Ghrelin

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Ghrelin
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facts of ghrelin
First there was the receptor, discovered as the
binding site of synthetic compounds that caused
the immediate secretion of growth hormone (GH)
from the somatotrophic cells of the anterior
pituitary. These compounds were developed as
potential medicaments aiming to restore body
growth (by boosting the production of GH). The
orphan receptor, lacking a physiological ligand,
was named growth hormone secretagogue receptor
(GSH-R, two splice variants 1a (full length) and
1b (truncated). Then there was the ligand which,
surprise, was isolated from extracts from the
stomach and not, as expected, from the pituitary
or hypothalamus. Because the newly identified
physiological ligand controled secretion of
growth hormone, it was named ghrelin, after ghre,
the proto-indo-european root of the word
 grow . Strangely enough, mice lacking either
ghrelin or its receptor grow normally .
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facts of ghrelin
Then it was discovered that, when injected into
the bloodstream or into cerebral ventricles,
ghrelin also stimulates food intake in rodents.
The attention shifted from studying its role in
growth to studying its role in appetite
control. Important evidence for its role in
control of appetite came from the observation
that mice lacking either ghrelin or its receptor
are protected from diet-induced obesity (although
there feeding behaviour does not differ from
control mice under normal feeding conditions ).
Soon after, it was also shown that blood levels
of ghrelin rise in starvation and decrease
postprandilly (after having eaten) Ghrelin is
low in obese, high in anorexia nervosa (empty
stomach) and in Prader-Willi syndrome (complex
genetic disorder characterized by hyperphagia,
mental retardation, short stature, muscular
hypotonia and distinctive behavioral features).
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facts of ghrelin
Ghrelin is a peptide hormone comprising 28
amino-acids that arise from a 94 amino-acid long
precursor (proghrelin). Other products of
proghrelin are des-Gln14-ghrelin (27 ghrelin),
C-ghrelin and obestatin.
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facts of ghrelin
About 20 of ghrelin is modified (on Ser-3) by
n-octanoic acid (process referred to as
octanoylation), through the action of
membrane-bound ghrelin O-acyltransferase (named
GOAT). This occurs in the rough-endoplasmic
reticulum. Octanoylation is essential for
binding to the GHS receptor and thus for the
induction of appetite (and other functions).
H2N-GSSFLSPEHQRVQQRKESKKPPAKLQPR-COOH
Ghrelin (28)
n-octanoic acid (n-octanoyl or C80)
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facts of ghrelin
Ghrelin qualifies as an orexigenic hormone It is
produced by X/A-cells of oxyntic glands,
abundantly present in the mucosal layer of the
fundus region of the stomach Ghrelin is
produced in small quantities in other parts of
the digestive tract. It is also produced in the
pancreas, in ghrelin neurons in the hypothalamus,
in glomeruli of the kidney and in
syncytio-trophoblast cells of placenta
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which ghrelin affects the NPY/AgRP neurons in the
arcuate nucleus the one produced by the stomach
or by ghrelin-containing neurons in the
hypothalamus?
the blood-brain barrier
Problems -very little ghrelin is transported
across the blood-brain barrier in the direction
of blood-to-brain how does it reach its
receptor? -vagotomy prevents ghrelin-mediated
appetite
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Ghrelin-producing neurons are present in the
hypothalamus, in an area adjacent to the arcuate
nucleus a modified neural circuit emerges
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Ghrelin receptors, GSHR, are present on
Npy/AgRP/GABA neurons in the arcuate nucleus
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the ghrelin receptor (GHS-R1a) is a 7TM G-protein
coupled receptor
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Ghrelin signals to phospholipase C-b via Gaq
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Structure of phospholipase C-d1
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cleavage of phosphatidyl 4,5-inositol by
phospholipase C
(IP3)
(DAG)
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the phospholipase C family
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Inositol 3,4,5-phosphate (IP3) binds its receptor
and causes release of Ca2 from the smooth
endoplasmic reticulum
membrane
IP3
Ca2
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IP3-mediated opening of the IP3 receptor leads to
an transient increase in intracellular free Ca2
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intracellular free Ca2 binds calmodulin (CaM),
this binds to CaMkinase kinase (CaMKK) which acts
as the activator of AMPK. This leads to
phosphorylation and activation of TSC1/TSC2. The
excess of RhebGDP prevents activation of mTOR,
giving rise to an orectic signal (appetite)
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Acetyl-CoA carboxylase (ACC) is another target
of ghrelin-activated AMPK. In moments of
 plentitude  (high glucose) the ACC-mediated
production of malonyl-CoA leads to inhibition of
b-oxidation
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Structure of carnitine, CoA, malonyl and palmitate
Malonyl-CoA
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Ghrelin-mediated activation of AMPK leads to
phosphorylation and inactivation of acetyl-CoA
carboxylase. The ensuing lack of fatty acid
synthesis and subsequent increase in b-oxidation
plays a role in the generation of an orectic
signal
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(No Transcript)
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Ghrelin augments the firing rate of NPY, AgRP,
GABA neurons and augments the production of
AgRP/NPY (neurotransmitters). Subsequent GABA
release reduces the firing rate of POMC neurons
(hyperpolarization). Result dominant activity of
orexigenic neurons
Image from Cowley et al Neuron 200337649