Gastrointestinal Peptides

Question 1

What is the role of the gut-brain axis?

Answer 1

• Provides sensory feedback to the CNS on: presence or absence of foods, quantity of nutrients ingested, type of nutrients ingested
• Involved in: regulation of GI secretions, regulating meal termination (satiation), inhibition of the next meal (satiety), promotion of food consumption (meal initiation)

Question 2

Explain how the gut-brain axis functions.

Answer 2

• Neural communication via activation of vagal afferents (lamina propria)
• Monitor presence/absence of nutrients
• Trigger appropriate behavioral changes
• Gastric, pancreatic secretion
• Gastric emptying
• Regulation of food intake

Question 3

How is the presence or absence of nutrients monitored?

Answer 3

• Enteroendocrine cells (EECS): release peptides in response to chemical or mechanical stimuli
• Neuromodulatory lipids: endocannabinoids
• Specific afferents respond to stretch and tension

Question 4

Explain signal production in the GI tract (orexigenic/ anorexigenic/ satiety).

Answer 4

1. Anorexigenic and orexigenic signals are secreted all along the GI tract
2. Stomach, proximal, and distal intestine can all produce satiety signals (signal causes the sensation of fullness -> decrease in meal size and impairing its activity results in an increase in food intake; it does not lead to an illness or malaise but is associated with a normal behavior and it is stimulated by ingested food with a temporal profile)
3. Stomach and proximal intestinal can produce orexigenic signals

Question 5

Explain anorexigenic signals in the stomach.

Answer 5

• Gastric leptin: accounts for 25% of circulating leptin
• Activates Ob-R (leptin receptor) on vagal afferents
• Can act centrally (hypothalamus)

Question 6

Explain orexigenic signals in the stomach.

Answer 6

• Ghrelin: produced in the absence of food (hunger) by A/X like cells in the fundus of the stomach
• Circulating ghrelin increases with fastin and peaks before a meal
• Acts via activation of the growth hormone secretagogue receptor (GHS-R) on vagal afferents

Question 7

Explain anorexigenic signals in the proximal small intestine (duodenum and jejunum).

Answer 7

• Cholecystokinin (CCK): released by I cells in the upper GI in the presence of fatty acids and proteins
• Delays gastric emptying, stimulate gastric and pancreatic secretions
• Reduces food intake
• Acts via activation of CCK1R on vagal afferents

Question 8

Explain anorexigenic signals in the distal GI tract.

Answer 8

• Glucagon like peptide 1 (GLP-1): released from L cells in the distal gut in response to nutrients, neuro-hormonal stimulation from the proximal gut (especially carbs, long-chain unsaturated fatty acids)
• Derived from proglucagon, degraded rapidly by dipeptidyl peptidase-4 (DPP-IV)
• Plasma levels increase within a few minutes after a meal and remain high for more than two hours
• Acts as an incretin (helps insulin function or be secreted), delays gastric emptying, and reduced food intake
• Acts via activation of GLP-1R on vagal afferents
• Major component of the ileal brake

Question 9

Ileal Brake

Answer 9

Negative feedback loop aimed at regulating nutrient transit and promoting satiety (everything slows)

Question 10

Peptide Tyrosine-Tyrosine (PYY)

Answer 10

• Major component of the ileal brake
• Localized in ileum and colon
• Secreted by L cells
• Degraded by DPP-IV
• Release stimulated by nutrients (proteins)
• Decreases food intake and gastric emptying
• High affinity for presynaptic inhibitory Y2 receptor, Y2R
• Stimulates vagal afferent firing

Question 11

Leptin

Answer 11

• Stomach
• Stimulated by presence of food
• Secreted from chief cells
• Receptor: Ob-r
• Decreases intake

Question 12

Ghrelin

Answer 12

• Stomach
• Stimulated by an empty stomach
• Secreted from A/X like in oxyntic glands
• Receptor: GHS-R
• Increases intake

Question 13

CCK

Answer 13

• Duodenum and jejunum
• Stimulated by lipids and proteins
• Secreted by I cells
• Receptor: CCKR1
• Decreases intake

Question 14

GLP-1

Answer 14

• Ileum and colon
• Stimulated by lipids and proteins
• Secreted by L cells
• Receptor: Y2-R
• Decreases intake

Question 15

Nucleus of the solitary tract (NTS)

Answer 15

• Signals from GI to vagus nerve to brainstem (NTS)
• POMC, Catecholamine neurons, TH neurons, and GLP-1 neurons activated in NTS

Question 16

POMC (pro-opiomelanocortin) neurons

Answer 16

• Anorexigenic neurons
• Activated in NTS
• Precursor polypeptide
• Cleaved into different peptides including alpha-melanocyte-stimulating hormones (alpha-MSH)
• Binds to MC4R (Melanocortin 4-receptor)
• To induce meal termination
• Isolated brainstem can induce meal termination

Question 17

Catecholamine neurons or TH neurons

Answer 17

• Tyrosine hydroxylase
• Catalyze the conversion of L-Tyrosine to L-3,4- dihydroxyphenylalanine (L-DOPA)
• Rate limiting step in catecholamine synthesis
• Dopamine, noradrenaline, adrenaline
• Neurons activated in NTS
• Project to hypothalamus

Question 18

GLP-1 Neurons

Answer 18

• Activated in NTS
• Recruited when consuming large meals
• Interact with gastric satiation signaling
• Interact with reward pathways

Question 19

What happens to the food we eat?

Answer 19

• Food in the GI tract is outside the body
• Taking food into the mouth does not assure admission to the body
• Food has to undergo digestion, absorption, and transport to be absorbed in the body (GI tract)

Question 20

What is the organization and function of the GI tract?

Answer 20

1. Organization: series of organs from mouth to anus, accessory organs (not part of the GI tract, but involved in digestion processes)
   - Ex: salivary glands, liver, pancreas, gallbladder
2. Functions: ingestion, transport, propulsion, and mixing of GI contents, secretion of digestive juices, digestion, absorption, elimination

Question 21

Explain the components and steps of the digestive process.

Answer 21

1. Consumption of food mastication
2. Salivary secretion (stimulated by the nervous system)
3. Voluntary swallowing of food (somatic)
4. Involuntary peristaltic muscular contraction
5. Digestion in stomach (endocrine signals start here)
6. Secretion of gastric juices (HCl and pepsin) as a consequence of neural, mechanical, and hormonal (gastrin) stimuli
7. Involuntary mechanical contractions

Question 22

What are the two types of processes that make up digestion in the stomach?

Answer 22

1. Mechanical (3 muscle layers): longitudinal, circular, diagonal; stomach muscles grind food together to make chyme
2. Enzymatic: pepsin (chief cells)

Question 23

How does gastric acid help digestion?

Answer 23

1. Parietal cells release gastric acid (decreased pH for pepsin function)
2. Gastrin release by G-cells stimulates gastric acid secretion
3. Histamine released by enterochromaffin-like cells stimulates gastric acid secretion
4. Somatostatin released by D cells inhibits gastric acid secretion

Question 24

What forms of signaling do gastric hormones use?

Answer 24

Paracrine and endocrine

Question 25

What are the seven substances being secreted in the stomach?

Answer 25

1. Pepsin: protein digestion (enzyme) 2. Gastrin: hormone that stimulates stomach to release gastric acid 3. Histamine: hormone that stimulates gastric acid secretions 4. Somatostatin: hormone that inhibits gastric acid secretion 5. Gastric (hydrochloric acid): unravels proteins, kills bacteria, activates pepsin, helps absorption of iron, calcium 6. Mucus: secreted by goblet cells, protects stomach, moistens food, prevent autodigestion 7. Intrinsic factor: protein needed for vitamin B12 absorption

Question 26

The Small Intestine

Answer 26

- Major site of digestion and absorption - Digestion of carbs, fats, proteins - Vitamins and minerals do not need digestion - Nutrients are absorbed into either capillaries (blood) or lacteals (lymph) - About 20 feet long - Duodenum, jejunum, and ileum

Question 27

What are the secretions of the small intestine?

Answer 27

1. Mucus (goblet cells) 2. Digestive enzymes (finish digestion of carbs, fats, and proteins) 3. Hormones: GIP, secretin, CCK, motilin

Question 28

What are the secretions into the small intestine?

Answer 28

1. Pancreatic secretions: sodium bicarbonate (neutralizes acidic chyme) and Digestive enzymes (digestion of carbs, fats, and proteins) 2. Liver and gallbladder (bile): liver makes bile and gallbladder concentrates and stores it

Question 29

What are the hormones of the small intestines?

Answer 29

1. Gastric inhibitory peptide: produced when chyme enters SI (slows gastric secretion, slows GI motility, incretin) 2. Secretin: produced when chyme enters SI with pH < 4.5 (stimulates pancreatic secretions (sodium bicarbonate)); acts via GPCR found on pancreatic acinar cells 3. Motilin: produced when chyme enters the SI (triggers muscle contractions in the SI, gallbladder emptying, increased insulin release) 4. CCK: produced when fat/proteins enter SI (stimulates gallbladder to release bile and pancreatic secretions (enzymes), slows GI motility, reduces food intake)