Metabolic Integration 1: Metabolic profiles of major organs, signaling and homeostasis, adaptations

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Metabolic Integration 1Metabolic profiles of
major organs, signaling and homeostasis,
adaptations to starvation
Bioc 460 Spring 2008 - Lecture 40 (Miesfeld)
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
Visceral fat (apple shape) is associated with a
higher risk of cardiovascular disease than
subcutaneous fat (pear shape)
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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.

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Metabolic Profiles of Major Organs
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What biochemical mechanisms determine G6P flux
through these pathways?
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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.
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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.
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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
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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
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Metabolic functions of adipose tissue
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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?
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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.
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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
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A liver-centric view of human metabolism
What are the two metabolic fuels exported by the
liver?
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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.
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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.
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Insulin and Glucagon Signaling
???
Glucagon circulates through the body,why no
effect in muscle and brain tissue?
???
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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.
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PPARs are lipid-activated transcription factors
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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 PPARg 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?
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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.
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PPARs are pharmaceutical targets for diabetes
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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.
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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 cant red blood cells utilize fatty acids as
an energy source?
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• 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.
• flux through the gluconeogenic pathway.
• switch most of the energy needs to using fatty
  acids as the primary metabolic fuel.

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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.
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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.