / 1/3 of body protein used for
energy
B. Enzymatic changes in fasting:
Opposite to those in fed state( most enzymes are
phosphorylated and inactive except .
Liver in fasting:
A. CHO metabolism:
1. Increased glycogen degradation : due to
phosphorylation of glycogen phosphorylase. Glycogen
stores exhausted after 10-18h of fasting.
2. Increased gluconeogenesis :
Carbon skeleton derived from glycerol from adipose,
glucogenic AAs, lactate from the muscle .
Drop in fructose 2,6 bisphosphate => activates fructose 1,6
bisphosphatase
Glucagon induces phosphoenolpyruvate carboxykinase(4-6h
after meal)
Acetyl CoA allosterically activates pyruvate carboxylase and
inhibits pyruvate dehydrogenase => pyruvate pushed to
gluconeogensis
Important for overnight and prolonged fasting.
B. Fat metabolism:
1. Increased FAs oxidation: .Major source of energy for
hepatic tissue in the fasted state by hydrolysis of TAG in
adipose tissue. FAs oxidation provides NADH and ATP
needed for gluconeogenesis.
2. Increased synthesis of ketone bodies:
This occurs in the first days of fasting when acetyl CoA
produced from FA metabolism exceeds the oxidative
capacity of the TCA cycle. They are water-soluble and
therefore can be used by most tissues as fuel including
the brain.

The Fed/Fast Cycle

Adipose tissue in fasting:
A. CHO metabolism:
Decreased uptake of glucose by insulin sensitive GLUT-4
due to low insulin levels.
B. Fat metabolism:
1. Increased TAG degradation:
Activation of hormone sensitive lipase by glucagon and
elevated catacholamines epinephrione, norepinephrine
released from sympatheric nerve endings in adipose
tissue .
2. Increased FA release by TAG hydrolysis and are bound
to albumin and transported to different tissue.
Glycerol used for gluconeogenesis.
3. Decreased uptake of fatty acids due to low lipoprotein
lipase in adipose tissue.
Resting skeletal muscle in fasting:

A. CHO metabolism:
Decreased uptake (by insulin-sensitive GLUT-4) and
metabolism of glucose.
B. Fat metabolism:
During the first 2 weeks of fasting, muscle uses fatty acids
and ketone bodies as fuel.
After 3 weeks of fasting, muscle decreases its use of ketone
bodies and oxidizes FAs exclusively => circulating ketone
bodies increase(brain)
C. Protein metabolism:
During the first days of fasting, rapid breakdown of muscle
protein to provide amino acids for gluconeogenesis in the
liver.(alanine and glutamine). Initiated by fall in insulin(no
glucagon receptors) and sustained by rise in glucocoritcoids.
By several weeks, proteolysis decreases(decreased glucose
demands by the brain as it uses ketone bodies).
Brain in fasting:
During the first days of fasting, the brain continues to use
glucose exclusively as fuel.

The Fed/Fast Cycle

- In prolonged fasting(>2-3wks), ketone bodies are primary
fuel=> spare muscle protein
Kidney in long-term fasting:
- 50% of gluoneogenesis occurs here(part of glucose used by
kidney itself)
- Compensate for ketoacidosis:
Glutamine released from muscles metabolism of branched
chain amino acids, taken up by kidneys and acted upon by
renal glutaminase and glutamate dehydrogenase,producing
alpha-ketoglutarate =>gluconeogenesis+ammonia
NH3(picks up H+ from ketone body and excreted in urine as
NH4+)=>decrease the acid load on the body