Integration of Metabolism

Dr. MK. Ali

• The human body functions as one community.
• Communication between tissues is mediated by:
1. nervous system,
2. Availability of circulating substrates
3. Variation in the levels of plasma hormones.
• The integration of energy metabolism is controlled
primarily by the action of hormones, including
insulin, glucagon and catecholamines (epinephrine
and nor epinephrine).
• The four major organs important in fuel
metabolism are liver, adipose tissue muscle and
brain.
 The Liver Processes and Distributes Nutrients
• The liver plays a central processing and distributing role in metabolism and
furnishes all other organs and tissues with an appropriate mix of nutrients
via the bloodstream.
• During digestion in mammals, the three main classes of nutrients undergo
enzymatic hydrolysis into their simple constituents. But the epithelial cells
lining the intestinal lumen absorb only relatively small molecules. Most
sugars and amino acids from intestinal epithelial cells into blood capillaries,
and travel in the bloodstream through the portal vein to the liver while
most triacylglycerols (TAGs) enter adipose tissue via the lymphatic system.
• The liver has two main cell types. (1) Kupffer cells are phagocytes,
important in immune function. (2) Hepatocytes that transform dietary
nutrients into the fuels and export them via the blood.
• Liver has remarkable metabolic flexibility because of high Liver enzymes
turn over (are synthesized and degraded) at 5 to 10 times the rate of
enzyme turnover in other tissues, such as muscle.
 Sugars metabolism in liver

Glucose entering hepatocytes is

phosphorylated by hexokinase IV
(glucokinase) to yield glucose 6-
phosphate. Glucokinase has a much
higher Km for glucose (10 mM) than
do the hexokinase isozymes in other
cells. The high Km of glucokinase also
ensures that the phosphorylation of
glucose in hepatocytes is minimal
when the glucose concentration is
low, preventing the liver from
consuming glucose as fuel via
glycolysis. This spares glucose for
other tissues.
Amino acid metabolism in liver
Lipids metabolism in liver
 Adipose Tissues Store and Supply Fatty Acids
There are two types of adipose tissue, white (WAT) and brown (BAT).
 White adipose tissue (WAT)
• WAT is amorphous, widely distributed in the body 15% of the mass of
young adult.
• WAT are metabolically very active, large (diameter 30 to 70 m), spherical
cells, filled with a single large lipid (TAG) droplet (65% of the cell mass ) that
squeezes the mitochondria and nucleus into a thin layer against the plasma
membrane.
• During high carbohydrate intake, adipose tissue can convert glucose to fatty
acids, convert the fatty acids to TAGs and store as large fat globules.
• When the demand for fuel rises, lipases in WAT hydrolyze stored TAGs to
release free fatty acids into bloodstream.
• The release of fatty acids from WAT is greatly accelerated by epinephrine,
which stimulates the cAMP-dependent phosphorylation of perilipin
(hormone-sensitive lipase) access to TAGs in the lipid droplet . Insulin
counterbalances this effect of epinephrine.
• In adipose tissue, glycerol liberated by perilipin cannot be reused in the
synthesis of TAGs, because WAT lack glycerol kinase. Instead, the glycerol
phosphate required for TAG synthesis is made from pyruvate by
glyceroneogenesis.
 Brown Adipose Tissue Is Thermogenic
• BAT is smaller than WAT (diameter 20 to 40 m), differently shaped (polygonal) and
store triacylglycerols in several smaller lipid droplets per cell.
• The cells have more mitochondria and a richer supply of blood capillaries thus
giving its characteristic brown color.
• BAT expressed UNC1, which encodes thermogenin, the mitochondrial uncoupling
protein responsible for thermogenesis.
• In brown adipocytes, fatty acids stored in lipid droplets are released, enter
mitochondria, and undergo complete conversion to CO2 via oxidation and
• the citric acid cycle.
• In BAT, thermogenin provides an alternative route for protons to reenter the
mitochondrial matrix that bypasses ATP synthase; the energy of the proton
gradient is thus dissipated as heat, which can maintain the body at its optimal
Temperature.
 Muscles Use ATP for Mechanical Work
• Metabolism in the cells of skeletal muscle—myocytes— is specialized to generate ATP as the
immediate source of energy for contraction.
• There are two general classes of muscle tissue.
• (a) Slow-twitch muscle, also called red muscle, provides relatively low tension but is highly
resistant to fatigue. It produces ATP by the relatively slow but steady process of oxidative
phosphorylation. Red muscle is very rich in mitochondria and is served by very dense
networks of blood vessels, which bring the oxygen essential to ATP production.
• (b) Fast-twitch muscle, or white muscle, has fewer mitochondria than red muscle and is less
well supplied with blood vessels, but it can develop greater tension, and do so faster. White
muscle is quicker to fatigue because when active, it uses ATP faster than it can replace it.
• Skeletal muscle can use free fatty acids, ketone bodies, or glucose as fuel, depending on the
degree of muscular activity.
• After a period of intense muscular activity,
the individual continues breathing heavily
for some time, using much of the extra O2
for oxidative phosphorylation in the liver.
• The ATP produced is used for
gluconeogenesis (in the liver) from lactate
that has been carried in the blood from the
muscles. The glucose thus formed returns
to the muscles to replenish their glycogen,
completing the Cori cycle.

CORI CYCLE
 Brain Uses Energy for Transmission of Electrical Impulses
• The neurons of the adult mammalian brain normally use only glucose as fuel and
have active respiratory metabolism and uses O2 at a fairly constant rate (20% of
the total O2 consumed by the body at rest).
• Brain contains little glycogen so dependent on incoming glucose in the blood. But
during prolonged fasting, brain can used beta-hydroxybutyrate (a ketone body),
formed from fatty acids in the liver as fuel.
• Energy obtained from oxidation glucose is critical for action potential as it
membrane contains an electrogenic ATP-driven antiporter, the NaK ATPase, which
simultaneously pumps 2 K ions into and 3 Na ions out of the neuron increasing
neuronal action potential. So depletion of ATP in neurons would have disastrous
effects on all activities coordinated by neuronal signaling.
Blood Carries Oxygen, Metabolites, and Hormones
• Blood mediates the metabolic
interactions among all tissues.
Oxygen moves in the bloodstream
from the lungs to the tissues, and
CO2 generated by tissue respiration
returns via the bloodstream to the
lungs for exhalation. Blood also
carries hormonal signals from one
tissue to another. The average adult
human has 5 to 6 L of blood.
 Hormonal Regulation of Fuel
Metabolism
• The minute-by-minute adjustments that keep the blood glucose level near 4.5 mM
involve the combined actions of insulin, glucagon, epinephrine, and cortisol on
metabolic processes in many body tissues, but especially in liver, muscle, and
adipose tissue.
• Insulin signals these tissues that blood glucose is higher than necessary; as a result,
cells take up excess glucose from the blood and convert it to glycogen and
triacylglycerols for storage.
• Glucagon signals that blood glucose is too low, and tissues respond by producing
glucose through glycogen breakdown and (in the liver) gluconeogenesis and by
oxidizing fats to reduce the use of glucose.
• Epinephrine is released into the blood to prepare the muscles, lungs, and heart for
a burst of activity. Cortisol mediates the body’s response to longer-term stresses.
 Insulin
• Insulin is a polypeptide
hormone produced by the B-
cells of the islets of
Langerhans of the pancreas.
• Insulin is one of the most
important hormones coordi-
nating the utilization of fuels
by tissues.
• Its metabolic effects are
anabolic, stimulating the
synthesis of glycogen
(glycogensis), triacylglycerols
(lipogenesis) and protein.
 Structure of insulin
•Insulin is composed of 51 amino acids (M.Wt 5700) arranged in two
polypeptide chains A and B which are linked together by two disulfide
bridges and is synthesized in the β-cells of the pancreatic islets.
•The insulin molecule also contains an intramolecular disulfide bridge in
A chain.
•Beef insulin differs from human insulin at three amino acid positions,
whereas pork insulin varies at only one position.
 Biosynthesis of insulin
• The gene for insulin codes for pre-proinsulin which is made up of a signal sequence
(approximately 23 amino acids) that are rapidly cleaved after it synthesis.
• B chain, connecting (or C) peptide and A chain has been directed to the
endoplasmic reticulum (ER).
• In ER, A and B peptides are joined together by two disulfide bonds between
common cysteine amino-acid residues.
• The C peptide is essential to the formation of these disulfide bonds.
• In Golgi apparatus C peptide is cleaved, leaving the joined A and B chains which
form the active insulin molecule.
• Insulin is stored in the cytosol in granules that are released by exocytosis. Insulin is
degraded by the enzyme insulinase present in the liver and to a lesser extent in the
kidneys. Insulin has a plasma half-life of about 6 minutes. This short duration of
action permits rapid changes in circulating levels of the hormone.
 Regulation of Insulin Secretion
1-Stimulation of insulin secretion:
The relative amounts of insulin secreted by the pancreas are regulated so that the rate
of hepatic glucose production is kept equal to the use of glucose by peripheral
tissues. Insulin secretion is stimulated by:
a) Glucose is the most important stimulus for insulin secretion. Ingestion of glucose
or a carbohydrate rich meal leads to a rise in blood glucose which stimulates
insulin secretion. However, the same amount of glucose given orally stimulates
more insulin secretion than if given intravenously.
b) Ingestion of protein (amino acid) leads to a rise in plasma amino acids which
stimulate insulin secretion. Elevation of one particular amino acid arginine in
blood plasma is a potent stimulant for insulin secretion.
c) Gastrointestinal hormones such as secretin as well as other stimulate insulin
secretion after the ingestion of the food.
2. Inhibition of insulin secretion:
• The synthesis and release of insulin are decreased during starvation and stress and
is mediated by epinephrine secreted by the adrenal medulla control by
sympathetic nervous system. Epinephrine stimulates glycogenolysis,
gluconeogenesis and lipolysis. Thus, in emergency situations, the sympathetic
nervous system largely replaces the plasma glucose concentration as the
controlling influence over β –cell secretion
 Mechanism of insulin secretion and secretory response to glucose

Entry of glucose into the β-cell

induces closure of K+ channels,
depolarization and opening of
voltage-gated calcium channels with
a consequent secretion of insulin.
Other factors that modulate insulin
release may act via stimulating
phospholipase C (PLC) or adenyl
cyclase (AC) that activate the inositol
pathway or cAMP, respectively.
Insulin secretion take place in two
phases in response to a glucose
infusion.
 Mechanism of Insulin Action
• Insulin binds to specific, high-affinity receptors in the cell membrane of most
tissues, including liver, muscle and adipose. This is the first step in a cascade of
reactions leading to many biological actions.
1-Insulin receptor: It is a tetramer linked by disulfide bonds. The extracellular -
subunit contains the insulin binding site. The cytoplasmic domain of the -subunit
is a tyrosine kinase, which is activated by insulin.
2-Signal transduction: At least four IRSs have been identified that show similar
structures but different tissue distributions. The actions of insulin are terminated
by dephosphorylation of the receptors.
3-Membrane effects of Insulin: Glucose transport in many tissues increases in the
presence of insulin. Insulin stimulates the recruitment of glucose transporters
(GLUT-4) from a pool present in intracellular vesicles. Some tissues have insulin
independent systems for glucose transport e.g. hepatocytes, erythrocytes, cells of
the nervous system, intestinal mucosa, renal tubules and cornea.
4-Time course of insulin actions: After insulin binding to the receptors the responses
will be: a) Increase glucose transport (seconds). b) Change in enzyme activity
(change in phosphorylation states) minutes to hours c) Increase in the amount of
enzymes e, g glucokinase, phosphofructokinase, and pyruvate kinase (hours to
days).
 Signalling at the insulin receptor
Insulin (I) binds to the two extracellular
α domains of the insulin receptor that
are linked by a disulfide bond (S-S). This
induces phosphorylation (P) of the
intracellular tyrosine kinase region of the
two β-subunits which are connected to
their α-units by a disulfide bond.
Activated tyrosine kinase phosphorylates
an insulin receptor substrate (IRS) and
subsequent binding of proteins with SH2
domains. These include
phosphatidylinositol 3-kinase (PI3) and
GRB. Subsequent signal transduction
linkages may involve Ras and Raf
proteins with activation of MAP kinases
and activation of nuclear transcription
factors. Activation of insulin receptors
translocate glucose transporters to the
cell membrane allowing the influx of
glucose.
 Metabolic effects of Insulin
1-Effects on carbohydrate metabolism:
The effects of insulin on glucose metabolism are most prominent in three tissues: liver,
muscle and adipose tissue. Insulin is the only hypoglycemic hormone. Insulin
increases glucose oxidation and utilization by tissues.
(a) In muscle and adipose tissue, insulin increase glucose uptake by increasing the
number of glucose transporters in the cell membrane.
(b) In muscle and liver, insulin increases glycogensis.
(c) In the liver, insulin decreases the production of glucose by inhibiting both
glycogenolysis and gluconeogenesis.
2-Effects on Lipid Metabolism:
Insulin decreases the release of fatty acids from adipose tissue by decreasing
triglycerol degradation and increasing triglycerol synthesis: Insulin increases the
transport and metabolism of glucose into adipocytes, providing glycerol 3-
phosphate for triglycerol synthesis. Insulin also increases lipoprotein lipase activity
of adipose tissue by increasing the enzyme synthesis, providing fatty acids for
esterification.
3-Effects on protein synthesis:
Insulin stimulates the entry of amino acids into cells and increases protein synthesis in
most tissues.
Biochemical reactions for the storage of triglycerides in adipose tissue: Lipids are
stored as triglycerides and transported around the body associated with proteins as
lipoproteins. Triglycerides may be formed by de novo synthesis from glucose which is
stimulated by (+) the action of insulin on the GLUT4 transporter and induction of the
dehydrogenase which converts glyceraldehyde-3-phosphate to glycerol-3-phosphate.
This is required for esterification of fatty acids. Most fat stores, however, are generated
from the triglycerides held in chylomicrons and VLDL complexes. Insulin stimulates
lipoprotein lipase which releases the fatty acids from these complexes and at the same
time inhibits (-) adipose tissue lipase which breaks down triglycerides.
 Glucagon
Glucagon is a polypeptide hormone secreted by the α-cells of the pancreatic islets of
Langerhans. Glucagon is composed of 29 amino acids arranged in a single polypeptide
chain. The amino acid sequence of glucagon is the same in all mammalian species.
Epinephrine, glucagon, cortisol, and growth hormone are anti-insulin (counter regulatory)
hormones.
(a) Regulation of Glucagon Secretion: Hypoglycemia (low blood glucose) is the primary
stimulus for glucagon secretion but under stress, trauma or severe exercise epinephrine
and norepinephrine are responsible for glucagon secretion. But amino acid is nonspecific
can stimulate the secretion of both insulin and glucagon.
(b) Inhibition of glucagon secretion: Glucagon secretion is markedly decreased by elevated
blood sugar and by insulin (carbohydrate-rich meal).
(c ) Metabolic Effects of Glucagon: (1) The most important action of glucagon is to maintain
blood glucose levels by stimulation of hepatic glycogenolysis and gluconeogenesis . (2)
Glucagon stimulates hepatic oxidation of fatty acids and formation of ketone bodies. The
lipolytic effect of glucagon in adipose tissue is minimal in humans (3) Glucagon increases
the uptake of amino acids by the liver for gluconeogenesis
(d) Mechanism of action of glucagon : Glucagon binds to high-affinity receptors on the cell
membrane of the hepatocyte → activation of adenylate cyclase in the plasma
membrane→ increase cAMP (second messenger). cAMP activates protein kinase and
increases the phosphorylation of specific enzymes or other proteins. The phosphorylation
activates or inhibits the key regulatory enzymes of carbohydrate and lipid metabolism.
The formation of ketone bodies
Insulin and glucagon regulation
Hypoglycemia : The brain with its absolute dependency on a continuous supply
of glucose is central to discussions on hypoglycemia and on how hypoglycemia
is defined. Glucose crosses the blood-brain barrier by facilitated diffusion via
endothelial GLUT 1 receptors and this is the major rate-limiting step. At normal
blood glucose concentrations, the rate of supply is approximately twice that of
neuronal glucose utilization. As the arterial plasma glucose concentration falls
below approximately 3.6 mmol/l, this transfer becomes rate limiting to
neuronal glucose metabolism.
Symptoms of hypoglycemia: (1) Autonomic: Hunger; Shakiness/tremor;
Palpitations; Sweatiness; Nervousness (2) Neuroglycopenic: Tiredness or
drowsiness; Blurred vision; Confusion; Difficulty speaking; Weakness; Seizures;
Coma; Death

Causes of hypoglycemia
(a) Fasting hypoglycemia: (1) Drugs - especially insulin, sulfonylureas, alcohol
(2) Hormone deficiencies - cortisol, somatotrophin, glucagon, epinephrine (3)
Liver failure (3) Critical illness - heart failure, renal failure, extreme starvation
(4) Endogenous hyperinsulinism - β-cell disorder – insulinoma
(b) Postprandial hypoglycemia: Congenital deficiency of enzyme of
carbohydrate metabolism e.g. galactosemia, fructose intolerance
Metabolism in the well –Fed state
 Enzymic changes in the fed state:
The flow of intermediates through metabolic pathways is controlled by
four mechanisms: (1) the availability of substrates (2) allosteric
activation and inhibition of enzymes (3) covalent modification of
enzymes and (4) induction repression of enzyme synthesis.

Allosteric effects
The allosteric changes usually affect the rate limiting reactions e.g.
glycolysis in the liver is stimulated following a meal by increase in
fructose 2, 6 – biphosphate, an allosteric activator of
phosphofructokinase I. Gluconeogenesis is inhibited by fructose 2,
6-biphosphate, an inhibitor of fructose 1, 6-biphosphate. Allosteric
effects work within minutes.
 Regulation of enzymes by covalent modification
Many enzymes are regulated by covalent modification, (phosphorylation
and de phosphorylation). In the fed state most of the enzymes
regulated by covalent modification are in dephosphorylated state
and active e.g. Pyruvate kinase, Pyruvate dehydrogenase complex,
glycogen synthase HMG – CoA reductase and acetyl –CoA
carboxylase. (Three exceptions) (active phosphorylated forms) are
glycogen phosphorylase, fructose bisphosphate phosphatase and
hormone-sensitive lipase of adipose tissue. Covalent modification
takes minutes to hours.

Induction and repression of enzyme synthesis

The key enzymes are usually regulated by hormones that affect their
synthesis e.g. insulin stimulates (induction) the synthesis of
glucokinase, phosphofructokinase I, pyruvate kinase, the key
enzyme of glycolysis, regulation of enzyme synthesis takes hours to
days
Metabolism in Fasting state
Fuel metabolism in the liver during prolonged fasting or in
uncontrolled diabetes mellitus
Plasma concentrations of fatty acids, glucose, and ketone
bodies during the first week of starvation.
 Epinephrine Signals Impending Activity
• Under stressful situation such as fighting or fleeing, neuronal signals from
the brain trigger the release of epinephrine and norepinephrine from the
adrenal medulla. Both hormones dilate the respiratory passages to facilitate
the uptake of O2, increase the rate and strength of the heartbeat, and raise
the blood pressure, thereby promoting the flow of O2 and fuels to the
tissues.
• Epinephrine activates glycogen phosphorylase and inactivates glycogen
synthase by cAMP-dependent phosphorylation of the enzymes, thus
stimulating the conversion of liver glycogen to blood glucose, the fuel for
anaerobic muscular work.
• Epinephrine also promotes the anaerobic breakdown of glycogen by lactic
acid fermentation, stimulating glycolytic ATP.
• Epinephrine also stimulates fat mobilization in adipose tissue, activating
hormonesensitive lipase.
• Finally, epinephrine stimulates glucagon secretion and inhibits insulin
secretion, reinforcing its effect of mobilizing fuels and inhibiting fuel
storage.
 Cortisol Signals Stress, Including Low Blood Glucose
• Stress signals stimulate release of the slow-acting corticosteroid hormone
cortisol from the adrenal cortex that alters metabolism by synthesizing
enzymes in spite of utilizing existing enzyme molecules in its target cells.
• In adipose tissue, cortisol leads to an increase in the release of fatty acids
from stored TAGs. The exported fatty acids serve as fuel for other tissues,
and the glycerol is used for gluconeogenesis in the liver.
• Cortisol stimulates the breakdown of muscle proteins and the export of
amino acids to the liver, where they serve as precursors for
gluconeogenesis.
• In the liver, cortisol promotes gluconeogenesis by stimulating synthesis of
the key enzyme PEP carboxykinase.
• The net effect of these metabolic changes is to restore blood glucose to its
normal level and to increase glycogen stores, ready to support the fight-or-
flight response commonly associated with stress.
• During extended periods of stress, the continued release of cortisol loses its
positive adaptive value and begins to cause damage to muscle and bone,
and to impair endocrine and immune function.
 Obesity and the Regulation
of Body Mass
• Obesity is the result of taking in more calories in the
diet than are expended by the body’s energy-
consuming activities.
• The body can deal with an excess of dietary calories in
three ways:
• (1) convert excess fuel to fat and store it in adipose
tissue,
• (2) burn excess fuel by extra exercise, and
• (3) “waste”fuel by diverting it to heat production
(thermogenesis)by uncoupled mitochondria.
 Adipose Tissue Has Important Endocrine Functions
• “adiposity negative-feedback” model,
postulated a mechanism that inhibits eating
behavior and increases energy consumption
whenever body weight exceeds a certain
value (the set point); the inhibition is relieved
when body weight drops below the set point.
• Later, it is found that adipose tissue is an
important endocrine organ that produces
peptide hormones, known as adipokines
(Leptin).
• Adipokines may act locally (autocrine and
paracrine action) or systemically (endocrine
action), carrying information about the
adequacy of the energy reserves (TAGs)
stored in adipose tissue to other tissues and
to the brain. Leptin deficient mice shows
obesity that can be prevented by early
injection of leptin.
 Defect in leptin receptor also contribute to obesity
• The leptin receptor is expressed primarily in regions of the brain
known to regulate feeding behavior—neurons of the arcuate nucleus
of the hypothalamus.
• Leptin-receptor interaction in the hypothalamus alters the release of
neuronal signals to the region of the brain that affects appetite.
• Leptin also stimulates the sympathetic nervous system, increasing
blood pressure, heart rate, and thermogenesis by uncoupling the
mitochondria of white adipocytes.
• Thermogenin, or UCP, forms a channel in the inner mitochondrial
membrane that allows protons to reenter the mitochondrial matrix
without passing through the ATP synthase complex.
• This permits continual oxidation of fuel (fatty acids in an adipocyte)
without ATP synthesis, dissipating energy as heat and consuming
dietary calories or stored fats in potentially very large amounts.
Hormones that control eating:Leptin Stimulates Production
of Anorexigenic Peptide Hormones
Leptin Triggers a Signaling Cascade That Regulates Gene
Expression
Cross-talk between receptors
for insulin and leptin
The role of AMP-activated protein kinase (AMPK) in
regulating ATP metabolism.
Formation of adiponectin and its actions through
AMPK.
 Diet Regulates the Expression of Genes Central to
Maintaining Body Mass
• Proteins in a family of ligand-activated transcription factors, the peroxisome
proliferator-activated receptors (PPARs), respond to changes in dietary lipid by
altering the expression of genes involved in fat and carbohydrate metabolism.
PPAR, expressed primarily in liver and adipose tissue, is involved in turning on
genes necessary to the differentiation of fibroblasts into adipocytes and genes that
encode proteins required for lipid synthesis and storage in adipocytes
Metabolic integration by PPARs
Variations in ghrelin and insulin relative to meal times