GI Hormones
11
10
• Introduction to the endocrinology of the GI
tract: neurogenic components, endocrine
components and regulatory mechanisms.
Enteroendocrine cells, hormone families,
hormones of the GI tract and their neuroendocrine control.
• GI hormones: Gastrin / CCK family: gastrin,
CCK; Secretin family: secretin, VIP, GIP, GLP;
PP family: PPY, peptide YY, NPY; Other GI
hormones: neurotensin, galanin, GRP, motilin,
TRH, CGRH, SS, enkephalins, endorphins, SP.
• Neuroendocrine control of food intake
• Pathologies associated with GI hormones
Introduction
GI Hormones and “story lines”
serosa
muscle, longuitudinal layer
myenteric plexus (synapses)
muscle, circular layer
submucosal plexus (synapses)
submucosa
muscularis mucosae
mucosa
lumen
oral
end
aboral
end
GI tract
Page 1
VIP
Introduction
• The GI tract
Stimulus
Brush border
• GI Hormones
Exocytosis
Paracrine
• Leptin and
food Intake
Endocrine
Intrinsic reflex
• Pathologies
Extrinsic reflex
Satiety
S
E
Overview of the GI tract: neurogenic and endocrine
components, and regulatory mechanisms
Stimulus
Brush border
Exocytosis
Paracrine
Endocrine
Intrinsic reflex
Extrinsic reflex
Satiety
Page 2
Introduction
• The GI tract
Integrator ()
ANS
PS
afferent /
efferent
communication
pathways
might be
neurogenic
and / or
endocrine
pathways
S
• GI Hormones
pre
• Leptin and
food Intake
• Pathologies
post
S
Ach
E
Ne
negative feedback
Overview of the GI tract: neurogenic and endocrine
components, and regulatory mechanisms
Introduction
• The GI tract
• GI Hormones
intrinsic
i/o
extrinsic
input /
output
•
•
• Leptin and
food Intake
•
•
•
• Pathologies
•
sensory receptors (mech / chem)
synapsis or neuro-musc-junction
intrinsic exocrine gland of GI syst
S
E
intrinsic vs
extrinsic
inputs vs
outputs
neuronal vs
endocrine
vago - vagal
reflexes
endocrine
reflexes
Neuroendocrine
reflexes
Overview of the GI tract: neurogenic and endocrine
components, and regulatory mechanisms
Page 3
Introduction
• The GI tract
esophagus
funds, HCl, pepsine, mucus
stomach
gastrin
• GI Hormones
antrum, hormone
• Leptin and
food Intake
gastrin, histamine, Ach
gall bladder, bile salts
duodenum
secretin
CCK, GIP
glicentin
motilin
liver, metabolism
• Pathologies
pancreas
enzymes
hormones
S
HCl, pepsine, mucus
gall bladder, bile salts
liver, metabolism
PPY
insulin
glucagon
somatostatin
small
intestine
E
Overview of the GI tract: neurogenic and endocrine
components, and regulatory mechanisms
Introduction
• The GI tract
• GI Hormones
• Leptin and
food Intake
cAMP Ca
S
-
PS
+
agonists
+
antagonists --
Ach
NE
NE
Gastrin
CCK
Ach
(+)
CCK
Gastrin
S
Ach
E
Ach
(-)
Secretin
LES
Ach
CCK
Secretin
Ach
HCl
Secretin
gastric muscle
oxyntic cell
(+)
common
intermediate
Oxyntic cell
NE
Ach
Ach
muscle, gland,
endocrine cell
Ca
Secretin
Ach
NE
• Pathologies
Ach, atropine
Gastrin
Histamine
proglumide
cimetidine
Enteroendocrine
Cells
(-)
Gastrin
pylorus
Ach
CCK
Ca
Ca
cAMP
common
intermediate
Pancreatic
cell
Enz
HCO3
Overview of the GI tract: neurogenic and endocrine
components, and regulatory mechanisms
Page 4
Gastrointestinal Hormones
• The GI tract
• GI Hormones
• Leptin and
food Intake
• Pathologies
S
GI hormones are clustered into families having
similar / overlaping functions
E
Gastrointestinal Hormones
• The GI tract
• GI Hormones
• Leptin and
food Intake
• Pathologies
S
E
Hormones
Physiological effects
Gastrin
Secretin
CCK
GIP
SS
VIP
GRP
Bulbogastrone
Urogastrone
Enteroglucagon
Villikinin
Enkephalins
Neurotensin
Motilin
Histamine
Prostagalndins
GI hormones are clustered into families having
similar / overlaping functions
Page 5
Gastrointestinal Hormones
• The GI tract
• GI Hormones
• Leptin and
food Intake
• Pathologies
S
examples of articles from Time magazine
on the importance of GI hormones
E
Gastrin / CCK family
• The GI tract
• GI Hormones
CCK 33
G34
• Leptin and
food Intake
• Pathologies
S
E
The gastrin / CCK family has a major role in
gastric / duodenal interactions
Page 6
Gastrin / CCK family
• The GI tract
• GI Hormones
• Leptin and
food Intake
• Pathologies
S
The gastrin / CCK family has a major role in
gastric / duodenal interactions
E
Gastrin / CCK family
• The GI tract
• GI Hormones
• Leptin and
food Intake
• Pathologies
S
E
The gastrin / CCK family has a major role in
gastric / duodenal interactions
Page 7
Gastrin / CCK family
• The GI tract
central
stimuli
• GI Hormones
+
vagal nuclei
+
+
Bombesin
• Leptin and
food Intake
• Pathologies
---
+
SS
+
Cephalic
phase
oxyntic
cell
S
Ach
+
G cell
+
HCl
The gastrin / CCK family has a major role in
gastric / duodenal interactions
E
Gastrin / CCK family
• The GI tract
gastric distension
+
• GI Hormones
• Leptin and
food Intake
• Pathologies
S
E
+
+
vago-vagal
reflex +
vago-vagal
reflex
local
+
reflex
+
Ach Bombesin
Gastric
phase
+
+ peptides
and aa
+
oxyntic cell
HCl
G cell
The gastrin / CCK family has a major role in
gastric / duodenal interactions
Page 8
Gastrin / CCK family
•
gastrin, stimulate gastric acid secretion. Its release
from G antral cells (open cells) is induced by aromatic
aa, small peptides, and Ca in the GI tract. SS release
from neighboring D cells in response to acidification is
a major inhibitor of gastrine
•
CCK (5 aa), inhibits gastric emptying, pancreatic
enzyme secretion, gallblader emptying, induced
satiation, and memory enhancement. Its release is
induced by fat and proteins in the GI tract. GRP and
Bombesin also stimulate CCK release. Stimulation of
PKA and PKC pathways result in increase CCK mRNA
the two CCK receptors (A in gut and B in brain) share
48 % homology at the aa level
the oxyntic gastrin receptor is identical to the CCK-B
one and both are coupled to PLC
glucocorticoids transiently stimulate increases in
CCK-A receptor mRNA stability with- out affecting
transcription
• The GI tract
• GI Hormones
• Leptin and
food Intake
•
• Pathologies
•
S
•
The gastrin / CCK family has a major role in
gastric / duodenal interactions
E
Gastrin / CCK family
• The GI tract
• GI Hormones
• Leptin and
food Intake
• Pathologies
S
E
The gastrin / CCK family has a major role in
gastric / duodenal interactions
Page 9
Gastrin / CCK family
• The GI tract
• GI Hormones
• Leptin and
food Intake
• Pathologies
S
The gastrin / CCK family has a major role in
gastric / duodenal interactions
E
Gastrin / CCK family
• The GI tract
• GI Hormones
• Leptin and
food Intake
• Pathologies
S
E
The gastrin / CCK family has a major role in
gastric / duodenal interactions
Page 10
Secretin / VIP family
• The GI tract
Secretin
• GI Hormones
Glucagon
• Leptin and
food Intake
GIP
• Pathologies
VIP
S
The secretin / VIP family also has a major
role in gastric / duodenal interactions
E
Secretin / VIP family
•
• The GI tract
•
• GI Hormones
• Leptin and
food Intake
•
•
• Pathologies
•
•
•
•
S
E
secretin, stimulate pancreatic bicarbonate / enzyme and
hepatic bile secretion, and LES relaxation. Its release is
induced by acid, bile, FA, and peptides GI
VIP, stimulates LES and gastric receptive relaxation,
descending relaxation of intestine, water / electrolyte secretion
from colon, biliary / pancreatic secretion, and promotes
lipolysis. VIP gene expression is regulated by cAMP, PKC, and
Ca. Outside the GI is modulated by E2, cortisol T3/T4, retinoic
acid and IGF I
GIP, stimulates insulin and inhibits acid secretion. Its release
is induced by Glu, Prot, aa, and FA in GI tract
GLP has insulinotropic effects and inhibits gastric motility. Its
release is induced by Glu and aa in GI tract
the VIP / PACAP receptor has homology with secretin, GLP-1,
PTH, GHRH, and calcitonin glycoprotein receptors
VIP-1 receptor is found in gut and VIP-2 receptor in brain. VIP,
cAMP, IP3, PKC, Ca
VIP and NO colocalize in the myenteric plexus of the gut. Both
are inhibitory in GI tract
secretin receptor couples to stimulation of AC, Ca, & PLC
The secretin / VIP family include secretin,
the VIP, GIP and GLP hormones
Page 11
Secretin / VIP family
• The GI tract
VIP
Secretin
• GI Hormones
Glucagon
GIP
• Leptin and
food Intake
• Pathologies
S
VIP
The secretin / VIP family include secretin,
the VIP, GIP and GLP hormones
E
Secretin / VIP family
• The GI tract
• GI Hormones
• Leptin and
food Intake
• Pathologies
S
E
The secretin / VIP family include secretin,
the VIP, GIP and GLP hormones
Page 12
Secretin / VIP family
• The GI tract
• GI Hormones
+
How GLP-1
might work?
• Leptin and
food Intake
_
• Pathologies
S
E
The secretin / VIP family include secretin,
the VIP, GIP and GLP hormones
Secretin / VIP family
Gut Sensations (recent news about GLP-1).
Recent studies have helped to define the proteins that transform the
arrival of sugars on the tongue into a sensation of sweetness. Two studies
suggest that the same pathway functions in the intestinal tract. Jang et al.
found that the sugar-sensitive G protein-coupled receptor (T1R2/T1R3)
and the G protein subunit gustducin could be detected in enteroendocrine
cells--specifically, the L cells, which secrete the appetite-regulating
glucagon-like peptide (GLP-1) of the human duodenum. Application of
glucose to human L cells resulted in GLP-1 release, which was blocked by
an antagonist of T1R3. In mice, gustducin was also present in L cells, and
delivering glucose directly into the duodenums (to bypass the tongue) of
normal mice and of gustducin-deficient mice showed that GLP-1 secretion
was absent in the latter group of animals and that the temporal pattern of
insulin secretion was altered. Margolskee et al. connect glucose
absorption to glucose sensing via the T1R2/T1R3 pathway. Normal mice,
unlike those deficient in gustducin or T1R3, showed an increase in
sodium-glucose cotransporter 1 (SGLT1) mRNA and protein and in
glucose uptake when fed a high-carbohydrate diet or a low-carb diet
containing artificial sweeteners. Proc. Natl. Acad. Sci. U.S.A. 104, 15069; 15075 (2007).
Page 13
Secretin / VIP family
http://www.economist.com/science/displaystory.cfm?story_id=11785235
Hormones influence how sensitive taste buds are to sugar (2008).
That sweetness is pleasant is no coincidence. Sweet food is at a premium in the wild
because the sugars it contains provide valuable calories. But even with sugar there can be too
much of a good thing, so it would be no surprise if the body were able to regulate the perception of
sweetness as its nutritional needs vary. According to two studies presented to the International
Symposium on Olfaction and Taste, held in San Francisco this week, that is exactly what happens.
The studies, one on mice and one on people, have identified two hormones that seem to fine-tune
perception of sweetness, and thus regulate intake of sugar independently of previously known
mechanism of satiation that is located in brain.
The mouse study was done by Steven Munger, a neurobiologist at the University of
Maryland, and his colleagues. They picked a hormone called glucagon-like peptide-1 (GLP-1) that is
made by intestinal cells in response to sugar and fat. This hormone is already known to act in the
pancreas and the brain, where it helps, respectively, to regulate blood-sugar levels and the feeling
of satiation that tells you when to stop eating. Dr Munger, though, found that both GLP-1 and the
receptor molecule that picks it up and thus allows it to act are found in taste buds too.
To investigate GLP-1's role in taste, the team used a strain of mice that were
genetically engineered to lack GLP-1 receptors. They found that such animals are much less
sensitive to sweetness than their un-engineered confr鑽es. Indeed, the mutants were no more
interested in a dilute sugar solution (or, indeed, a solution of artificial sweetener) than they were in
plain water—though they did respond to concentrated solutions of sweetness. The "wild-type"
mice, by contrast, drank significantly more of the sweet solution than they did of the water, even
when the sweet solution was dilute. Moreover, the effect was limited to sweetness. The animals'
responses to the other four fundamentals of taste—bitterness, sourness, saltiness and
"umami" (the flavour of monosodium glutamate)—were unaffected. That suggests, though it does
not yet prove, that there is feedback from the gut to regulate the desirability of eating sweet food.
Secretin / VIP family
http://www.economist.com/science/displaystory.cfm?story_id=11785235
Hormones influence how sensitive taste buds are to sugar (2008).
The human study was done by Yuzo Ninomiya, a neuroscientist at Kyushu University, in
Japan. He and his colleagues looked at leptin, another hormone that is known to regulate
appetite and metabolism. Leptin levels are also known to fluctuate naturally over a 24-hour
period, being lowest in the morning and highest at night, at least in people who eat three
meals a day.
In their experiments, Dr Ninomiya and his colleagues found that their volunteers were more
sensitive to sweetness when their leptin levels were low. As the level of the hormone
increased over the course of a day, the threshold for detecting sweetness rose. And when the
researchers shifted the pattern of leptin production by changing the number of meals their
volunteers ate, the volunteers' sensitivity to sweetness shifted as well, suggesting that it was
the hormone rather than merely the time of day that was causing the effect. As in the case of
the mice, the humans did not show any changes in their sensitivity to other tastes. However,
individuals who had lower leptin levels, and thus more sweet-taste sensitivity before a meal,
experienced sharper increases in blood-sugar levels when they had eaten.
Whether either of these results cast light on the perpetual search for pain-free ways of
cutting calorie-intake in the modern world of abundant sweetness is not yet clear. But they
may, at least, explain why so many people like lashings of sugar on their breakfast cereal.
Page 14
Secretin / VIP family
• The GI tract
• GI Hormones
• Leptin and
food Intake
• Pathologies
S
The secretin / VIP family include secretin,
the VIP, GIP and GLP hormones
E
PP family and others
• The GI tract
NPY
• GI Hormones
• Leptin and
food Intake
PYY
• Pathologies
PP
S
E
The PP family include PPY, peptide YY and
NPY
Page 15
PP family and others
somatostatin
• The GI tract
• GI Hormones
ocreotide
• Leptin and
food Intake
• Pathologies
Somatostatinoma
with typical
electro- dense
granules
lanotride
A duodenal
endocrine tumor
showing dense
immunoreactivity for
somatostatin
S
Others neuropeptides include neurotensin,
galanin, GRP, motilin, TRH, CGRH, SS,
enkaphline, endothelin, substance P
E
PP family and others
• The GI tract
•
•
• GI Hormones
•
• Leptin and
food Intake
•
•
• Pathologies
•
•
•
•
S
•
•
E
PPY, inhibits pancreatic excretion. Its release is induced by fat in the GI
tract
PYY, inhibits acid and pepsine secretion from stomach, water and chloride
from jejunum, slows small intestine transit time, inhibits pancreatic
exocrine secretion and colonic motor activity. Its release is induced by
Prot, FA bile acids and aa in GI tract
NPY, inhibits gastric and small intestinal motility and secretion. Centrally is
a potent enhancer of food intake. It acts through a 7 transmembrane
domain receptor ne-gatively coupled to AC and is associated to Ca
mobilization
At least 5 receptor types (Y1, Y2, Y3, Y4, Y5) have been reported
neurotensin, inhibits gastric / pancreatic secretion, and stimulates colonic
motility. Its release is induced by fat
galanin, inhibits gastric emptying, slows colonic transit time, and increase
food intake in the CNS through a G-protein. Its release is induced by
intestinal distention
GRP, stimulates gastrin release from antrum, contracts LES. Its release is
induced by cholinergic stimulation
motilin, regulates motor complexes, contracts gall bladder, relea
pepsinogen. Its release is induced by acidification of duodenum and
gastric contraction
TRH, release by pancreas / stomach, inhibits gastric acid, amylase, lipase,
mucosal cholesterol synthesis
CGRH, induced vasodilation in respone to glucose
SS, inhibits peptide hormone, fluid / electrolyte secretion
The PP family include PPY, peptide YY and
NPY, others include neurotensin, galanin,
GRP, motilin, TRH, CGRH, SS, enk, end, SP
Page 16
PP family and others
• The GI tract
• GI Hormones
• Leptin and
food Intake
• Pathologies
S
E
Control of GI function by hormones /
metabolites
Leptin and food intake
• The GI tract
• GI Hormones
Leptin
• Leptin and
food Intake
Insulin
NPY
• Pathologies
CCK
S
E
Some hormones involved in the
neuroendocrine control of food intake
Page 17
Leptin and food intake
• The GI tract
No
Leptin
• GI Hormones
• Leptin and
food Intake
No
Leptin-R
• Pathologies
S
E
Leptin, an adipocyte hormone, inhibits
food intake & promote energy expenditure
Leptin and food intake
• The GI tract
• GI Hormones
• Leptin and
food Intake
decrease
energy intake
and
Increase energy
expenditure
• Pathologies
S
E
Leptin, an adipocyte hormone, inhibits
food intake & promote energy expenditure
Page 18
Leptin and food intake
• The GI tract
• GI Hormones
• Leptin and
food Intake
• Pathologies
S
E
Leptin, an adipocyte hormone, inhibits
food intake & promote energy expenditure
Leptin and food intake
• The GI tract
• GI Hormones
• Leptin and
food Intake
• Pathologies
S
E
Some endocrine pathologies involved in
disfunction of the GI system
Page 19
Leptin and food intake
• The GI tract
• GI Hormones
• Leptin and
food Intake
• Pathologies
S
E
Some endocrine pathologies involved in
disfunction of the GI system
Leptin and food intake
• The GI tract
acute diarrhea
bowel resection
• GI Hormones
• Leptin and
food Intake
malabsorption
• Pathologies
celiac disease
S
E
pancreatitis
Some endocrine pathologies involved in
disfunction of the GI system
Page 20