Transcript 7 Ghrelin signalling

Ghrelin
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 .
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).
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; desGln14-ghrelin (27 ghrelin), C-ghrelin and obestatin.
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 Oacyltransferase “(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)
O-C-CH2-CH2-CH2-CH2-CH2-CH2-CH3
O
n-octanoic acid (n-octanoyl or C8:0)
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 syncytiotrophoblast cells of placenta
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 ghrelinmediated appetite
Ghrelin-producing neurons are present in the hypothalamus, in an area
adjacent to the arcuate nucleus: a modified neural circuit emerges
Ghrelin receptors, GSHR, are present on Npy/AgRP/GABA neurons in the
arcuate nucleus
the ghrelin receptor (GHS-R1a) is a 7TM G-protein coupled receptor
Ghrelin signals to phospholipase C-b via Gaq
Structure of phospholipase C-d1
cleavage of phosphatidyl 4,5-inositol by phospholipase C
(DAG)
(IP3)
the phospholipase C family
Inositol 3,4,5phosphate (IP3)
binds its receptor
and causes
release of Ca2+
from the smooth
endoplasmic
reticulum
IP3
membrane
Ca2+
IP3-mediated opening of the IP3 receptor leads to an transient
increase in intracellular free Ca2+
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)
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
Structure of carnitine, CoA, malonyl and palmitate
Malonyl-CoA
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
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 2003;37:649