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GI Hormones

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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

VIP

Introduction
GI Hormones and story lines
serosa muscle, longu itudinal layer myenteric plexus (synapses) muscle, circular layer submucosal plexus (synapses) submucosa muscularis mucosae mucosa

lumen

oral end
GI tract

aboral end

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Introduction
The GI tract GI Hormones Leptin and food Intake Pathologies
S E
Stimulus Brush border Exocytosis Paracrine Endocrine Intrinsic reflex Extrinsic reflex Satiety

Overview of the GI tract: neurogenic and endocrine components, and regulatory mechanisms

Stimulus Brush border Exocytosis Paracrine Endocrine Intrinsic reflex Extrinsic reflex Satiety

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Introduction
The GI tract
PS ANS S pre

Integrator () afferent / efferent communication pathways might be neurogenic and / or endocrine pathways negative feedback

GI Hormones Leptin and food Intake Pathologies


post

S E

Ach

Ne

Overview of the GI tract: neurogenic and endocrine components, and regulatory mechanisms

Introduction
The GI tract GI Hormones Leptin and food Intake Pathologies
S E
sensory receptors (mech / chem) synapsis or neuro-musc-junction intrinsic exocrine gland of GI syst extrinsic input / output
intrinsic i/o

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

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Introduction
The GI tract GI Hormones
antrum, hormone

funds, HCl, pepsine, mucus

esophagus

HCl, pepsine, mucus

stomach gastrin

gastrin, histamine, Ach


gall bladder, bile salts liver, metabolism

Leptin and food Intake Pathologies


S E

gall bladder, bile salts


liver, metabolism

pancreas enzymes hormones

duodenum secretin CCK, GIP glicentin motilin

small intestine

PPY insulin glucagon somatostatin

Overview of the GI tract: neurogenic and endocrine components, and regulatory mechanisms

Introduction
The GI tract GI Hormones Leptin and food Intake Pathologies
S E
PS +

Enteroendocrine Cells
S agonists +
Ach

Ach, atropine Gastrin Histamine proglumide cimetidine

cAMP Ca antagonists -NE common intermediate Oxyntic cell

Ca

NE

Ach NE Ach muscle, gland, endocrine cell


(+) CCK Gastrin
Ach

Gastrin CCK

Secretin
Ach
NE

HCl

Secretin

Ach

CCK Ca

Ach

Ca

gastric muscle oxyntic cell


(+) CCK Secretin

cAMP common intermediate Pancreatic cell

(-)

Ach

(-)

Ach

Secretin LES

Gastrin
pylorus

Ach

Enz HCO3

Overview of the GI tract: neurogenic and endocrine components, and regulatory mechanisms

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Gastrointestinal Hormones
The GI tract GI Hormones Leptin and food Intake Pathologies
S E GI hormones are clustered into families having similar / overlaping functions

Gastrointestinal Hormones
The GI tract GI Hormones Leptin and food Intake Pathologies
S E Hormones
Gastrin Secretin CCK GIP SS VIP GRP Bulbogastrone Urogastrone Enteroglucagon Villikinin Enkephalins Neurotensin Motilin Histamine Prostagalndins

Physiological effects

GI hormones are clustered into families having similar / overlaping functions

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Gastrointestinal Hormones
The GI tract GI Hormones Leptin and food Intake Pathologies
S E examples of articles from Time magazine on the importance of GI hormones

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 CCK 33

G34

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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

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

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Gastrin / CCK family


The GI tract GI Hormones Leptin and food Intake Pathologies
S E

central stimuli

+ + +

vagal nuclei

+ --+
SS

+
Ach

Bombesin

G cell Cephalic phase

oxyntic cell

HCl

The gastrin / CCK family has a major role in gastric / duodenal interactions

Gastrin / CCK family


The GI tract GI Hormones Leptin and food Intake Pathologies
S E

gastric distension

+
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

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Gastrin / CCK family


The GI tract GI Hormones Leptin and food Intake


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

Pathologies
S E

The gastrin / CCK family has a major role in gastric / duodenal interactions

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

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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

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

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Secretin / VIP family


The GI tract GI Hormones
Glucagon Secretin

Leptin and food Intake


GIP

Pathologies
S E
VIP

The secretin / VIP family also has a major role in gastric / duodenal interactions

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

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Secretin / VIP family


The GI tract GI Hormones Leptin and food Intake Pathologies
S E
VIP Secretin Glucagon GIP

VIP The secretin / VIP family include secretin, the VIP, GIP and GLP hormones

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

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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 _ How GLP-1 might work?

Secretin / VIP family


Gut Sensations (recent news about GLP-1). Recent studies have helped to dene 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--specically, 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-decient 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 decient 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 articial sweeteners. Proc. Natl. Acad. Sci. U.S.A. 104, 15069; 15075 (2007).

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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 confres. Indeed, the mutants were no more interested in a dilute sugar solution (or, indeed, a solution of artificial sweetener) than they were in plain waterthough 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 tastebitterness, 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.

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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

PP family and others


The GI tract GI Hormones Leptin and food Intake Pathologies
S E PP The PP family include PPY, peptide YY and NPY NPY

PYY

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PP family and others


somatostatin

The GI tract GI Hormones


ocreotide

Leptin and food Intake Pathologies


S E
lanotride
Somatostatinoma with typical electro- dense granules A duodenal endocrine tumor showing dense immunoreactivity for somatostatin

Others neuropeptides include neurotensin, galanin, GRP, motilin, TRH, CGRH, SS, enkaphline, endothelin, substance P

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

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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 and food Intake Pathologies
S E Some hormones involved in the neuroendocrine control of food intake

Leptin Insulin NPY CCK

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Leptin and food intake


The GI tract
No Leptin

GI Hormones Leptin and food Intake Pathologies


S E Leptin, an adipocyte hormone, inhibits food intake & promote energy expenditure
No Leptin-R

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
decrease energy intake and Increase energy expenditure

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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

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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 GI Hormones Leptin and food Intake Pathologies

celiac disease pancreatitis

acute diarrhea

bowel resection

malabsorption

Some endocrine pathologies involved in disfunction of the GI system

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