Regulation and

Interrelation of
Metabolism
Dr. Ban Mahmoud Shaker
Four major tissues play a
dominant role in fuel
metabolism: liver,
adipose,muscle, and brain.
These tissues contain unique
sets of enzymes, such that each
tissue is specialized for the
storage, use, or generation of
specific fuels. These tissues do
not function in isolation but
rather form part of a network
and communication between
them is mediated by the nervous
system, by the availability of
circulating substrates, and by
variation in the levels
of plasma hormones
u Theintegration of energy metabolism is
controlled primarily by the actions of two
peptide hormones, insulin and glucagon
(secreted in response to changing substrate
levels in the blood), with the
catecholamines epinephrine and
norepinephrine (secreted in response to
neural signals) playing a supporting role.
 INSULIN
u Insulin is a peptide hormone produced by
the β cells of the islets of Langerhans, and is
the most important hormone coordinating
the use of fuels by tissues.
u Its metabolic effects are anabolic, favoring,
for example, synthesis of glycogen,
triacylglycerol (TAG), and protein
 Secretion regulation
u 1.Increased secretion: Insulin secretion increased by
glucose, amino acids(for example, arginine) , and
gastrointestinal peptide hormones

u 2.Decreased secretion: The synthesis and release of

insulin are decreased when there is a scarcity of dietary
fuels and also during periods of physiologic stress (for
example, infection, hypoxia, and vigorous exercise), thus
preventing hypoglycemia.

u These effects are mediated primarily by the

catecholamines norepinephrine and epinephrine.
What stimulates insulin release?
Insulin is secreted primarily in response to glucose,
while other nutrients such as free fatty acids and
amino acids can augment glucose-induced insulin
secretion.
Secretin participates in the augmentation of insulin
release after oral stimuli, and that a rapid sequence of
humoral events takes place, gastrin releasing secretin
and secretin releasing insulin
In addition, various hormones, such as melatonin,
estrogen, leptin, growth hormone, and glucagon like
peptide-1 also regulate insulin secretion.
Metabolic effects
Insulin promotes the storage of nutrients as glycogen, TAG, and protein and inhibits their
mobilization

1. Effects on carbohydrate metabolism: insulin promote glucose storage and are most prominent in
three tissues: liver, muscle, and adipose.

In liver and muscle, insulin increases glycogen synthesis. In muscle and adipose, insulin increases
glucose uptake by increasing the number of glucose transporters (GLUT-4) in the cell membrane.

.In the liver, insulin decreases the production of glucose through the inhibition of glycogenolysis
and gluconeogenesis

2. Effects on lipid metabolism: A rise in insulin rapidly causes a significant reduction in the release
of FA from adipose tissue by inhibiting the activity of hormone-sensitive lipase, a key enzyme of
The LPL regulation by insulin associated with determining LPL enzyme
TAG degradation in adipocytes. activity, mRNA levels, protein synthetic rate, and transcription run-off activity

also increases the transport and metabolism of glucose into adipocytes, providing the glycerol 3-
phosphate substrate for TAG synthesis

3. Effects on protein synthesis: In most tissues, insulin stimulates both the entry of amino acids
into cells and protein synthesis (translation)
 GLUCAGON
u Glucagon is a peptide hormone secreted by the α
cells of the pancreatic islets of Langerhans.
Glucagon, along with epinephrine, norepinephrine,
cortisol, and growth hormone (the
counterregulatory hormones), opposes many of the
actions of insulin.
u Most importantly, acts to maintain blood glucose
levels by activation of hepatic glycogenolysis and
gluconeogenesis.
u A.Increased
secretion: glucagon
secretion is increased
by low blood glucose,
amino acids such as
arginin, and
catecholamines as
epinephrine
,norepinephrine ,or
both.
u B. Decreased secretion
Glucagon secretion is
significantly decreased by
elevated blood glucose
and by insulin. Both
substances are increased
following ingestion of
glucose or a
carbohydrate-rich meal
u C. Metabolic effects:
Glucagon is a catabolic
hormone that promotes
the maintenance of blood
glucose levels. Its primary
target is the liver.
u D. Mechanism: Glucagon
binds to high-affinity G
protein–coupled receptors
(GPCR) on the cell membrane
of hepatocytes. The GPCR for
glucagon is distinct from the
GPCR that bind epinephrine.
[Note: Glucagon receptors
are not found on skeletal
muscle.]
The Feed–Fast Cycle

u The absorptive (well-fed) state is the 2- to 4-hour

period after ingestion of a normal meal.
u During this interval, transient increases in plasma
glucose, amino acid, and triacylglycerols (TAG) occur
u Islet tissue of the pancreas responds to the elevated
level of glucose with increased secretion of insulin and
decreased secretion of glucagon.
u During this absorptive period, virtually all tissues use
glucose as a fuel, and the metabolic response of the
body is dominated by alterations in the metabolism of
liver, adipose tissue, skeletal muscle, and brain
 REGULATORY MECHANISMS
u The flow of intermediates through metabolic
pathways is controlled by four mechanisms:
u 1) the availability of substrates,
u 2) allosteric regulation of enzymes,
u 3) covalent modification of enzymes, and
u 4) induction-repression of enzyme synthesis,
 ORGAN SPECIALIZATION AND
METABOLIC INTEGRATION
LIVER: NUTRIENT DISTRIBUTION CENTER

u The liver is uniquely situated to process and

distribute dietary nutrients because the venous
drainage of the gut and pancreas passes through
the hepatic portal vein before entry into the
general circulation
u During
the absorptive period, the liver takes up
carbohydrates, lipids, and most amino acids
u 1. Carbohydrate metabolism : Increased
glycolysis, glycogenesis and hexose
monophosphate shunt and decreased
gluconeogenesis.
u 2. Lipid metabolism : Increased synthesis of
fatty acids and triacylglycerols.
u 3. Protein metabolism : Increased degradation
of amino acids and protein synthesis.
Major metabolic pathways in the
liver in the absorptive state.
ADIPOSE TISSUE: ENERGY
STORAGE DEPOT
RESTING SKELETAL MUSCLE
u The metabolism of skeletal muscle is rather variable
depending on its needs. For instance, the resting muscle
of the body utilizes about 30% of body’s oxygen
consumption. However, during strenuous exercise, this
may be as high as 90%. The important metabolic functions
of skeletal muscle in an absorptive state are listed.
u 1. Carbohydrate metabolism : The uptake of glucose is
higher, and glycogen synthesis is increased.
u 2. Lipid metabolism : Fatty acids taken up from the
circulation are also important fuel sources for the
skeletal muscle.
u 3. Protein metabolism : Incorporation of amino acids into
proteins is higher.
• Increased branched-
chain amino acid
uptake: Muscle is the
principal site for
degradation of the
BCAA because it
contains the
required
transaminase . The
dietary BCAA escape
metabolism by the
liver and are taken
up by muscle,
 BRAIN
u Because the 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 [BBB]). In the fed
state, the brain exclusively uses glucose as a fuel
(GLUT-1
u Because the brain contains no significant stores of
glycogen, it is completely dependent on the
availability of blood glucose
u The brain also lacks significant stores of TAG, and the FA
circulating in the blood make little contribution to
energy production for reasons that are unclear
Major metabolic pathways in the brain in the
absorptive state
Intertissue relationships in the absorptive state
and the hormonal signals that promote them
OVERVIEW OF THE FASTED STATE
u In the absence of food, plasma levels of glucose, amino acids, and TAG
fall, triggering a decline in insulin secretion and an increase in
glucagon, epinephrine, and cortisol secretion. The decreased
insulin/counterregulatory hormone ratio and the decreased availability
of circulating substrates make the postabsorptive period of nutrient
deprivation a catabolic period characterized by degradation of TAG,
glycogen, and protein.
u This sets into motion an exchange of substrates among the liver,
adipose tissue, skeletal muscle, and brain that is guided by two
priorities:
u 1) the need to maintain adequate plasma levels of glucose to sustain
energy metabolism in the brain, red blood cells, and other glucose-
requiring tissues and
u 2) the need to mobilize FA from TAG in WAT for the synthesis and
release of ketone bodies by the liver to supply energy to other tissues
and spare body protein. As a result, blood glucose levels are
maintained within a narrow range in fasting, while FA and ketone body
levels increase
LIVER IN FASTING
u The primary role of the liver in fasting is
maintenance of blood glucose through the
production of glucose (from glycogenolysis and
gluconeogenesis) for glucose-requiring tissues and
the synthesis and distribution of ketone bodies for
use by other tissues.
u 1. Carbohydrate metabolism : An important function of liver is to
act as a blood glucose buffering organ. The action of liver is to suit
the metabolic needs of the body. During starvation, increased
gluconeogenesis and elevated glycogen degradation furnish
glucose to the needy tissues (mostly brain)
u 2. Lipid metabolism : Fatty acid oxidation is increased with
an elevated synthesis of ketone bodies. This is due to the
fact that TCA (Krebs) cycle cannot cope up with the excess
production of acetyl CoA, hence the latter is diverted for
ketone body synthesis.
u Ketone bodies (primarily `Bu-hydroxybutyrate) effectively
serve as fuel source for the peripheral tissues. The brain
slowly adapts itself to use ketone bodies. Thus, after a 3-day
fast, about 1/3rd of the brain’s fuel demands are met by
ketone bodies, while, after 40 days’ starvation, they
countribute to about 70% of energy needs
Adipose tissue in starvation
u 1. Carbohydrate metabolism : Glucose uptake and its
metabolism are lowered.
u 2. Lipid metabolism : The degradation of
triacylglycerol is elevated, leading to an increased
release of fatty acids from the adipose tissue which
serve as fuel source for various tissues (brain is an
exception). The glycerol liberated in lipolysis serves as
a precursor for glucose synthesis by liver. The synthesis
of fatty acids and triacylglycerols is totally stopped in
adipose tissue
Major metabolic
pathways in adipose
tissue during fasting
RESTING SKELETAL MUSCLE
IN FASTING
u Resting muscle switches from glucose to FA as
u its major fuel source in fasting.
u 1. Carbohydrate metabolism : Glucose uptake and its metabolism are
very much depressed.
u 2. Lipid metabolism : Both fatty acids and ketone bodies are utilized by
the muscle as fuel source. However, on prolonged starvation beyond 3
weeks, the muscle adapts to exclusively utilize fatty acids. This further
increases the level of ketone bodies in the circulation.
u 3. Protein metabolism : During the early period of starvation, muscle
proteins are degraded to liberate the amino acids which are effectively
utilized by the liver for glucose synthesis (gluconeogenesis). On
prolonged starvation, however, protein breakdown is reduced.
. BRAIN IN FASTING
u During the early days of fasting, the brain continues to use only
glucose as a fuel
u Blood glucose is maintained by hepatic gluconeogenesis from
glucogenic precursors, such as amino acids from proteolysis and
glycerol from lipolysis.
u In prolonged fasting (beyond 2–3 weeks), plasma ketone bodies
reach significantly elevated levels and replace glucose as the
primary fuel for the brain
u . This reduces the need for protein catabolism for
gluconeogenesis: Ketone bodies spare glucose and, thus, muscle
protein.
u [Note: As the duration of a fast extends from overnight to days
to weeks, blood glucose levels initially drop and then are
maintained at the lower level (65–70 mg/dl).
Major
metabolic
pathways in
the brain
during fasting
Intertissue
relationships
during fasting and
the hormonal
signals that
promote them
KIDNEY IN LONG-TERM
FASTING
u As fasting continues into early starvation and beyond, the kidney
plays important roles.
u The renal cortex expresses the enzymes of gluconeogenesis,
including glucose 6-phosphatase, and, in late fasting, ~50% of
gluconeogenesis occurs here.
u The kidney also provides compensation for the acidosis that
accompanies the increased production of ketone bodies (organic
acids).
u The 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 αketoglutarate, which can be
used as a substrate for gluconeogenesis, plus ammonia (NH3).
u 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 .
Use of glutamine from BCAA catabolism in muscle to
generate ammonia (NH3) used for the excretion of
protons (H+) as ammonium (NH4 +) in the kidneys.