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Technical Discussion Structure of Ghrelin
and Its Receptor
Ghrelin is synthesized as a preprohormone, then
proteolytically processed to yield a 28-amino acid peptide. An
interesting and unique modification is imposed on the hormone during
synthesis in the form of an n-octanoic acid bound to one of its
amino acids; this modification is necessary for biologic activity.
Synthesis of ghrelin occurs predominantly in
epithelial cells lining the fundus of the stomach, with smaller
amounts produced in the placenta, kidney, pituitary and
hypothalamus.
The ghrelin receptor was known well before ghrelin
was discovered. Cells within the
anterior pituitary bear a receptor that, when activated,
potently stimulates secretion of
growth hormone - that receptor was named the growth hormone
secretagogoue receptor (GHS-R). The natural ligand for the GHS-R
was announced in 1999 as ghrelin, and ghrelin was named for its
ability to provoke growth hormone secretion (the prefix, "ghre" means
"grow").
Ghrelin receptors are present on the cells in the
pituitary that secrete growth hormone, and also have been identified
in the hypothalamus, heart and adipose tissue.
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Lay Interpretation
Ghrelin is a 28 amino acid peptide. It is made
primarily in the lining of the top of the stomach. Smaller
amounts are produced in the placenta of the uterus, kidneys,
pituitary and hypothalamus.
Ghrelin receptor sites are named growth hormone
secretagogoue receptor.
Ghrelin receptors are found on the pituitary cells
that produce growth hormone. Other receptors for ghrelin have
been found in the hypothalamus, heart and fatty tissue. |
Control and Physiologic Effects of Ghrelin
At least two major biologic activities have been
ascribed to ghrelin:
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Stimulation of growth hormone secretion:
Ghrelin, as the ligand for the growth hormone secretagogoue
receptor, potently stimulates secretion of growth hormone. The
ghrelin signal is integrated with that of growth hormone
releasing hormone and somatostatin to
control the timing and magnitude of growth hormone secretion.
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Regulation of energy balance: In both
rodents and humans, ghrelin functions to increase hunger
though its action on hypothalamic feeding centres. This makes
sense relative to increasing plasma ghrelin concentrations
observed during fasting (see below). Additionally, humans
injected with ghrelin reported sensations of intense hunger.
Ghrelin also appears to suppress fat utilization in adipose
tissue, which is somewhat paradoxical considering that
growth hormone has the opposite effect. Overall, ghrelin seems
to be one of several hormonal signals that communicates the
state of energy balance in the body to the brain.
Other effects of ghrelin include stimulating gastric
emptying and having a variety of positive effects on cardiovascular
function (e.g. increased cardiac output). It is not totally clear
whether the cardiovascular effects are a direct effect of ghrelin or
represent an indirect effect of ghrelin's ability to stimulate
growth hormone secretion.
Blood concentrations of ghrelin are lowest shortly
after consumption of a meal, then rise during the fast just prior to
the next meal. The figure to the right shows this pattern based on
assays of plasma ghrelin in 10 humans during the course of a day.
Given the effects of ghrelin on energy metabolism
and hunger, it is a prominent target for development of anti-obesity
treatments. It has been reported that immunization of rats against
ghrelin resulted in decreased weight gain and adiposity relative
control rats, even though both groups consumed an equivalent amount
of food. This intriguing experiment suggests the possibility of a
vaccine against obesity.
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Two major functions of ghrelin have been
identified thus:
Ghrelin acts to stimulate hGH production and
secretion. The body co-ordinates ghrelin and somatostatin to
regulate hGH levels.
Ghrelin is noted to invoke hunger and suppress fat
utilisation of adipose (fatty) tissues. This makes it a key to
the energy control and demand systems of the body.
Ghrelin stimulates gastric emptying and is at its
lowest blood concentrations are noted when the stomach is full or
has been empty for a while.
This lends a great credence to the grazing theory of
small meals eaten often being better for weight control than
skipping meals.
Much obesity related research centres on ghrelin.
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Disease States
Ghrelin concentrations in blood are reduced in obese
humans compared to lean control subjects, but whether this is cause
or effect is not defined. Patients with anorexia nervosa have higher
than normal plasma ghrelin levels, which decrease if weight gain
occurs.
Prader-Willi syndrome is another disorder relevant
to ghrelin science. Affected patients develop extreme obesity
associated with uncontrollable and voracious appetite. The plasma
ghrelin levels are exceptionally high in comparison to patients
similarly obese due to other causes. Prader-Willi syndrome is
clearly a complex disease with many defects; it may be that
excessive ghrelin production contributes to the appetite and obesity
components. |
Ghrelin imbalances can be found in a variety
of conditions including anorexia nervosa and morbid obesity.
The kicker here is that ghrelin levels are elevated
in both counts!
It still comes back to balance folks. |
