Hormones Digesting, absorbing and assimilating a meal requires precise coordination of a huge number

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Hormones Digesting, absorbing and assimilating
a meal requires precise coordination of a huge
number of physiologic processes. Control over GI
functions is provided by nervous and endocrine
systems.

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Gastrointestinal (GI) The hormones most
important in controlling digestive function are
synthesized within the GI tract by cells
scattered in the epithelium of the stomach and
SI. These endocrine cells and the hormones they
secrete are referred to as the enteric endocrine
system. Interestingly, most if not all "GI
hormones" are also synthesized in the brain.

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Overview of the Digestive System Consider for a
moment a Big Mac. The purpose of eating a Big Mac
(besides hedonism), is to assimlate the nutrients
it represents and make them available to build,
repair and maintain your own tissues, as well as
provide energy for studying and occasional other
pursuits. You may have asked yourself - "Exactly
what nutrients are present in a Big Mac that I
can assimilate?" MacDonald's comes close to full
disclosure in this regard- They don't tell you
that in order to take advantage of these
nutrients, you have to provide the means to
carefully break them down into much smaller
molecules that can be imported into blood.
Luckily, your digestive system takes care of
this very complex process so efficiently

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Overview of the Digestive System At its
simplest, the digestive system it is a tube
running from mouth to anus. This tube is like an
assembly line, or more properly-a disassembly
line. chief goal is to break down huge
macromolecules (proteins, fats and starch), which
cannot be absorbed into smaller molecules (amino
acids, fatty acids and glucose) that can be
absorbed across the wall of the tube, and into
the circulatory system for dissemination around
your body.

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The breakdown of foodstuffs is accomplished
through a combination of mechanical and enzymatic
processes. -the digestive tube requires
considerable assistance from accessory digestive
organs such as the salivary glands, liver and
pancreas, which dump their secretions into the
tube. The name "accessory" should not be taken to
mean dispensible-without pancreatic enzymes you
would starve to death in short order.

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In many ways, the digestive system can be thought
of as a well-run factory in which a large number
of complex tasks are performed. The three
fundamental processes that take place are
Secretion Delivery of enzymes, mucus, ions and
the like into the lumen, and hormones into blood
Absorption Transport of water, ions and
nutrients from the lumen, across the epithelium
and into blood Motility Contractions of smooth
muscle in the wall of the tube that crush, mix
and propel its contents

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Like any well-run factory, proper function of the
digestive system requires robust control systems.
Control systems must facilitate communication
among different sections of the digestive tract
(i.e. control on the factory floor), and between
the digestive tract and the brain (i.e. between
workers and management). Control of digestive
function is achieved through a combination of
electrical and hormonal messages which originate
either within the digestive system's own nervous
and endocrine systems, as well as from the CNS
and from endocrine organs such as the adrenal
gland.

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Different parts of these systems are constantly
talking to one another. The basic messages are
along the lines of "I just received an
extraordinary load of food, so I suggest you get
prepared" (stomach to large intestine) or "For
goodness sake, please slow down until I can catch
up with what you've already given me" (small
intestine to stomach).

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Finally, a note about differences in digestive
anatomy and physiology among animals. The
digestive systems of humans, dogs, mice, horses,
kangaroos and great white sharks are, to a first
approximation, virtually identical. If you look
more carefully however, it becomes apparent that
each of these species has evolved certain
digestive specializations that have allowed it to
adapt to a particular diet.
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These differences become particularly apparent
when you compare a carnivore like a cat with a
herbivore like a goat or a horse. Goats and
horses evolved from ancestors that subsisted on
plants and adapted parts of their digestive
tracts into massive fermentation vats which
enabled them to efficiently utilize cellulose,
the major carbohydrate of plants.

In contrast, cats evolved from animals that lived
on the carcasses of other animals, and have
digestive systems that reflect this history -
extremely small fermentation vats and essentially
no ability to utilize cellulose. Bridging the gap
between carnivores and herbivores are omnivores
like humans and pigs, whose digestive tracts
attest to a historical diet that included both
plants and animals. The image above shows a young
omnivore in the company of herbivore and
carnivore friends.
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Basic Functional Anatomy of the Digestive System

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The digestive system depicted on previous
slide- a carnivore is the simplest among
mammals. Other species, even humans, have a
more or very much more extensive large intestine,
and ruminants like cattle and sheep have a large
set of forestomachs through which food passes
before it reaches the stomach. Each of the
organs contributes to the digestive process in
several unique ways. If you were to describe
their most important or predominant function, and
summarize shamelessly, the list would look
something like this

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Mouth Foodstuffs are broken down mechanically by
chewing and saliva is added as a lubricant. In
some species, saliva contains amylase, an enzyme
that digests starch. Esophagus A simple
conduit between the mouth and stomach - clearly
important but only marginally interesting
compared to other regions of the tube. Stomach
Where the real action begins - enzymatic
digestion of proteins initiated and foodstuffs
reduced to liquid form. Liver The center of
metabolic activity in the body - its major role
in the digestive process is to provide bile salts
to the small intestine, which are critical for
digestion and absorption of fats.

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Pancreas Important roles as both an endocrine
and exocrine organ - provides a potent mixture of
digestive enzymes to the small intestine which
are critical for digestion of fats, carbohydrates
and protein. Small Intestine The most exciting
place to be in the entire digestive system - this
is where the final stages of chemical enzymatic
digestion occur and where almost almost all
nutrients are absorbed. Large Intestine Major
differences among species in extent and
importance - in all animals water is absorbed,
bacterial fermentation takes place and feces are
formed. In carnivores, that's about the extent of
it, but in herbivores like the horse, the large
intestine is huge and of critical importance for
utilization of cellulose.

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Microbial Life in the Digestive Tract The GI
contains an immensely complex ecology of
microorganisms. A typical person harbors more
than 500 distinct species of bacteria,
representing dozens of different lifestyles and
capabilities. The composition and distribution
of this menagerie varies with age, state of
health and diet.

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The number and type of bacteria in the GI tract
vary dramatically by region. In healthy
individuals the stomach and proximal SI contain
few microorganisms, largely a result of the
bacteriocidal activity of GASTRIC ACID In sharp
contrast to the stomach and SI, the contents of
the colon literally teem with bacteria,
predominantly strict anaerobes . Between these
two extremes is a transitional zone, usually in
the ileum, where moderate numbers of both aerobic
and anaerobic bacteria are found.

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The GI tract is sterile at birth, but
colonization typically begins within a few hours
of birth, starting in the SI and progressing
caudally over a period of several days. In most
circumstances, a "mature" microbial flora is
established by 3 to 4 weeks of age. It is also
clear that microbial populations exert a profound
effect on structure and function of the digestive
tract.

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For example The morphology of the intestine of
germ-free animals differs considerably from
normal animals - villi of the SI are remarkably
regular and the rate of epithelial cell renew is
reduced The cecum of germ-free rats is roughly
10 times the size of that in a conventional
rat.

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Bacteria in the intestinal lumen metabolize a
variety of sterols and steroids. For example,
bacteria convert the bile salt cholic acid to
deoxycholic acid. Small intestinal bacteria
also have a important role in sex steroid
metabolism.

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Finally, bacterial populations in the large
intestine digest carbohydrates, proteins and
lipids that escape digestion and absorption in
SI. This fermentation, particularly of
cellulose, is of critical importance to
herbivores like cattle and horses which make a
living by consuming plants. However, it seems
that even species like humans and rodents derive
significant benefit from the nutrients liberated
by intestinal microorganisms.

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Overview of GI Hormones If you are like most
people, you eat several meals and occasional
snacks each day, but rarely think about the
immense number of tasks that must be performed by
your digestive system to break down, absorb and
assimilate those nutrients. Robust control
systems are required to coordinate digestive
processes in man and animals, and are provided by
both the nervous and endocrine systems. There
are a bunch of hormones, neuropeptides and
neurotransmitters that affect GI function.
Interestingly, a number of the classical GI
hormones are also synthesized in the brain, and
sometimes referred to as "brain-gut peptides".

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Major PLAYERS
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Hormone -Major Activities-Stimuli for
Release Gastrin-Stimulates gastric acid
secretion proliferation of gastric epithelium
Presence of peptides and amino acids in
gastric lumen Cholecystokinin-Stimulates
secretion of pancreatic enzymes, and contraction
and emptying of the gall bladder Presence of
fatty acids and amino acids in the small
intestine Secretin-Stimulates secretion of water
and bicarbonate from the pancreas and bile ducts
Acidic pH in the lumen of the small SI
Ghrelin- a strong stimulant for appetite and
feeding also a potent stimulator of GH
secretion. Not clear, but secretion peaks prior
to feeding and diminishes with gastric filling

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Hormone Major Activities Stimuli for
Release Motilin-Apparently involved in
stimulating housekeeping patterns of motility in
the stomach and small intestine-Not clear, but
secretion is associated with fasting Gastric
inhibitory polypeptide-Inhibits gastric secretion
and motility and potentiates release of insulin
from beta cells in response to elevated blood
glucose concentration-Presence of fat and glucose
in the small intestine

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Gastrin Gastrin is a major physiological
regulator of gastric acid secretion. Also has an
important trophic or growth-promoting influence
on the gastric mucosa. Gastrin is synthesized in
G cells, which are located in gastric pits,
primarily in the antrum region of the stomach and
binds receptors found predominantly on parietal
and enterochromaffin-like cells.

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4 major types of secretory epithelial cells cover
the surface of the stomach and extend down into
gastric pits and glands Mucous cells secrete
an alkaline mucus that protects the epithelium
against shear stress and acidParietal cells
secrete hydrochloric acid! Chief cells secrete
pepsin, a proteolytic enzyme G cells secrete
the hormone gastrin

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Structure of Gastrin and the Gastrin
Receptor Gastrin is a linear peptide that is
synthesized as a preprohormone and is
post-translationally cleaved to form a family of
peptides with identical carboxy termini. The
predominant circulating form is gastrin-34 ("big
gastrin"), but full biologic activity is present
in the smallest peptide (gastrin-14 or
minigastrin). Further, full bioactivity is
preserved in the 5 C-terminal aas of gastrin,
which is known as pentagastrin. The five
C-terminal amino acids of gastrin and
cholecystokinin are identical, which explains
their overlapping biological effects.

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The gastrin receptor is also one of the receptors
that bind cholecystokinin, and is known as the
CCK-B receptor. It is a member of the G
protein-coupled receptor family. Binding of
gastrin stimulates an increase in intracellular
Ca, activation of protein kinase C, and
production of inositol phosphate.
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Control and Physiologic Effects of Gastrin The
primary stimulus for secretion of gastrin is the
presence of certain foodstuffs, especially
peptides, certain amino acids and calcium, in the
gastric lumen. Also, as yet unidentified
compounds in coffee, wine and beer are potent
stimulants for gastrin secretion. Secretion of
this hormone is inhibited when the lumenal pH of
the stomach becomes very low (less than about 3).


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Control and Physiologic Effects of
Gastrin Gastrin appears to have at least two
major effects on gastrointestinal
function Stimulation of gastric acid secretion
Gastrin receptors are found on parietal cells,
and binding of gastrin, along with histamine and
acetylcholine, leads to fully-stimulated acid
secretion by those cells. Canine parietal cells
have roughly 44,000 gastrin receptors each, and
in that species, it has been demonstrated that
immunoneutralization of gastrin blocks secretion
of acid in response to intragastric
administration of peptides.

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Control and Physiologic Effects of
Gastrin Gastrin appears to have at least two
major effects on gastrointestinal function
Enterochromaffin-like (ECL) cells also bear
gastrin receptors, and recent evidence indicates
that this cell may be the most important target
of gastrin with regard to regulating acid
secretion. Stimulation of ECL cells by gastrin
leads to histamine release, and histamine binding
to H2 receptors on parietal cells is necessary
for full-blown acid secretion.

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Control and Physiologic Effects of
Gastrin Gastrin appears to have at least two
major effects on gastrointestinal
function Promotion of gastric mucosal growth
Gastrin clearly has the ability to stimulate many
aspects of mucosal development and growth in the
stomach. Treatment with gastrin stimulates DNA,
RNA and protein synthesis in gastric mucosa and
increases the number of parietal cells. Another
observation supporting this function is that
humans with hypergastrinemia (abnormally high
blood levels of gastrin) consistently show
gastric mucosal hypertrophy.

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In addition to parietal and ECL cell targets,
gastrin also stimulates pancreatic acinar cells
via binding to CCK receptors, and gastrin
receptors have been demonstrated on certain
populations of gastric smooth muscle cells,
supporting pharmacologic studies that demonstrate
a role for gastrin in regulating gastric
motility.
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Disease States Excessive secretion of gastrin,
or hypergastrinemia, is a well-recognized cause
of a severe disease known as Zollinger-Ellison
syndrome, which is seen at low frequency in man
and dogs. The hallmark of this disease is
gastric and duodenal ulceration due to excessive
and unregulated secretion of gastric acid. Most
commonly, hypergastrinemia is the result of
gastrin-secreting tumors (gastrinomas), which
develop in the pancreas or duodenum.

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• Zollinger-Ellison Syndrome (ZES)
• rare disorder that causes tumors in the pancreas
  and duodenum and ulcers in the stomach and
  duodenum.
• Excesss gastrin cause the stomach to produce too
  much acid, which in turn causes stomach and
  duodenal ulcers (peptic ulcers). The ulcers
  caused by ZES are less responsive to treatment
  than ordinary peptic ulcers.
• What causes people with ZES to develop tumors is
  unknown, but approximately 25 of ZES cases are
  associated with a genetic disorder called MEN 1.

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Zollinger-Ellison Syndrome (ZES) The symptoms of
ZES include signs of peptic ulcers gnawing,
burning pain in the abdomen diarrhea nausea
vomiting fatigue weakness weight loss and
bleeding. Physicians diagnose ZES through blood
tests to measure levels of gastrin and gastric
acid secretion. They may check for ulcers by
doing an endoscopy.

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Zollinger-Ellison Syndrome (ZES) The primary
treatment for ZES is medication to reduce the
production of stomach acid. Proton pump
inhibitors that suppress acid production and
promote healing are the first line of treatment.
H-2 blockers (cimetidine, famotidine,
ranitidine) may also be used, but are less
effective in reducing stomach acid. Surgery to
treat peptic ulcers or to remove tumors in the
pancreas or duodenum are other treatment options.
People who have been treated for ZES should be
monitored in case the ulcers or tumors recur.

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Cholecystokinin (CCK) Cholecystokinin plays a
key role in facilitating digestion within the SI.
It is secreted from mucosal epithelial cells in
the first segment of the small intestine
(duodenum), and stimulates delivery into the
small intestine of digestive enzymes for the
pancreas and bile from the gall bladder. CCK is
also produced by neurons in the enteric nervous
system and is widely and abundantly distributed
in the brain.

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Structure of Cholecystokinin and Its
Receptors CCK and gastrin are highly similar
peptides. Like gastrin, CCK is a linear peptide
that is synthesized as a preprohormone, then
proteolytically cleaved to generate a family of
peptides having the same carboxy ends. Full
biologic activity is retained in CCK-8 (8 amino
acids), but peptides of 33, 38 and 59 amino acids
are also produced. In all of these CCK peptides,
the tyrosine seven residues from the end is
sulfated, which is necessary for activity.

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Structure of Cholecystokinin and Its
Receptors Two receptors that bind
cholecystokinin have been identified. CCKA
receptor is found abundantly on pancreatic acinar
cells. CCKB receptor, which also functions as
the gastrin receptor, is the predominant form in
brain and stomach. Both receptors are have 7TMD
typical of G protein-coupled receptors.
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Control and Physiologic Effects of
Cholecystokinin Foodstuffs flowing into the SI
consist mostly of large macromolecules (proteins,
polysaccharides and triglyceride) that must be
digested into small molecules (amino acids,
monosaccharides, fatty acids) in order to be
absorbed. Digestive enzymes from the pancreas
and bile salts from the liver (which are stored
in the gallbladder) are critical for such
digestion.

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Control and Physiologic Effects of
Cholecystokinin CCK is the principle stimulus
for delivery of pancreatic enzymes and bile into
the SI. Most potent stimuli for secretion of CCK
are the presence of partially-digested fats and
proteins in the lumen of the duodenum (a
particularly potent stimulus is pictured below).

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An elevation in blood concentration of CCK has 2
major effects that facilitate digestion
Release of digestive enzymes from the pancreas
into the duodenum. Older literature refers to CCK
as pancreozymin, a term coined to describe this
effect.

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An elevation in blood concentration of CCK has 2
major effects that facilitate digestion
Contraction of the gallbladder to deliver bile
into the duodenum. The name cholecystokinin (to
"move the gallbladder") was given to describe
this effect. CCK is also known to stimulate
secretion of bile salts into the biliary system

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Pancreatic enzymes and bile flow through ducts
into the duodenum, leading to digestion and
absorption of the very molecules that stimulate
CCK secretion. Thus, when absorption is
completed, CCK secretion ceases. Injection of
CCK into the ventricles of the brain induces
satiety (lack of hunger) in laboratory animals.
In view of its pattern of secretion relative to
feeding, it would make physiologic sense that
this hormone might participate in control of food
intake. However, recent experiments suggest that
CCK is at best a minor player in regulation of
food intake.

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In addition to its synthesis in small intestinal
epithelial cells, CCK has been clearly
demonstrated in neurons within the wall of the
intestine and in many areas of the brain. It
seems, in fact, to be the most abundant
neuropeptide in the CNS. Secretion of CCK from
neurons appears to modulate the activity of other
hormones and neuropeptides, but it seems safe to
say the understanding its role in function of the
brain is rudimentary at best.

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Disease States Diseases resulting from excessive
or deficient secretion of CCK are rare. CCK
deficiency has been described in humans as part
of autoimmune polyglandular syndrome, and was
manifest as a malabsorption syndrome clinically
similar to pancreatic exocrine insufficiency.

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Disease States Diseases resulting from excessive
or deficient secretion of CCK are rare.
Additionally, there is mounting evidence that
aberrations in expression of CCK or its receptor
within the human brain may play a part in the
pathogenesis of certain types of anxiety and
schizophrenia. Clearly, a much better
understanding of the role of CCK in brain
function is required.

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Secretin The SI is periodically assaulted by a
flood of acid from the stomach, and it is
important to put out that fire in a hurry to
avoid acid burns. Secretin functions as a type
of fireman it is released in response to acid in
the SI, and stimulates the pancreas to release a
flood of bicarbonate base, which neutralizes the
acid. Secretin is also of some historical
interest, as it was the first hormone to be
discovered.

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Structure of Secretin and Its Receptors Secretin
is synthesized as a preprohormone, then
proteolytically processed to yield a single 27 aa
peptide by removal of the signal peptide plus
amino and carboxy-terminal extensions. The
sequence of the mature peptide is related to that
of glucagon, vasoactive intestinal peptide and
gastric inhibitory peptide. The secretin
receptor has seven membrane-spanning domains and
characteristics typical of a G protein-coupled
receptor.

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Control and Physiologic Effects of Secretin
Secretin is secreted in response to one known
stimulus acidification of the duodenum, which
occurs most commonly when liquified ingesta from
the stomach are released into the SI. The
principal target for secretin is the
pancreas-which responds by secreting a
bicarbonate-rich fluid, which flows into the
first part of the intestine through the
pancreatic duct.

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Control and Physiologic Effects of Secretin
Bicarbonate ion is a base and serves to
neutralize the acid, thus preventing acid burns
and establishing a pH conducive to the action of
other digestive enzymes.

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Control and Physiologic Effects of Secretin A
similar, but quantitatively less important
response to secretin is elicited by bile duct
cells, resulting in additional bicarbonate being
dumped into the small gut. As acid is
neutralized by bicarbonate, the intestinal pH
rises toward neutrality, and secretion of
secretin is turned off.

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Disease States Diseases associated with
excessive or deficient secretion of secretin
have not been identified.

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Ghrelin Ghrelin was discovered as the peptide
hormone that potently stimulates release of GH
from the anterior pituitary. It was subsequently
determined that ghrelin, along with several other
hormones, has significant effects on appetite and
energy balance. The predominant source of
ghrelin is epithelial cells in the stomach.

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Structure of Ghrelin and Its Receptor Ghrelin is
synthesized as a preprohormone, then
proteolytically processed to yield a 28 aa
peptide. An interesting and unique modification
is imposed on the hormone during synthesis in the
form of an n-octanoic acid bound to one of its
amino acids this modification is necessary for
biological activity.

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Structure of Ghrelin and Its Receptor Synthesis
of ghrelin occurs predominantly in epithelial
cells lining the fundus of the stomach, with
smaller amounts produced in the placenta, kidney,
pituitary and hypothalamus.

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Structure of Ghrelin and Its Receptor The
ghrelin receptor was known well before ghrelin
was discovered. Cells within the anterior
pituitary bear a receptor that, when activated,
potently stimulates secretion of GH - that
receptor was named the growth hormone secretagoue
receptor (GHS-R). The natural ligand for the
GHS-R was announced in 1999 as ghrelin, and
ghrelin was named for its ability to provoke
growth hormone secretion (the suffix ghre means
"grow"). Ghrelin receptors are present on the
cells in the pituitary that secrete growth
hormone, and also have been identified in the
hypothalamus, heart and adipose tissue.

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Control and Physiologic Effects of Ghrelin At
least 2 major biologic activities have been
ascribed to ghrelin Stimulation of GH
secretion Ghrelin, as the ligand for the growth
hormone secretagogue receptor, potently
stimulates secretion of GH. The ghrelin signal is
integrated with that of GHRH and SS to control
the timing and magnitude of GH secretion.

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Control and Physiologic Effects of Ghrelin At
least 2 major biologic activities have been
ascribed to ghrelin Regulation of energy
balance In rodents and humans, ghrelin functions
to increase hunger though its action on
hypothalamic feeding centers. This makes sense
relative to increasing plasma ghrelin
concentrations observed during fasting.
Additionally, humans injected with ghrelin
reported sensations of intense hunger. Ghrelin
also appears to suppress fat utilization in
adipose tissue, which is somewhat paradoxical
considering that GH has the opposite effect.
Overall, ghrelin seems to be one of several
hormonal signals that communicates the state of
energy balance in the body to the brain.

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Control and Physiologic Effects of Ghrelin
Other effects of ghrelin include stimulating
gastric emptying and having a variety of positive
effects on cardiovascular function (e.g.
increased cardiac output). It is not totally
clear whether the cardiovascular effects are a
direct effect of ghrelin or represent an indirect
effect of ghrelin's ability to stimulate GH
secretion.

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Blood concentrations of ghrelin are lowest
shortly after consumption of a meal, then rise
during the fast just prior to the next meal. The
figure to the right shows this pattern based on
assays of plasma ghrelin in 10 humans during the
course of a day.

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Disease States Ghrelin concentrations in blood
are reduced in obese humans compared to lean
control subjects, but whether this is cause or
effect is not defined. Patients with anorexia
nervosa have higher than normal plasma ghrelin
levels, which decrease if weight gain occurs.

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Disease States Prader-Willi syndrome is another
disorder relevant to ghrelin science. Affected
patients develop extreme obesity associated with
uncontrollable and voracious appetite. The plasma
ghrelin levels are exceptionally high in
comparison to patients similarly obese due to
other causes. Prader-Willi syndrome is clearly a
complex disease with many defects it may be that
excessive ghrelin production contributes to the
appetite and obesity components.

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Disease States PWS is an uncommon inherited
disorder characterized by mental retardation,
decreased muscle tone, short stature, emotional
lability and an insatiable appetite which can
lead to life-threatening obesity. The syndrome
was first described in 1956 by Drs. Prader,
Labhart, and Willi.

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PWS is caused by the absence of segment 11-13 on
the long arm of the paternally derived chromosome
15. In 70-80 of PWS cases, the region is
missing due to a deletion. Certain genes in this
region are normally suppressed on the maternal
chromosome, so, for normal development to occur,
they must be expressed on the paternal
chromosome. When these paternally derived genes
are absent or disrupted, the PWS phenotype
results.

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When this same segment is missing from the
maternally derived chromosome 15, a completely
different disease, Angelman syndrome, arises.
This pattern of inheritance when expression of
a gene depends on whether it is inherited from
the mother or the father is called genomic
imprinting. The mechanism of imprinting is
uncertain, but, it appears to involve DNA
methylation.

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Genes found in the PWS chromosomal region code
for the small ribonucleoprotein N (SNRPN). SNRPN
is involved in mRNA processing. A mouse model
of PWS has been developed with a large deletion
which includes the SNRPN region and the PWS
'imprinting centre' (IC) and shows a phenotype
similar to infants with PWS. These and other
molecular biology techniques may lead to a better
understanding of PWS and the mechanisms of
genomic imprinting.
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