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 liver is the central processing facility and metabolic hub in the
human body.
• 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.
• Metabolic adaptations to starvation are an increase in gluconeogenesis
and a switch to dependency on fatty acids as the major energy source.
Metabolic Profiles of Major Organs
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. 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
The ATP pool is replenished with ATP made by a phosphoryl transfer
reaction using phosphocreatine. The creatine kinase reaction is
readily reversible.
Support muscle contraction
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).
Subcutaneous
Visceral
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
Skinny
Nice
Chunky
Chubby
Metabolic functions of adipose tissue
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.
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.
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
The brain requires as much as 120 grams of glucose each day
which accounts for 60% of the glucose used by our bodies.
The brain, unlike most other organs, is
exclusively dependent on glucose
under normal conditions to provide
chemical energy for ATP production.
High rates of glucose metabolism is
indicative of neuronal activity
A liver-centric
view of human
metabolism
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.
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.
Physical homeostasis
Population
homeostasis
Physiological
homeostasis
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. They are the yin and yang of glucose homeostasis.
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
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.
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.
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
PPARs are pharmaceutical targets for diabetes
The size of the ligand pocked in PPARs was confirmed by the PPAR
protein structure which revealed the position of a bound agonist.
Metabolic Adaptations to Starvation
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 neuronal cell functions; the brain cannot use
fatty acids for metabolic fuel because of the blood-brain barrier.
Red blood cells (erythrocytes) are also dependent on serum glucose
as a sole source of energy to generate ATP because they lack
mitochondria and are not able to utilize fatty acids.
Why can’t red blood cells utilize fatty acids as an energy source?
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.
2) switch most of the
energy needs to using
fatty acids as the primary
metabolic fuel.
Metabolic Adaptations to Starvation
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.