Post on 18-Dec-2015
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; des-Gln14-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 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
O-C-CH2-CH2-CH2-CH2-CH2-CH2-CH3
O n-octanoic acid (n-octanoyl or C8:0)
Ghrelin (28)
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
facts of ghrelin
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?
?
?
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
the blood-brain barrier
Ghrelin-producing neurons are present in the hypothalamus, in an area adjacent to the arcuate nucleus: a modified neural circuit emerges
Inositol 3,4,5-phosphate (IP3)
binds its receptor and causes
release of Ca2+ from the smooth
endoplasmic reticulum
membraneIP3
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 -oxidation
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 -oxidation plays a role in the generation of an orectic signal