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Bioc 460 - Dr. Miesfeld Spring 2008
Metabolic Integration 1
Body shape is important
Key Concepts
- Metabolic profiles of major organs
- Metabolic homeostasis and signaling
- Metabolic adaptations to starvation
KEY QUESTION IN METABOLIC INTEGRATION:
How do the pancreas, liver, skeletal muscle, and adipose tissues
control serum glucose levels?
Metabolic profiles of major organs
We have focused primarily on cellular biochemistry up to this point, now we turn our attention to
physiological biochemistry which
involves metabolic integration
Figure 1.
throughout the organism. We will use
humans as our organism of choice for
this discussion, but of course metabolic
integration is critical for all multi-cellular
organisms, and even for single cell
organisms such as yeast and bacteria
which colonize environmental niches
and depend on cell-cell communication.
The metabolic map in figure 1 has been
streamlined to better illustrate how the
three major sources of metabolic fuel
in our diets; carbohydrates, lipids (fats)
and protein, contribute directly to ATP
production. This version of the
metabolic map emphasizes five energy
conversion processes that we have
discussed in some detail; 1)
carbohydrate metabolism (glycolysis
and gluconeogenesis), 2) lipid
metabolism (fatty acid oxidation and
synthesis), 3) amino acid metabolism
(oxidation and synthesis), 4) the citrate
cycle, and 5) oxidative phosphorylation.
Note that liver cells can perform all of
the synthesis and degradation reactions
shown in figure 1, however, most other
cell types are primarily limited to
catabolizing glucose and fatty acids to
generate ATP through mitochondrial oxidative phosphorylation reactions.
The term energy balance relates energy input in the whole organism to energy
expenditure. Positive and negative energy balance is determined by the energy content of the
metabolic fuels ingested, compared to the amount of energy expended through endergonic
chemical reactions, physical exertion, and thermogenic processes. In the simplest case, energy
balance is achieved when energy input measured in kilocalories, also referred to as "food" Calories
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(1 Calorie = 1 kilocalorie = 4.184 kilojoules), equals energy expenditure on a daily basis. Note that
the relative proportions of carbohydrate, fat, and protein in our diets needs to be optimized to
prevent metabolic disorders that can occur even under conditions of Caloric energy balance. For
example, obtaining too many daily Calories from saturated fats can lead to cardiovascular disease,
whereas, excessive amounts of protein can cause nitrogen toxicity due to NH4+ overload.
The utilization of various metabolic fuels by different organs in the human body is controlled at the
cellular level as a function of nutrient availability. Some of these biochemical processes are
developmentally determined (cell-specific expression of required enzymes), while others are
controlled more acutely by hormonal signaling through receptor proteins. Two of these hormones
are insulin and glucagon which we have discussed numerous times throughout the course.
Another important signaling pathway we introduce here is one that controls inter-organ metabolic
flux through a subfamily of nuclear receptors known as the peroxisome proliferator-activated
receptors (PPARs). The PPARs are a family of transcription factors (PPARγ, PPARα, PPARδ)
that regulate gene expression in response to activation by fatty acid-derived ligands. PPARs are
targets for a new class of pharmaceutical drugs used to treat metabolic disorders, including type 2
diabetes.
Figure 2 shows the location and function of the primary tissues and organs in the human
body that play a direct role in metabolic flux. In addition to the liver, muscle (skeletal and heart),
Figure 2.
adipose, brain and kidney which are described below, several other organs play an important
supporting role in metabolic integration. One of these is the pancreas which secretes insulin and
glucagon in response to changes in serum glucose levels and also produces a variety of proteases
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that degrade dietary proteins in the small intestine (trypsin, chymotrypsin, elastase). Also shown in
figure 2 is the small intestine which is an critical component of the gastrointestinal tract because it
serves as the major site of dietary nutrient absorption. The large intestine or colon, absorbs water
and electrolytes and also secretes a neuropeptide called PYY3-36 that controls eating behavior.
The stomach prepares food for the small intestine by initiating the digestive process through
protein hydrolysis at a low pH in the presence of the protease pepsin. Moreover, the stomach
secretes a neuropeptide called ghrelin that sends hunger signals to the brain. Let's look a little
more closely at the key metabolic organs in humans.
LIVER
The liver serves as the central processing facility and metabolic hub of the body by determining
what dietary nutrients and metabolic fuels are distributed to the peripheral (non-liver) tissues. The
liver also functions as a physiological glucose regulator that helps remove excess glucose from
blood when carbohydrate levels are high, and releases glucose from stored glycogen, or as a
product of gluconeogenesis, when serum glucose levels are low. Serum glucose regulation by the
liver is controlled primarily through the
Figure 3.
insulin and glucagon signaling
pathways which modulate metabolic
flux through glycolysis,
gluconeogenesis, and glycogen
metabolism. With the exception of
dietary triacylglycerols that are
transported from the small intestine to
peripheral tissues by chylomicrons
that enter the lymphatic system, most
nutrients absorbed in the small
intestine are delivered directly to the
liver via the portal vein. This
anatomy explains why the liver plays
such a key role in coordinating the
distribution of dietary nutrients as it is
the first organ to inventory the
contents of your last meal. A large
proportion of the dietary
monosaccharides delivered by the
portal vein are retained by the liver in
the form of glucose-6-phosphate
following phosphorylation of glucose
by the enzymes hexokinase or
glucokinase. As shown in figure 3,
glucose-6-phosphate has several
fates depending on the metabolic needs of the liver and the peripheral tissues. Most of the
glucose-6-phosphate is used to synthesize liver glycogen following its isomerization to glucose-1phosphate by the enzyme phosphoglucomutase. Glucose-6-phospate can also be
dephosphorylated in the liver by glucose-6-phosphatase and released into the blood to be used by
other tissues, in particular the brain. If liver cells are in need of NADPH for biosynthetic reactions,
then glucose-6-phosphate is converted to 6-phosphoglucolactone by glucose-6P dehydrogenase
in the first reaction of the pentose phosphate pathway. Lastly, glucose-6-phosphate can be
converted to fructose-6-phosphate by phosphoglucose isomerase and then metabolized by the
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glycolytic pathway and the pyruvate dehydrogenase reaction to yield acetyl-CoA for use in lipid
biosynthesis, oxidative phosphorylation or ketogenesis.
MUSCLE
The human body contains two types of muscle tissue that play a major role in metabolic
integration, 1) skeletal muscle which utilizes different amounts of free fatty acids, glucose or
ketone bodies for metabolic fuel depending on the physical movements required (rapid burst of
activity or endurance activity), and 2) cardiac muscle which uses mostly fatty acids and ketone
bodies as metabolic fuel to sustain a steady heart beat which averages over 100,000 beats per
day. During the resting state, skeletal muscle primarily uses fatty acids released from adipose
tissue as a source of energy. The fatty acids are oxidized to generate acetyl-CoA which is then
used by the citrate cycle to produce reducing power (NADH and FADH2) for oxidative
phosphorylation. However, when muscle contraction is required for a very short burst of activity,
for example serving a tennis ball to your opponent
(2-3 seconds), the exercising muscles make use
Figure 4.
of the intracellular ATP pool. If a more sustained
level of muscle activity is needed, such as a short
sprint across the tennis court to return a serve (38 seconds), then the ATP pool is replenished with
ATP made by a phosphoryl transfer reaction using
phosphocreatine (figure 4). The creatine
kinase reaction is readily reversible and catalyzes
the resynthesis of phosphocreatine when cellular
ATP levels return to normal during muscle
recovery.
Most of the stored glycogen in humans exists in muscle tissue that is spread throughout the
body. However, unlike the liver that contains 10% glycogen by weight, individual muscle groups
contain only ~1% glycogen by weight. Therefore, glycogen stores in any one muscle group
become depleted when muscle contraction continues beyond about an hour. As glucose levels
decline, the muscle tissue becomes more dependent on fatty acids released from adipose tissue,
and on ketone bodies produced in the liver, to maintain the high rates of ATP synthesis needed for
contraction. Muscle cells lack fatty acid synthase and glucose-6-phosphatase which means that
they can neither synthesize fatty acids for export to other tissues nor release glucose from
glycogen degradation. In this regard, muscle is truly a selfish tissue, using energy made available
from other parts of the body for its own purpose of mechanical movement. Note however, that
during long term starvation, skeletal muscle can be used as an energy source for the body by
providing amino acid substrates for liver and kidney gluconeogenesis as described later.
ADIPOSE TISSUE
Adipose tissue was once thought of as a simple fat depot in the body that stores and releases fatty
acids from adipocytes (fat cells) in response to metabolic needs. However, it is now known to be
an active player in metabolic integration serving as an endocrine organ that secretes peptide
hormones called adipokines (adipocyte hormones). As described later, adipokines are key
regulators of metabolism and control important immunological, neurological and developmental
functions in the body. Adipose tissue is widely distributed throughout the body, making up ~1525% of the mass of an individual and accounts for over 500,000 kJ of stored energy. Although
adipocytes are present in many parts of the body, for example, near skeletal muscle, surrounding
blood vessels, and in the mammary gland, there are two locations in the body where the majority
of adipose tissue can be found. One is subcutaneous fat that is located just below the skin
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surface, most noticeable in the thighs, buttocks, arms and face. The other is visceral fat which
lies deep within the abdominal cavity and is responsible for the size of your waistline.
The biochemical and endocrine functions of visceral fat and subcutaneous fat are distinct,
which explains why the physiological consequences of extra body fat is not the same for everyone.
One way to predict if someone has too much body fat is to determine their body mass index (BMI)
using a ratio of their weight and height. BMI values are derived by dividing the weight in kilograms
of a person by the square of their height in meters:
Body Mass Index (BMI) = weight (kg)/[height (m)]2
It is generally accepted that a BMI value of less than 18.5 is considered underweight, 18.525 is within the normal weight range, 25-30 is overweight, and greater than 30 is obese.
Importantly, a BMI value is only an approximation of stored fat since it cannot distinguish between
body weight due to excess fat stores or a large muscle mass (figure 5). Moreover, BMI values do
not provide information about the relative amounts of visceral fat and subcutaneous fat stores.
Despite these shortcomings, epidemiological studies have shown that on average, people with a
BMI value of >30 have a higher risk of developing type 2 diabetes, heart disease, and cancer as a
result of metabolic conditions
Figure 5.
associated with obesity. Because
adipokines produced in visceral fat
contribute to the development of
obesity-related diseases, one of the
best ways to predict an individual's
disease risk is to use both their BMI
value and a quantitative measurement
of body fat distribution as determined
by the circumference of a their waist
in relationship to the size of their hips.
By determining a person's waist to hip
ratio (WHR), it is possible to obtain an
approximate measurement of the
relative amounts of visceral and
subcutaneous fat stored on their
body. A high WHR value corresponds
to an "apple-shaped" body (more
visceral fat in the waist than
subcutaneous fat on the hips),
whereas, a low WHR value leads to a "pear-shaped" body. An explanation for why disease risks
are elevated in overweight people with a high WHR is that increased amounts of visceral fat alters
the expression of certain adipocyte hormones such as leptin, tumor necrosis factor α (TNF-α),
and adiponectin. High levels of visceral fat lead to increased expression of the leptin and TNF-α
genes, with reduced expression of adiponectin. We will look more closely at the biochemical
processes underlying the connection between adipose metabolism, adipokines and human
metabolic disease later in the chapter.
Adipose tissue is responsible for regulating the triacylglycerol cycle which is an interorgan process that continuously circulates fatty acids and triacylglycerols between adipose tissue
and liver. As illustrated in figure 6, there are two parts to the triacylglycerol cycle, 1) the systemic
component that recycles fatty acids released from adipose tissue by hormone-sensitive lipase and
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triacylglycerols synthesized in liver cells, and 2)
the intracellular component that recycles fatty
acids that enter adipocytes following
triacylglycerol hydrolysis by lipoprotein lipase
and triacylglycerols synthesized inside
adipocytes. Under normal conditions, ~75% the
free fatty acids released by hormone-sensitive
lipase in adipocytes is returned to lipid droplets
as triacylglycerols through either the systemic or
intracellular routes. The metabolic relevance of
the triacylglycerol cycle is not completely
understood but it may provide a mechanism to
maintain a pool of free fatty acids that can be
readily used for metabolic fuel in peripheral
tissues such as skeletal muscle.
Figure 6.
BRAIN
The brain is the control center of our bodies, consisting of 100 billion nerve cells (neurons) that
transmit electrical information along the neuronal axon using action potentials that are driven by
changes in charge distribution across the plasma membrane. The key to these electrical impulses
are ions that cross the membrane through channels that are controlled by neurotransmitter
substances such as acetylcholine that function as signaling molecules between adjacent neurons.
The steady-state electrical charge across the membrane is maintained by ATP-dependent ion
pumps, most importantly the Na+K+ ATPase ion transport protein. Based on studies using oaubain
to inhibit the Na+K+ ATPase transporter, up to half of all the ATP generated in the brain goes
toward keeping this critical ion pump fully active. Studies have shown that about 20% of the
oxygen consumed by the body is used for oxidative phosphorylation in the brain. Moreover, the
brain requires as much as 120 grams of glucose each day which accounts for 60% of the glucose
used by our bodies under normal conditions. The brain's dependence on glucose is illustrated by
the dizzy feeling you experience when your serum glucose levels fall from normal levels of ~4.5mM
(~80 mg/dl) to ~3.5mM (~60 mg/dl) as a result of glycogen depletion brought on by prolonged
intense exercise. The brain, unlike most other organs, is exclusively dependent on glucose under
normal conditions to provide the necessary chemical energy for ATP production. Fatty acids
cannot cross the blood-brain barrier because they are bound to carrier proteins, however, the
energy-rich ketone bodies acetoacetate and D-β-hydroxybutyrate are able to enter the brain.
Since the brain has no energy stores of its own, the demand for glucose to maintain brain function
must be met by the liver which devotes much of its ATP to generating glucose for the brain via the
gluconeogenic pathway. During prolonged starvation when glucose levels are abnormally low, the
brain adapts to using ketone bodies to supply the acetyl-CoA needed for ATP synthesis by
oxidative phosphorylation.
CIRCULATORY SYSTEM
Metabolic integration within the human body depends on the redistribution of metabolites, ions and
hormones between the various tissues. This is the job of the circulatory system which consists
of 150,000 kilometers of blood vessels that deliver six liters of blood to cells through a complex
network of microcapillaries. The circulatory system links together the major tissues and organs of
the body in such a way that biochemical pathways in different cells share metabolites to ensure
that the metabolic efficiency of the whole organism is greater than the sum of the parts. Figure 7
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summarizes the primary metabolic pathways in six major tissues and organs of the human body
under normal homeostatic conditions. It can be seen that the liver is the control center of this
metabolic network and plays a crucial role in regulating metabolite flux between tissues and
organs. One of the primary roles of the liver is to export glucose and triacylglycerols to the
peripheral tissues for use as metabolic fuel. The brain has arguably the most important job of all in
Figure 7.
terms of defining life, but metabolically speaking, it is an energy drain on the system that requires a
constant input of glucose, one of the body's most precious metabolites. Cardiac muscle makes
use of fatty acids and ketone bodies for most of its energy needs, but also uses glucose at a low
level. The exchange of fatty acids and triacylglycerols between the liver and adipocyte tissue
constitutes the triacylglycerol cycle. Skeletal muscle uses glucose and fatty acids derived from the
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liver and dietary sources for ATP synthesis, whereas, it exports lactate back to the liver to
complete the Cori Cycle during times of prolonged physical exertion. Importantly, the amino acids
glutamine and alanine transport excess nitrogen obtained from protein degradation in the muscle
to the liver and kidney for excretion as nitrogen waste in the form of urea. It is easy to see that
abnormal function in one tissue or organ will have metabolic consequences in other parts of the
body. Indeed, it is the primary task of physicians with training in internal medicine to unravel the
biochemical and physiological bases for altered metabolic interactions in their patients.
Metabolic homeostasis and signaling
In order to cope with constant changes in the environment, our bodies must be able to maintain a
metabolic state that optimizes available energy stores. For example, the brain requires a constant
supply of glucose to ensure high fidelity neuronal transmissions, and skeletal muscle must have
enough glycogen on hand to permit rapid muscle contraction in response to imminent danger or a
chance to obtain food. Similarly, adipose tissue must be able to control the release and storage of
triacylglycerols obtained from the diet, or generated from carbohydrates in the liver, to effectively
manage this high energy metabolic fuel. Metabolic homeostasis describes steady-state
conditions in the body and can apply to a wide variety of physiological parameters. These include
glucose, lipid, and amino acid levels in the blood, electrolyte concentrations, blood pressure and
pulse rate. During times of physical activity, psychological stress, or feeding, biochemical
processes are altered to counteract the effects of these environmental stimuli in an attempt to
return the body to metabolic homeostasis. Regulation of metabolic homeostasis requires both
neuronal signaling from the brain and the release of small molecules into the blood that function as
ligands for receptor-mediated cell signaling pathways.
Two of the most important global metabolic regulators in humans are the peptide hormones
insulin and glucagon, both of which are secreted by the pancreas. Insulin and glucagon are the
"yin and yang" of glucose homeostasis in that they have complementary, but opposing, functions in
controlling serum glucose levels. Insulin and glucagon are synthesized as prohormones in a region
of the pancreas called the islets of Langerhans which was
Figure 8.
named after the German medical student Paul Langerhans
who first described these hormone-secreting cells in 1869.
There are three cell types in the islets of Langerhans that
produce peptide hormones (figure 8). The β cells, which
make up the majority of cells in this region of the pancreas,
are responsible for insulin secretion, whereas, the α cells
secrete glucagon. A third cell type, the δ cells, produce
somatostatin which is paracrine hormone that functions
locally to control the secretion of insulin, glucagon, and
digestive proteases. In addition to hormone secretion by
cells in the islet of Langerhans, the pancreatic acinar cells
in the pancreas secrete digestive proteases into the
pancreatic duct which connects to gastrointestinal track.
As shown in figure 9, insulin signaling stimulates
glucose uptake in liver, skeletal muscle and adipose tissue,
as well as, activating fatty acid uptake and triacylglycerol
storage in adipose tissue. Glucose uptake in liver cells is primarily due to increased metabolic flux
through glycolytic, glycogen synthesis and triacylglycerol synthesis pathways. Besides activating
glycolysis and glycogen synthesis in skeletal muscle cells, insulin also stimulates translocation of
the GLUT4 glucose transporter protein to the plasma membrane. In adipose tissue, insulin
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signaling leads to GLUT4 translocation and increase rates of fatty acid uptake and triacylglycerol
storage. As described later in
Figure 9.
the chapter, insulin stimulates
neuronal signaling in the
hypothalamus region of the brain
that controls eating behavior and
energy expenditure. Glucagon
signaling in liver tissue
stimulates glucose export as a
result of increased rates of
gluconeogenesis and glycogen
degradation, whereas in adipose
tissue, glucagon activates
triacylglycerol hydrolysis and
fatty acid export. Note that
skeletal muscle and brain cells
lack appreciable levels of
glucagon receptors and are
considered to be glucagoninsensitive.
First discovered in the
early 1990s, the PPARα, PPARγ
and PPARδ nuclear receptor
proteins are now known to be key players in controlling metabolic homeostasis in humans.
However, unlike the insulin and glucagon receptors that rapidly activate intracellular
phosphorylation signaling
Figure 10.
cascades in response to
high affinity endocrine
hormones, the PPARs
function as transcription
factors that regulate gene
expression in response to
the binding of low affinity
fatty-acid derived nutrients
such as polyunsaturated
fatty acids and
eicosanoids (figure 10).
This property of PPARs
makes them ideal
metabolic sensors of lipid
homeostasis and results
in long term control of
pathway flux by directly
altering the steady-state
levels of key proteins.
The name "peroxisome
proliferator-activated
receptor" was originally
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coined to describe PPARα which was discovered in
Figure 11.
rat hepatocytes as the mediator of peroxisome
biogenesis in response to the drug clofibrate.
Clofibrate-related drugs (fibrates) have been used
to treat high serum cholesterol in humans, and
even though they do not cause peroxisome
proliferation in human hepatocytes, the name has
stuck and been applied to the other two members
of this family, PPARγ and PPARδ.
PPARs have a variety of functions in lipid
metabolism, ranging from regulation of lipid
transport and mobilization, to fatty acid oxidation
and lipid synthesis. They also play an important
role in energy metabolism and insulin-sensitivity.
One of the most important functions of PPARγ is to
control adipocyte differentiation and lipid synthesis
in adipose tissue, but it also regulates insulinsensitivity in all three tissues, as well as, lipid
Figure 12.
synthesis in liver cells. PPARγ is the therapeutic
target of thiazolidinediones (TZDs) which improve
insulin-sensitivity in type 2 diabetics by activating
PPARγ target genes involved in lipid synthesis. The
PPARs represent an attractive class of protein
targets for the development of pharmaceutical drugs
for treating human metabolic disease. Not only are
they responsible for controlling lipid homeostasis in
liver and adipose tissue, but they also regulate
glucose metabolism and thermogenesis in skeletal
muscle. Indeed, both fibrates and TZDs were used
to treat cardiovascular disease and diabetes,
respectively, well before they were known to be
PPAR ligands. However, a problem with some of the
PPAR agonists is that they can bind to more than one
PPAR family member which can lead to undesirable
side effects. Figure 11 shows the chemical
Figure 13.
structure of three PPAR-selective agonists that
have been developed to address this problem.
Gemfibrozil is a PPARα-selective fibrate currently
in use to treat high cholesterol in patients, and
rosiglitazone is a TZD compound that binds with
high affinity to PPARγ and is used to treat type 2
diabetes. The PPARδ-selective agonist GW501516
has been evaluated in human clinical trials for the
treatment of atherosclerosis and obesity by altering
flux through lipid metabolic pathways. One of the
biggest challenges in developing selective PPAR
ligands is that the hydrophobic pocket in the Cterminal ligand binding domain is unusually large
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for a nuclear receptor. For example as shown in figure 12, the ligand binding domain of human
PPARδ can accommodate the ω-3 polyunsaturated fatty acid eicosapentaenoate (all cis 20:5
Δ5,8,11,14,17) in either the tail-up or tail-down orientation, indicating that the hydrophobic pocket is
shaped like the letter "Y." This prediction was confirmed by the PPARδ protein structure shown in
figure 13 where it can be seen that the synthetic PPARd/PPARa agonist GW2433 is able to
completely fill the binding ligand-binding pocket.
Metabolic adaptations to starvation
Figure 14.
Metabolic adaptation to food shortages has been
preserved over evolutionary time to ensure survival
during famine. The human body adapts to these
near starvation conditions by altering the flux of
metabolites between various tissues in order to
extend life as long as possible. The primary
metabolic challenge is to provide enough glucose
for the brain to maintain normal neuronal cell
functions. Although fatty acids released from
adipose tissue are plentiful in the blood, the brain
cannot use fatty acids for metabolic fuel because
they cannot cross the blood-brain barrier. Red
blood cells (erythrocytes) are also dependent on
serum glucose as a sole source of energy to
generate ATP. Mature erythrocytes lack
mitochondria, and therefore, are not able to utilize
fatty acids for energy because fatty acid oxidation
takes place in the mitochondrial matrix.
The glucose required at the onset of
starvation (24 hour fast) is initially supplied by the
degradation of liver glycogen in response to
glucagon signaling, however, this form of metabolic
fuel is quickly depleted resulting in a drop in serum
glucose levels (figure 14). In order to make up for
this loss of liver glycogen as an energy source, the body's metabolism changes in two important
ways. First, flux through the gluconeogenic pathway in the liver and kidneys is increased to
generate glucose for the brain and erythrocytes. The major substrates for gluconeogenesis
under these conditions are glycerol, alanine, glutamate, and lactate. The glycerol comes from
triacylglycerol hydrolysis in adipose tissue, whereas, alanine and lactate are produced by
transamination reactions
Figure 15.
and anaerobic respiration,
respectively, in muscle
cells. Glutamate, which is
the preferred
gluconeogenic precursor
in kidney cells, is an
abundant metabolite in
the blood that is
deaminated to generate
α-ketoglutarate, a citrate
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cycle intermediate that gives rise to the gluconeogenic intermediate oxaloacetate. The second
way our bodies cope with the depletion of liver glycogen is to switch most of the energy needs to
using fatty acids as the primary metabolic fuel. This spares whatever glucose is available for
the brain and erythrocytes. The fatty acids used as metabolic fuel during starvation are derived
from triacylglycerol hydrolysis in the adipose tissue following glucagon stimulation of protein kinase
A-mediated signaling.
As shown above in figure 15, an average size man of 70 kg contains enough metabolic fuel
to live ~98 days without food assuming a minimum energy expenditure of 1700 Calories per day
(166,000/1700 = 97.6). By far, the bulk of stored metabolic fuel is in the form of triacylglycerols in
adipose tissue which is sufficient to prolong life for 3 months. Protein is the second most abundant
stored fuel (14 days worth of energy), but as described earlier, metabolic adaptations to starvation
Figure 16.
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ensure that this form of energy is spared for as long as possible. Interestingly, an obese individual
with three times as much body fat as a normal person could theoretically survive starvation for up
to eight months (249 days). However, as discussed in the next section, chronic obesity, a disease
state that has reached epidemic proportions in the United States, actually shortens life span due to
an increase incidence of type 2 diabetes and cardiovascular disease.
Metabolite flux between major tissues and organs in the human body under starvation
conditions is illustrated in figure 16. Once glycogen stores are depleted (first 24 hours), adipose
tissue and skeletal muscle are the primary sources of metabolic fuel during starvation. Fatty acids
released from triacylglycerol hydrolysis in adipose tissue are transported to skeletal muscle and
the heart by serum albumin protein and used to generate acetyl-CoA for the citrate cycle and
oxidative phosphorylation. Acetyl-CoA produced from fatty acids transported to the liver is used
the production of ketone bodies that are an important energy source for the heart and brain during
starvation. Amino acids derived from protein degradation in skeletal muscle provides the
necessary carbon from gluconeogenic amino acids and lactate to produce glucose in liver cells by
gluconeogenesis. Amino acids are also used by kidney cells for gluconeogenesis. Glucose
produced by gluconeogenesis is used by the brain and erythrocytes for aerobic and anaerobic
respiration, respectively.
The four major alterations in metabolic flux that permit humans to survive long periods of
time without food can be summarized as follows:
1)
Increased triacylglycerol hydrolysis in adipose tissue. Following depletion of liver
glycogen within the first 12-24 hours of starvation, triacylglycerol hydrolysis is stimulated in
adipose tissue resulting in fatty acid and glycerol release into the blood. Moreover, glucose
uptake by skeletal muscle is inhibited due to the low levels of insulin in the blood. This has
the effect of shifting energy away from glucose utilization and toward fatty acid oxidation for
most tissues.
2)
Increased gluconeogenesis in liver and kidney cells. In order to keep serum glucose
levels above ~3.5 mM, which is needed for brain and erythrocyte functions, flux through the
gluconeogenic pathway is increased in liver and kidney cells. The major substrates for
glucose biosynthesis in the liver are glycerol, alanine and lactate, which are all converted to
pyruvate. Kidney cells primarily use glutamate from the blood to generate oxaloacetate.
3)
Increased ketogenesis in liver cells. As a result of high rates of fatty acid oxidation, and
decreased amounts of oxaloacetate which is redirected toward gluconeogenesis, acetylCoA levels in the liver increase dramatically. This leads to high levels of ketogenesis which
produces acetoacetate and D-β-hydroxybutyrate for export to other tissues. Under these
conditions, the brain and heart can use significant amounts of ketone bodies as a source of
acetyl-CoA for aerobic respiration. In contrast, erythrocytes are totally dependent on
glucose for glycolysis because they lack mitochondria which are required to oxidize acetylCoA by the citrate cycle.
4)
Protein degradation in skeletal muscle tissue. Muscle protein provides amino acids that
serve as gluconeogenic substrates in the liver and kidneys. While this is a good source of
energy reserves from a storage point of view, catabolism of skeletal muscle is delayed as
long as possible to maintain mobility and enable the ongoing search for food. Once protein
stores fall below 50% of pre-starvation levels, life can no longer be sustained.
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ANSWER TO KEY QUESTION IN METABOLIC INTEGRATION
The pancreas, liver, skeletal muscle, and adipose tissue each play distinctive roles in
maintaining serum glucose levels in our bodies at ~4.5mM. The pancreas is an endocrine
organ that produces insulin and glucagon, the two major peptide hormones involved in serum
glucose regulation. Insulin and glucagon are synthesized in a region of the pancreas called the
islet of Langerhans, with the β cells secreting insulin and the α cells secreting glucagon. Insulin
signaling stimulates glucose uptake primarily into liver, skeletal muscle, and adipose tissue in
response to elevated serum glucose levels. In liver cells, the glucose is used for glycogen
synthesis, or it is converted to acetyl-CoA which is a substrate for fatty acid synthesis. In contrast,
glucagon secretion from the pancreas promotes glucose efflux from liver cells by activating
glycogen degradation and gluconeogenesis. The major role of skeletal muscle in regulating serum
glucose levels is to remove excess glucose from the blood in response to insulin signaling.
Skeletal muscle tissue constitutes a large fraction of body mass and it is where the majority of
glycogen in our bodies is stored. Since muscle cells lack the enzymes glucose-6-phosphatase and
fatty acid synthase, once glucose enters the muscle cell, it cannot be exported to other tissues as
an energy source. Lastly, adipose tissue uses glucose to synthesis glycerol for triacylglycerol
production, but it also affects glucose homeostasis indirectly by being the storage depot for fatty
acids that are synthesized in the liver from excess carbohydrates obtained in the diet.
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