Psyc 417 Gastrointestinal Signaling

Questions

What happens to an animal if the food it eats just gets drained away? <details>Non-stop eating</details> How does your GI track influence your feeling of satiety? Where does the signal that tells your body you are full and eaten a meal come from? Where do meal-related gut signals come from? What are enteroendocrine cells? <details>These are cells that detect nutrients and signal tho the Vagus nerve that you have received nutrients</details> What is the autonomic nervous system? <details> It is a word for the parasympathetic, sympathetic, and enteric nervous system </details> What are a bunch of neurons found in the spinal cord called? What are all of the differences between the sympathetic and parasympathetic nervous system: What is CCK? What cells secret it, when is it released in a meal, what does it do? Why has CCK not become an anti-obesity drug? <details>It decreases meal size but increases meal frequency, resulting in unchanged overall chaloric intake</details> What is cNST, and where does it receive information from? <details>the gut</details> What does SDA stand for? What does humoral gut-brain axis mean? <details>Something impact the brain through the blood</details> What does nueral gut-brain axis mean? <details>Something impacts the brain through neurons</details> How does the stomach signal satiety? <details>When the muscles are tensed and stretched then it signals that you are full.</details> How does ghrelin change for different number of meals? What does the dorsal vagal complex consist of? (What regions)? What is the dorsal vagal complex? <details> The DVC is a hub in the medulla of the brainstem that mediates food intake based on signals from the GI tract and the forebrain feeding relays.</details> What is an adiposity signal? How do adiposity signals control weight? How does the biology of using fatty acid for energy work? How does your body control blood-glucose levels? How does glycogen in the muscles change when working out? What is amylin? What does it do? Where does it work in the brain? What does insulin do? What 2 factors contribute to blood glucose levels rising? <details>Food intake and muscle/liver gluconeogenisis. </details> How can you measure satiety? <details> measure gastric empying, hepatic glucose production, and GI motility.</details>

Notes

There is a device to drain stomach contents in humans!

There was an experiment where two rats (one that was starved and the other that was fed freely) exchanged blood before a meal and the food intake of the starved rat decreased by 50%. This shows that there is something in the blood that signals satiety.

Meal-related gut stimuli come from sensors in the gut that detect if there are macronutrients. They are from gut enteroendocrine cells, which have nutrient recepts such as sodium-glucose cotransporter 1 and free fatty acid receptor 1 and GDPRs

The other is the stretch of your stomach and intestines.

The vagus nerve innervates the gastrointestinal tract. That is how they detect the digestion of absorption of nutrients.

The enteric nervous system is responsible for digestion and absorption of food.

Vagal primary afferent neurons are in close proximity to the entrendocrine cells.

Sympathetic and Parasympathetic

The sympathetic and parasympathetic are systems that are not under your control.

Sympathetic The cell bodies of sympathetic neurons found in the spinal cord, called ganglia (ganglion) The sympathetic nervous system is innervated in many parts of the spinal cord. It is the cause of the fight or flight response, one way it does this is by the sympathetic nervous system releasing glucose. It also is involved in thermogenesis. Inhibits digestion.

Parasympathetic The para-sympathic system has neurons that are found in the cranial nerve, (tippy top of spinal cord). It makes the body more peaceful. Parasympathetic tries to keep blood glucose levels calm and leveled. Parasympathetic system also is responsible for resting and digesting. Also is involved in excreting body waste.

Gut satiation peptides

All gastric peptides that signal satiety must reduce gastric emptying, modulate intestinal motility, and reduce hepatic glucose production. Most common peptides include: CCK, GIP, GLP-1, PPY

Cholecystokinin (CCK) CCK is secreted from I cells within the duodenal and jejunal mucose and acts through CCK receptors which are GPCR, on the vagal afferents. It peaks within 5 minutes of a meal. Fat is a potent secretor. It also reduces hepatic glucose production (makes it so liver stops producing glucose), this signals meal termination. CCK also decreases the intake of liquid and solid food but not water.

CCK causes CTA, which might explain why it decreases food intake.

CCK is a paracrine. It acts via the afferenting abdominal vagus nerve, not the efferenting vagus nerve.

Gastric inhibitory polypeptide (GIP) - It is an incretin

Glucagon-like peptide 1 (GLP-1) GLP1 Gets released from the small intestine, it flows through the blood and eventually goes to Beta cells in the pancreas which causes them to secrete insulin. GLP-1 is also produced by a population of neurons in the cordal nuclus of the solidary track, this is different than the one where taste goes. GLP-1 receptors are expressed everywhere. It is slowly secreted following a meal and secretion can persist for several hours. It peaks 1.5 hours after a meal.

There are multiple forms of GLP-1, the full-length version is inactive, but hte truncated form is biologically active. GLP-1 is an incretin (stimulates insulin release). It is degraded by DDPIV minutes after it is injected, so normal GLP-1 cannot be injected and have a large effect.

Exendin-4 is a compound that was founded in the venom of a gila-monster and it is very similar to GLP-1, but resistant to DDPIV, so it can be used to manage type-2 diabetes.

After a year of being on exendide patients decreases their HbA1c by 1.3%!

Peptide YY (PYY)

Where they are released:

Duodenum (CCK)
Jejunum (CCK & GIP)
Ileum¹ (GLP-1 & PYY)

Exendin-4 increases pica rates in rodents.s An interesting fact is that when animals eat toxins, they will start eating dirt to try to cure themselves.

When SDA is performed, the effect of GLP-1 is attenuated. This shows that GLP-1 can directly affect the brain.

The active ingredient in GLP-1 is semaglutide where 0.25-0.5mg is injected once weekly to treat type 2 diabetes.

Another drug is Wegovy, which is where 2.4 mg is injected once weekly for weight management in adults.

Another drug is mounjaro which activates both GLP-1 and GIP receptors. This effect is synergistic.

Macronutrients cause the most satiety, micronutrients do not impact satiation.

Mechanosensory Signals

The gastric and hepatic vagal nerves afferate the stomach muscle and they response to stretch and tension.

Gastric satiation is volumetric and intestinal satiation is nutritive.

Maestro Rechargeable System is a device that tries to make people feel full by stimulating the vagus nerve.

Gut Hunger Peptide

Ghrelin is the main gut hunger peptide and it is produced within the oxyntic gland of the stomach,. Glucagon, dopamine, and cannabinoids can stimulate its release, while CCK-8, GLP-1, and insulin can inhibit its release. Ghrelin acts through the growth hormone secretagogue receptor (GHSR), and only when it is acylated. Ghrelin levels rise differently in different people, some release it before a meal (preprandial rise) and some people after they eat (postprandial fall).

Hunger peptides stimulates gastric motility and acid secretion.

Injecting ghrelin exogenously will increase the number of meals the person eats.

Vagal deafferation has no effect on peripheral exogenous ghrelin eating stimulation. Ghrelin interacts with the vagus nerve. SDA eliminates caloric deprivation-stimulated ghrelin release. Ghrelin impacts the brain through the humoral gut-brain axis.

Prader-Willi syndrome

This is a syndrome where a person has insatiable hunger. Caused by missing genes chromosome 15. Prader-Willi syndrome causes problems with spine problems and chronic hunger. Extreme anxiety, osteoporosis.

Infants born with this have low muscle tone, they don't move, and they don't feed very well. They don't grow as fast as other kids. Insatiable hunger and extreme obesity. It is caused by impaired hypothalamus development.

People with Prader-Willi syndrome have EXTREME plasma ghrelin levels. However, reducing ghrelin level does not alleviate hyperphagia (insatiable hunger).

Gut-Brain control of meals

Humoral Gut-brain axis: When peptides are released direclty into the blood supply and these factors pass the blood-brain-barriar and affect the brain. Neural Gut-Brain axis: Afferent signals elicided by gut contact with nutrients from the GI tract to the CNS, affect the brainstem dorsal vagal complex. The caudal nucleus of the solitary tract (cNST) is where the vagal nerve ends. The dorsal motor nucleus of the vaugs control the movement of your intestines.

The vagus nerve contributes to controlling our emotions, being hungry makes you have more negative emotions. Vagal nerve stimulation can be used to treat depression and prevention of seizures!

Adiposity Signals

These are hormones secreted in proportion to body fat (insulin, amylin, and leptin). Does not correspond to blood volume. These work through humoral gut-brain axis. They help control weight by promoting the efficacy of meal-generated satiation signals?

Energy Metabolism after eating

Glucose in the food you eat immediately go to the brain and rest of the body for them to use. Muscles will also use the amino acids for protein synthesis.

If you eat too much glucose, then it will be stored in the liver as a short-term resivoir, liver only can hold ~120 kCal. This is in the form of glucagen.

All excess energy is stored in the adipose tissue as triglycerides.

Glucagon convers glycogen into glucose (primarily for the brain).

When you need to use your triglycerides for energy then it gets turned into fatty acids and glycerol (glycerol gets turned into glucose). Your body uses fatty acids.

The brain doesn't only use glucose! It can use fatty acids.

Control of blood-glucose

To increase blood glucose levels (when fasted), you convert glucose from the glycogen in the liver.

Insulin promotes flucose uptake in the muscles, but inhibits gluconeogensis and lipolysis.

Glugacon promotes gluconeogenesis in the liver.

Alpaa cells in the pancreas secrete glycagon. Amylin and insluin are secreted by the beta cells in the pancreas. Glucagon is also secreted in the intestines.

Amylin binds to the calcitonin receptor. Amylin is a hormone. It works in the area postream.

The area postrema is an area of the brain where the blood-brain barrier doesn't really exist. Amylin inhibits gastric emptying and gastric acid secretion, it lowers glucagon concentrations and reduces food intake. There is a synthetic analog of pramlintide for diabetics.