Dr. Amita k. Mevada
Tutor and 2nd year resident,
Ghrelin has emerged as the first identified
circulating hunger hormone.
Ghrelin is both a hormone in the endocrine
system and a neurotransmitter in the nervous
It is known as the
circulating orexigen, or
appetite-regulating hormone or appetite enhancing
growth hormone secretagogue or
The discovery of ghrelin followed after the
discovery of the growth hormone secretagogue
type 1A receptor in 1996 and was reported by
Masayasu Kojima and colleagues in 1999.
The name is based on its role as a growth
hormone-releasing peptide, with reference to
the Proto-Indo-European root ghre, meaning to
grow.(Growth Hormone Release Inducing =
It is encoded by the GHRLgene.
The mRNA from the GHRL gene
codes for a 117 amino acid
preproghrelin, containing 4 exons.
The signalling peptide molecule of
this larger precursor is cleaved to
produce proghrelin(94 aa).
Proghrelin is cleaved in two to
produce the 28 amino acid peptide
ghrelin (unacylated) and C-ghrelin
(of which obestatin is presumed
to be a cleaved form).
Ghrelin is produced mainly by P/D1 cells, lining the fundus
of the human stomach, that contain granules filled with
Also by epsilon cells of the pancreas that stimulates
It has been found that during fetal development, the ghrelin
concentration in the pancreas is six to seven times higher
than in the stomach. In fetus, the stomach may not be the
major source for circulating ghrelin.
The number of epsilon cells increases during fetal
development, and close to birth they begin to localise at the
periphery of the developing islets.
In rodents, X/A-like cells produce ghrelin.
Aside from the
adults, ghrelin cells are
also found in the
duodenum, jejunum, i
leum, and colon, with
decreasing from the
duodenum to the
Hypothalamic arcuate nucleus and the anterior
In the hypothalamic arcuate nucleus, ghrelin
primarily induces the release of appetite-
In the anterior pituitary gland ghrelin acts on GH-
releasing somatotrophs and caused the
immediate secretion of growth hormone (GH) by
increasing their intracellular Ca2+ concentration.
Also secreted by the lungs, gonads, adrenal
cortex, glomeruli of the kidney and syncytio-
trophoblast cells of placenta.
'Ghrelin' usually refers to the octanoylated
form of ghrelin (acyl ghrelin). This is the 28
amino acid peptide sequence with an
octanoylation on the third amino acid
About 20% of ghrelin is octanoylated
The octanoylation is performed by the ghrelin O-
acyltransferase (GOAT) protein (a member of the
membrane-bound O-acyltransferase family of
proteins), located in the stomach and pancreas.
Only this n-octanoylated form is active and able to bind
to GHS-R receptor to stimulate GH secretion and is thus
known as the acyl ghrelin or active form of ghrelin.
The non-octanoylated form is known as
desacyl ghrelin or the inactive
form, and does not activate GHSR1a
and thus does not release growth
hormone like acyl ghrelin; however
studies have shown it has its own
The normal ghrelin concentration of
plasma samples in humans
total ghrelin= 100–150 fmol/ml
n-octanoyl ghrelin= 10–20 fmol/ml
The ghrelin acts by binding to the GHSR1a(growth
hormone secretagogue receptor) splice-variant of
GHSR1a is a G protein-coupled receptor with seven
Ghrelin after binding to the GHSR1a activates
phospholipase C1 generates IP3 and
diacylglycerol, resulting in an increase in the
intracellular Ca2+ concentration stimulates the
release of GH.
Receptors for ghrelin are located primarily in the
lateral hypothalamus and pituitary, it is also found
in various peripheral organs, such as the
stomach, pancreas, thymus, gonads, thyroid, heart
, lung, liver and vagal afferent endings throughout
the gastro-intestinal tract.
It is also found in the hippocampus, which implies
a possible link between ghrelin and memory
The diversity of ghrelin receptor locations suggests
ghrelin has widespread and diverse biological
The hypothalamus is a region of the brain that
strongly controls feeding patterns and appetite.
Ghrelin-containing neurons are found primarily
in hypothalamic arcuate nuclei (ARC) and
hypothalamic paraventricular nuclei
(PVN), although the ARC is the primary site of
In the ARC, ghrelin stimulates the release
of neuropeptide Y (NPY) and agouti-
related protein (AgRP)-expressing
neurons (increase the appetite), and it
suppresses the release of
proopiomelanocortin (POMC) neurons
(decrease the appetite).
In the PVN, ghrelin neurons send efferent
fibers onto NPY neurons, which suppress the
release of GABA and in turn stimulate
neurons, leading to adrenocorticotropic
hormone (ACTH) and cortisol release.
ACTH and cortisol have numerous effects in
the body, one of which includes increasing
blood sugar levels.
Ghrelin and synthetic ghrelin mimetics
(the growth hormone secretagogues)
increase food intake and increase fat
mass by an action exerted at the level of
Ghrelin-responsiveness of these neurons
is both leptin- and insulin-sensitive.
There is also strong evidence that ghrelin has a
peripheral appetite modulatory effect on satiety by
affecting the mechano-sensitivity of gastric vagal
afferents, making them less sensitive to distension
resulting in over eating.
The vagus nerve is a major pathway in conveying
ghrelin‟s signals from the stomach to the brain.
satiety centre (lesion
Hunger / feeding
(lesion leads to
N.arcuate – pivotal
role in the integration
of signals regulating
Recently ghrelin has also been shown to act on
regions of the brain involved in reward processing
such as the amygdala.
It activates the mesolimbic cholinergic-
dopaminergic reward link, a circuit that
communicates the hedonic and reinforcing aspects
of natural rewards, such as food, as well as of
addictive drugs, such as ethanol.
Indeed, central ghrelin signalling is required for
reward from alcohol and palatable/rewarding foods.
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
Obestatin is a putative hormone that was described, in late
Obestatin was originally identified as an anorectic peptide.
Both obestatin and ghrelin are encoded by the same gene;
the gene's product breaks into two smaller peptides, ghrelin
The purpose of this mechanism that produces two
hormones with opposing effects remains unclear, however
may explain earlier findings, namely that removing the
ghrelin gene from mice did not significantly reduce their
Obestatin has been shown to antagonise growth hormone
secretion and food intake induced by ghrelin
Ghrelin levels increase before
meals and decrease after
It is considered the
counterpart of the hormone
leptin, produced by adipose
tissue, which induces satiation
when present at higher levels.
(1) Appetite Inducer
It is termed the „hunger hormone / orexigenic
hormone. ‟ because it stimulates appetite, increases
food intake and promotes fat storage.
Ghrelin has a peripheral appetite modulatory effect on
satiety by affecting the mechanosensitivity of
gastric vagal afferent.
Ghrelin also appears to suppress fat utilization in
Blood levels of ghrelin rise during fasting, peak just
before eating, and then fall rapidly after a
meal, suggesting a possible role in stimulating feeding.
When administered to humans, ghrelin increases
food intake by up to 30% by circulating in the
bloodstream at the hypothalamus, an area of the
brain crucial in the control of appetite.
Ghrelin does not increase meal size, only meal
Ghrelin injections also increase an animals‟
motivation to seek out food, behaviours
including increased sniffing, foraging for
food, and hoarding food.
Ghrelin also readies the body for the incoming
nutrients by stimulating gastrointestinal
motility and gastric acid secretions (acting
through vagus nerve which also has GHS-
R1a receptor),as does motilin called as
(2) Body Weight Regulation
Studies have shown that ghrelin levels are
negatively correlated with weight.
When a person loses weight, their ghrelin levels
increase, which causes increased food
consumption and weight gain.
Conversely, when a person gains weight, their
ghrelin levels drops, leading to a decrease in food
consumption and weight loss.
This data suggests that ghrelin functions as an
adiposity signal, acts as a body weight regulator,
continually keeping one‟s body weight and energy
stores in check.
(3) Gastrointestinal tract
Ghrelin has been proposed as a hormone which
promotes intestinal cell proliferation and inhibits its
apoptosis during inflammatory states and oxidative
It also suppresses the pro-inflammatory mechanisms
and augments anti-inflammatory mechanisms, thus
creating a possibility of its therapeutic use in various
conditions, (colitis, ischemia reperfusion injury and
Ghrelin decreases pro-inflammatory cytokines in
sepsis by means of activation of the vagus nerve.
This is so since the vagus
mediator, acetylcholine, has potent anti-inflammatory
It has also been shown to have regenerative capacity
and is beneficial in case of mucosal injury to the
stomach. But Ghrelin also appears to promote
gastrointestinal and pancreatic malignancy.
(4) Ghrelin also stimulates the release of growth
hormone from the pituitary gland, and causes the
build-up of muscle.
(5) Lung development
Ghrelin protein has been found in the endocrine cells
of the fetal lung in decreasing amounts from the
embryonic to late fetal periods and promotes growth.
Its expression was shown to be maintained in
newborns and children under 2 years, but it was
found to be virtually absent in older individuals
(6) Learning and memory
Animal models indicate that ghrelin may enter the
hippocampus from the bloodstream, altering nerve-
cell connections, and so enhancing learning and
It is suggested that learning may be best during the
day and when the stomach is empty, since ghrelin
levels are higher at these times.
Ghrelin plays a significant role in
neurotrophy, particularly in the
hippocampus, and is essential for cognitive
adaptation to changing environments and the
process of learning.
(7) Stress-induced depression
The hormone might help defend against
symptoms of stress-induced depression and
The researchers stressed both wild-type mice and
altered mice that were unable to respond to
ghrelin, by exposing them to very aggressive
“bully” mice. .
They found that, after experiencing stress, both
types of mice had significantly elevated levels of
ghrelin that persisted at least four weeks after their
last defeat encounter.
The altered mice, however, displayed significantly
greater social avoidance than their wild-type
counterparts, indicating an exacerbation of
depression-like symptoms. They also ate less than
the wild-type mice.
(8) Sleep duration
An inverse relationship between the hours of sleep
and blood plasma concentrations of ghrelin exists
As the hours of sleep increase, ghrelin
concentrations lower, thereby potentially reducing
appetite and avoiding potential obesity.
Short sleep duration is associated with high levels
of ghrelin and obesity.
"When sleep is restricted to four hours a
night, ghrelin levels go up and leptin levels go
down," says National Sleep Foundation
spokesperson William Orr, PhD, president and CEO
of the Lynn Health Science Institute.
(9) The presence of the Ghrelin-R on
pancreatic β-cells already suggested a role
for ghrelin in the function of the β-
cell, leading to the hypothesis that ghrelin
also has a regulatory role in insulin
(10) Regarding the reproductive
system, ghrelin has inhibitory effects
on GnRH secretion from
the hypothalamus, thus appearing to
potentially cause decreased fertility.
(11) Ghrelin also has protective effects on the
An intravenous bolus of human ghrelin decreased
mean arterial pressure without changing the heart
Ghrelin also increased the cardiac index and
stroke volume indices.
Ghrelin levels are primarily regulated by food intake.
Levels of ghrelin in the blood rise just before eating and
when fasting (in line with increased hunger) , with the
timing of these rises being affected by our normal meal
Hence, ghrelin is thought to play a role in mealtime
„hunger pangs‟ and the need to begin meals.
Eating reduces concentrations of ghrelin.
Levels of ghrelin are lower in individuals with a higher
body weight compared to lean individuals, which
suggests ghrelin could be involved in the long-term
regulation of body weight.
Ghrelin level increases
1-2 hr prior to
meal, max just before
eating and decreases
dramatically within 1 hr
Different nutrients slow down ghrelin release to
varying degrees; carbohydrates and proteins
restrict the production and release of ghrelin to a
greater extent than fats.
Somatostatin also restricts ghrelin release, as well
as many other hormones released from the
Ghrelin levels increase after dieting, which may
explain why diet-induced weight loss can be difficult
Prader-Willi syndrome is a complex genetic
disorder characterized by hyperphagia, mental
retardation, short stature, muscular hypotonia.
Patients may have severe obesity and learning
Unlike more common forms of
obesity, circulating ghrelin levels are high in
Prader-Willi syndrome patients and start before
the development of obesity.
Visceral adiposity and insulin resistance are
reduced in PWS, which might lead to
hyperghrelinemia, this ghrelin may contribute to
their increased appetite and body weight.
Ghrelin levels are high in the eating
disorder, anorexia nervosa.
Anorexia nervosa is characterized by an
obsessive fear of gaining weight and a distorted
self image, the compulsion of course, is to starve
Ghrelin levels are also high in cancer-induced
This may be the body‟s way of making up for
weight loss by stimulating food intake and fat
The level of ghrelin increases during the time of day
from midnight to dawn in thinner people which
suggests there is a flaw in the circadian system of
obese individuals. Short sleep duration may also
lead to obesity, through an increase of appetite via
hormonal changes. Lack of sleep produces
ghrelin, which stimulates appetite and creates less
One would expect higher levels in people with
obesity. However, ghrelin levels are usually lower
in people with higher body weight compared to
lean people which suggests ghrelin is not a cause
Obese people are actually more sensitive to the
Serum ghrelin levels are inversely related to
changes of body weight.
Gastric bypass surgery, which involves
reducing the size of the stomach, is
considered to be the most effective
treatment for severe, life-threatening
Patients who lose weight after
bypass surgery have been found to have
lower ghrelin levels than those who lose
weight by other means such as diet and
physical restriction of the
stomach (gastric pouch)
The reduction of nutrient
digestion and absorption
suppression of plasma
ghrelin by gastric bypass
surgery can contribute
to the more efficacy of
this procedure as weight
This might be related to the finding that some patients
develop some level of cognitive impairment after
gastric bypass surgery because of the significant role
of ghrelin in cognitive function.
Ghrelin through its receptor increases the production
and release of dopamine in the substantia nigra, a
region of the brain where dopamine cell degeneration
leads to Parkinson's disease. Hence ghrelin may
find application in slowing down the onset of
In fact, animal models of colitis, ischemia
reperfusion, and sepsis-related gut dysfunction
have been shown to benefit from therapeutic doses
increase body weight without increasing body fat and to improve
motility and appetite in the elderly, it has the potential for many
uses, including GERD
Used in development for non-small cell lung cancer (NSCLC)-related
It displays both orexigenic and anabolic properties via ghrelin
mimetic activity and transient increases in growth hormone (GH).
accelerates gastric emptying and improves upper gastrointestinal
symptoms in diabetic patients with gastroparesis.
These all drugs are under clinical trial in phase 2 and 3
lacks the ability to bind somatostatin receptors but
retains ghrelin receptor binding.
Acts as a ghrelin receptor antagonist; counteracts the
response of ghrelin on gastric acid secretion.
Ghrelin receptor antagonist (GHS-R1a).
Displays no significant affinity for the motilin receptor.
Blocks the effects of ghrelin on insulin secretion both in
vivo and in vitro. Improves glucose homeostasis in
Specifically, Zorrilla et al. developed a vaccination
strategy designed to neutralize the actions of the
orexigenic hormone ghrelin
In a recent publication from the Proceedings of the
National Academy of Sciences, Zorilla and
colleagues addressed this novel approach of
vaccinating rats against their own endogenous
The vaccine uses the immune system, specifically
antibodies, to bind to selected targets, directing the
body's own immune response against them.
The vaccines consisted of molecules mimicking the
structure of the acylated form of ghrelin and, as
intended, led to the production of specific anti-ghrelin
antibodies that specifically recognized n-octanoyl-
This prevents ghrelin from reaching the central
nervous system, increase their energy expenditure
and decrease their food intake, thus producing a
desired reduction in weight gain.
Guyton and Hall. Textbook of Medical Physiology, 12th Edition
Endocrine physiology, Third Edition. Patricia E. Molina, MD, PhD
Indu Khurana. Textbook of Medical Physiology, 1st Edition
Ganong‟s Review of Medical Physiology - 23rd Ed
Kojima M, Kangawa K. Ghrelin: structure and function. Physiol
Rev. 2005; 85:495.
Zorrilla et al. Vaccination against weight gain. Proceedings of
the National Academy of Sciences. (2006) 103 (35):13266-
www.ncbi.nlm.nih.gov/pubmed/17035664: Prospects for an
anti-ghrelin vaccine to treat obesity.
obesity vaccine reduces food consumption in animals