Lecture 17 Flashcards
Homeostasis
Body’s characteristics like temp and glucose level are maintained at their optimum level
Ingestive behavior
eating or drinking
Physiological regulatory mechanisms (3)
System variable - variable controlled by a regulatory mechanism (like temp is controlled by a heating system)
Set point - Optimal value of the system variable in a regulatory mechanism
Correctional mechanism - In regulatory process, the mechanism that is capable of changing the value of a system variable
Physiological regulatory mechanisms (2)
Negative feedback - the effect produced by a correctional mechanism serves to diminish the corrective action
Satiety Mechanism - Brain mechanism that causes cessation of hunger or thirst, produced by adequate and available supplies of nutrients or water
Water negative feedback (6 steps)
1 body loses water therefore body fluid low
2 detectors signal loss of water
3 drinking occurs
4 stomach fills with water, signals brain -> 5a and 5b
5a satiety mechanism inhibits further drinking
5b water is absorbed, body fluid goes back to normal
5a INHIBITS 3
Body fluid compartments
67% pf water is stored as intracellular fluid
26% as extracellular fluid
7% as intravascular fluid (blood plasma)
1% or less - CSF
Thirst occurs when (2 things)
(1) there is not enoigh blood circulating - Volumetric thirst
(2) there is too much salt in the blood (osmometric thirst)
Volumetric thirst basics
Occurs when there is not enough blood circulating
Hypovolemia causes volumetric thirst: this is why people feel thirst after blood loss
Blood flow is monitored by the kidneys. Low blood flow causes renin release. This causes a hormone cascade which activates hypothalamic neurons in the anteroventral tip - the AV3V region where the blood brain barrier is weak
Volumetric thirst cascade
Hypovolemia
Reduced blood flow to kidneys
Renin - converts angiotensin 1 to angiotensin 2
Angiotensin 2 promotes
- Retention of sodium
- Retention of water
- Increase in BP
- Salt appetite
- Drinking
Osmometric thirst and tonicity
Tonicity is the relative concentration of dissolves solutes on either side of a semipermeable membrane. It is used to describe the direction and extent across the membrane of water movement (osmosis)
Isotonic - equal solute concentrations, no net flow of water
Hypotonic solution - solute is less concentrated outside than in so water enters cell
Hypertonic solution - solute is more concentrated outside cell than in so water will leave the cell
Osmoreceptors
Hypertonic solutions cause cell dehydration
Osmoreceptors are neurons that detect changes in cell size which corresponds to the interstitial solute concentration. The membrane potential and release of neurotransmitter from osmoreceptor cells relates to the volume of these cells
Osmometric thirst
Some neurons of the Av3V region of the hypothalamus are osmoreceptors
Ingestion of hypertonic saline activates neurons in the Av3V region and the anterior cingulate cortex
Drinking water immediately quenches activity in the anterior cingulate cortex. So there IS a rapid feedback system.
BUT Av3V neurons mostly remain active if their osmoreceptor proteins remain active
Cold sensors in mouth and sensory fibers in the stomach are part of the rapid feedback system. When these firs the activity in the anterior cingulate cortex drops off.
Insulin/Glucagon and sugar
Pancreases detects blood glucose. When high, releases insulin which causes muscle and liver cells to store glucose as glycogen.
Cells internalize glucose with a transporter that only works with insulin present EXCEPT the brain which has another transporter that always works
This means cells outside the brain can only use glucose when there is excess around (and hence, insulin). Without this, they must use fatty acids.
A drop in blood glucose causes the stopping of insulin release. This means that most cells cannot use glucose. This reserves glucose in the blood for the CNS
Insulin
Homone
1 - glucose to glycogen
2 - entry of glucose and AAs into cells
3 - Transport fat into adipose cells
Glucagon
Hormone
1 - Conversion of liver glycogen into glucose
2 - Conversion of adipose triglycerides into fatty acids
Troiglyceride
Glycerol + 3 fatty acids
The liver can convert glycerol into sugar
Cells outside the brain can turn fatty acids into sugar
Stomach signals
An empty duodenum is communicated to the bran by release of ghrelin
Levels of this increase with hunger and fall with satiation
Exogenous administration of ghrelin increases hunger and food intake
BUT decrease of it does not stop hunger, just decreases big meals and makes small, snack like meals more likley
What starts a meal
Ghrelin released by empty stomach increases eating
Regulated by presence or absence of ghrelin from the stomach
What stops a meal
Short term satiety signals are released after eating and before digestion (NOT swelling of the stomach)
Cholecystokinin (CCK) and PYY are secreted by the duodenum in proportion to calories ingested. They correlate with feelings of fullness but inhibit food intake. They are short lived and mostly influence how long we eat for.
(CCK also regulates gastric motility and cases digestive enzyme release by the gallbladder).
Administration of CCK and PYY does not lead to weight loss. It causes lower meal size but the body reacts with more meals.
Ghrelin, CCK and PYY regulate
MEAL TIME HUNGER
After a meal
The satiety produced by CCK and PYY is anticipatory, your cells have not yet received the nutrients
Not until nutrients are absorbed can they be used as fuel
This stage is signaled by the liver and pancreas as they detect when food has been absorbed into the blood and available to the body
The liver measures glucose and FAs in the blood and signals through the Vegas nerve
The pancreas measures glucose and releases blood insulin which is actively transported across the BBB. The detection of insulin by the hypothalamus reduces hunger
Long term satiety signals (adipose tissue)
If an animal is force-fed it will reduce its food intake when it is allowed to do so
Body weight is regulated in most people over a long term period
Leptin
Secreted by adipocytes
Signals size of peripheral energy store
More fat = more leptin = lower hunger
Exogenous leptin administration drops meal size temporarily in healthy people
Leptin deficiency causes massive obesity, resolved with administration of exogenous leptin
Emergency hunger citrcuits
Glucoprivation
Low glucose available to cells. Detected in brainstem and liver
Can be caused by excess signaling or drugs that inhibit glucose metabolism
Often caused by insulin misuse
Lipoprivation
Low fatty acid level detected in liver and brain
Usually caused by drugs that inhibit FA metabolism but could also be with too little bodyfat
Hypoglycemia
When brain senses it doesn’t have enough glucose:
Drops insulin secreting to keep sugar in blood
Triggers glucose production in the liver
Slows energy expenditure BMR and drops growth
Promotes a sustained feeling of hunger
This can stimulate feeding irrespective of the bodies stores
Excess insulin can trigger hypoglycemia and hunger cos it forces sugar and FAs into cells
Lipoprivation
When the brain senses dangerously low leptin levels it thinks the body has no fat to support homeostasis
Same circuits as low sugar
Hyperglycemia
Disruptions in insulin signaling may cause this
Causes ongoing weight loss and loss of BF
Drop in leptin can initiate intense hunger, even if the person is hyperglycemic
Used to happen to diabetics and killed them before insulin was available 100 years go
Homeostatic regulation of feeding - leptin
Drops food intake, increases BMR by acting on receptors all throughout the brain
In the ARCUATE NUCLEUS OF THE HYPOTHALAMUS, this inhibits AGRP/NPY neurons and activates POMC/alpha-MSH neurons which regulate hunger
Leptin signaling also sensitizes the brain to satiety peptides like CCK and desensitizers it to hunger peptides like ghrelin
Arcuate Nucleus (ARC) of the hypothalamus
ARGP and POMS neurons
AGRP/NPY neurons are orexigenic ( ake hunger)
Inhibited by leptin - excited by ghrelin
POMC/alpha-MSH are anorexigenic. Activated by leptin and inhibited by ghrelin
Activity in these two clusters of cells can have immediate effect on hunger
In addition, their sensitivity to leptin influences how much fat an animal thinks is needed for glucose storage
Brain mechanisms
Arcuate nucleus of the hypothalamus: Very sensitive to leptin
Contains AGRP and NPY neurons and POMC/alpha-MSH neurons involved in feeding and metabolic rate
Paraventricular nucleus (PVN) of the hypothalamus
received input from arcuate nucleus
Contains oxytocin neurons that signal the body had adequate levels of fat
Paraventricular Nucleus PVN of the hypothalamus
Contains oxytocin neurons which signal the body has enough fat and inhibits hunger
Low firing = intense hunger
Excess activity does not prevent feeding triggered by other part of the circuitry hence, this part is thought to play a role in low leptin emergency feeding
Prader Willi Syndrome and the loss of PVN neurons
Rare abnormality, up to 7 genes deleted from chromosome 15
One is critical for oxytocin neurons in the PVN
Born with low muscle mass and have no interest in eating
Later, between 2 and 8 develop painful hunger
Average life expectancy is 30, die sof obesity related causes
People with this disorder have no vomit or full signal, They can eat so much they rupture heir stomach
Modern obesity and leptin
50% of fat variability is due to DNA
Overweight peoples hunger systems seem to act to defend the high levels of fat. Have an elevated leptin point hey are trying to maintain
Leptin resistance
In overweight animals people have observed:
- drop in leptins ability to cross the BBB
- drop in neuronal response to leptin signaling
- drop in downstream consequences of leptin neurons
Many days of cafeterias diet (high fat and sugar) causes inflammation of the arcuate nucleus in rodents. This causes drop in leptin sensitivity
So animals eat more
Hedonistic aspects of Hunger
Motivational and reinforcing aspects of food which fluctuate in accordance with hunger and available food
Hunger increased the rewarding value of food
Satiety drops it
Hypothalamic neurons regulate this by releasing neuropeptides like NOY, orexin, and MCH (melanin-concentrating hormone) all play an important role in regulating hunger, especially the hedonistic aspects
These all influence dopamine neuron activity which regulates motivational processing and reinforcement
Could change reward and cause addiction
Stress induced lack of hunger
Threat, trauma or illness can inhibit hunger, turning off the whole feeding system
Occurs when animals find foreign food. Neophobia, animals eat a tiny bit and wait to see if they get sick
Real or artificially triggered food poisoning includes a lack of hunger
Enhanced activity in the brain regions responsible for detecting food poisoning and stress drip hunger to the point of starvation. They can be abnormally active in wasting diseases like in certain cancers
In general, stress that is strong enough to inhibit homeostatic and emergency hunger systems, feeding will not resume until stress has passed
Obesity Treatment
Roux-en-y gastric bypass (RYGB)
The jejunum is cut and the upper end is attached to the stomach
The digestive enzymes from the duodenum now go up to the upper intestines’ to the meal in the stomach pouch
Rats with this lose weight and show lower levels of ghrelin and increases PYY
Perhaps months of this retrains the brain and drops the hedonistic aspects vs the others
Binge eating responds to serotonin signaling
