Transcript Lecture 33 - University of Arizona

Metabolic Integration 1:
Metabolic profiles of major organs, signaling
and homeostasis, adaptations to starvation
Bioc 460 Spring 2008 - Lecture 40 (Miesfeld)
Visceral fat (apple shape) is
associated with a higher risk of
cardiovascular disease than
subcutaneous fat (pear shape)
Insulin hormone is a key
regulator of glucose
homeostasis and is produced
by pancreatic  cells
Eicosapentaenoic
acid (EPA) is an
omega-3 fatty acid
that stimulates
PPAR activity
Key Concepts in Metabolic Integration
•
Metabolic homeostasis is a physiological state in which metabolite levels are
maintained by regulatory systems acting on multiple tissues in the organism.
The hormones insulin and glucagon maintain glucose homeostasis in blood.
•
The liver is the central processing facility and metabolic hub in the human body.
Its main functions are to manage nutrient levels that enter the liver through the
portal vein, and to detoxify harmful substances in the circulatory system.
Glucose-6P is a key metabolite in the liver that has many different fates.
•
Adipose tissue is not only a energy storage depot, but it is also an endocrine
organ that plays a major role in controlling fatty acid homeostasis. The recently
discovered PPAR regulatory proteins control many aspects of lipid metabolism.
•
The two major metabolic adaptations to starvation are an increase in
gluconeogenesis to supply glucose to the brain and red blood cells, and a switch
to dependency on fatty acids as the major energy source for most tissues.
Metabolic Profiles
of Major Organs
The three major sources of
metabolic fuel in our diets
are carbohydrates, lipids
(fats) and protein which
contribute directly to ATP
production. The five major
energy conversion processes
responsible for fuel utilization
are:
1) carbohydrate metabolism
2) lipid metabolism
3) amino acid metabolism
4) the citrate cycle
5) oxidative phosphorylation.
Metabolic Profiles of Major Organs
Metabolic functions
of the liver
Glucose-6P has several
fates depending on the
metabolic needs of the
liver and other tissues.
Most of the glucose-6P is
used to either synthesize
liver glycogen, or it is
dephosphorylated and
released into the blood
to be used by other
tissues.
Two other fates of
glucose-6P are the
pentose phosphate
pathway for NADPH
generation, and
conversion to precursors
for lipid synthesis.
What biochemical
mechanisms
determine G6P
flux through
these pathways?
Metabolic functions of skeletal muscle
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, the exercising muscles make use of the
intracellular ATP pool.
Metabolic functions of skeletal muscle
If a more sustained level of muscle activity is needed, such as a short
sprint across the tennis court to return a serve (3-8 seconds), then the
ATP pool is replenished with ATP made by a phosphoryl transfer
reaction using phosphocreatine. The creatine kinase reaction is
readily reversible and catalyzes the resynthesis of phosphocreatine
when cellular ATP levels return to normal during muscle recovery.
Metabolic functions of 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. 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). Adipokines are key regulators of
metabolism and control important immunological, neurological and
developmental functions in the body.
There are two major types of fat.
One is subcutaneous fat that is
located just below the skin 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.
Metabolic functions of adipose tissue
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.
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,
18.5-25 is within the normal
weight range, 25-30 is
overweight, and greater than
30 is obese.
Find your approximate BMI on
this chart using your height
and weight (no math required).
Metabolic functions of adipose tissue
BMI values do not provide information about the relative amounts of
visceral fat and subcutaneous fat stores. Because adipokines
produced in visceral fat contribute to the development of obesityrelated diseases, one of the best ways to predict an individual's
disease risk is to use both their BMI value and 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 CVD risks in 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  (TNF-), and adiponectin.
Body Mass Index (BMI) = weight (kg)/[height (m)]2
Metabolic functions of adipose tissue
Adipose tissue is responsible for regulating the triacylglycerol cycle which is
an inter-organ process that continuously circulates fatty acids and
triacylglycerols between adipose tissue and liver. There are two parts to the
triacylglycerol cycle, 1) the systemic component that recycles fatty acids
released from adipose tissue, and 2) the intracellular component that recycles
fatty acids that enter adipocytes following triacylglycerol hydrolysis.
What might be the
metabolic logic of
maintaining
circulating fatty
acids even though
75% of it is returned
to the adipose
tissue and stored?
Metabolic functions of the 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.
Left brain is the time to go to work center,
the right brain is the time to party center.
Blood glucose is distributed to
neurons through microcapillaries.
Metabolic functions of the brain
About 20% of the oxygen consumed by the body is used for oxidative
phosphorylation in the brain. 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, unlike most other organs, is
exclusively dependent on glucose
under normal conditions to provide
chemical energy for ATP production.
Fatty acids cannot cross the bloodbrain barrier because they are bound
to carrier proteins, however, the
energy-rich ketone bodies
acetoacetate and D--hydroxybutyrate
are able to enter the brain.
High rates of glucose metabolism is
indicative of neuronal activity
A liver-centric
view of human
metabolism
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.
What are the
two metabolic
fuels exported
by the liver?
Metabolic homeostasis and signaling
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.
Insulin and Glucagon Signaling
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 synthesized as
prohormones in a region of the pancreas called the islets of
Langerhans.
The  cells, which make up the
majority of cells in this region of
the pancreas, are responsible for
insulin secretion, whereas, the 
cells secrete glucagon. A third
cell type, the  cells, produce
somatostatin which is paracrine
hormone that functions locally to
control the secretion of insulin,
glucagon, and digestive proteases.
Insulin and Glucagon Signaling
???
Glucagon circulates
through the body,why
“no effect” in muscle
and brain tissue?
???
Peroxisome-proliferator activated receptors (PPAR) are
recently discovered metabolic regulators
First discovered in the early 1990s, the PPAR, PPAR and PPAR
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 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.
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.
PPARs are lipid-activated transcription factors
PPARs are pharmaceutical targets for diabetes
One of the most important functions of PPAR is to control adipocyte
differentiation and lipid synthesis in adipose tissue, but it also
regulates insulin-sensitivity in all three tissues, as well as, lipid
synthesis in liver cells.
PPAR is the therapeutic target of thiazolidinediones (TZDs) which
improve insulin-sensitivity in type 2 diabetics by activating PPAR
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 because they control lipid homeostasis in liver and
adipose tissue, as well as, regulate glucose metabolism and
thermogenesis in skeletal muscle.
Diabetics who are treated with TZDs see a drop in blood glucose levels
which is good, but they also gain weight. What explains this side effect?
PPARs are pharmaceutical targets for diabetes
Gemfibrozil is a PPARselective fibrate currently in
use to treat high
cholesterol in patients, and
rosiglitazone is a TZD
compound that binds with
high affinity to PPAR and
is used to treat type 2
diabetes. The PPARselective agonist
GW501516 has been
evaluated in human clinical
trials for the treatment of
atherosclerosis and obesity
by altering flux through lipid
metabolic pathways.
PPARs are pharmaceutical targets for diabetes
The ligand binding
domain of human
PPAR can
accommodate the 3 polyunsaturated
fatty acid
eicosapentaenoate
(all cis 20:5
5,8,11,14,17) in either
the tail-up or taildown orientation,
indicating that the
hydrophobic pocket
is shaped like the
letter "Y."
PPARs are pharmaceutical targets for diabetes
The size of the ligand pocked in PPARs was confirmed by the PPAR
protein structure shown below where it can be seen that the synthetic
PPAR/PPAR agonist GW2433 is able to completely fill the binding
ligand-binding pocket.
Metabolic Adaptations to Starvation
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.
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 are not able to utilize fatty acids for energy
because fatty acid oxidation takes place in the mitochondrial matrix.
In order to make up for the
loss of liver glycogen after
the first 24 hours, the body's
metabolism changes in two
important ways.
1) flux through the
gluconeogenic pathway in the
liver and kidneys is increased
to generate glucose for the
brain and erythrocytes.
2) 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.
Metabolic Adaptations to Starvation
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).
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) which is spared for as long as possible to permit mobility.
The four major
adaptations are:
• Increased
triacylglycerol
hydrolysis in
adipose tissue.
• Increased
gluconeogenesis
in liver and kidney
cells.
• Increased
ketogenesis in liver
cells.
• Protein
degradation in
skeletal muscle
tissue.