7 ghrelin signalling

7/28/2019 7 Ghrelin Signalling

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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 fromstudying 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

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)


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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


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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?

?

?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


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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

membraneIP3

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 ofb-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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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

7 ghrelin signalling

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