1b// Appetite Flashcards
What was being overweight associated with before?
high-income countries, now also prevalent in low and middle income countries
What are the 3 main triggers of thirst?
body fluid osmolarity
blood volume is reduced
blood pressure is reduced
Which is the most potent stimulus for the trigger of thirst?
Plasma osmolarity increase is the more potent stimulus- change of 2-3% induces desire to drink
Decrease of 10-15% in blood volume or arterial pressure is required to produce the same response
Where is ADH stores?
anti diuretic hormone is stored in posterior pituitary
What is the other name for ADH?
vasopressin
What does ADH act on?
on kidneys to regulate the volume and osmolarity of urine
- collecting duct=> aquaporin 2 channel
What happens when plasma ADH is low/ high?
low= lots of urine (aka water diuresis)
high= little pee (anti diuresis)
How and where does the body measure osmolality?
osmoreceptors
osmolarity vs osmolality?
Osmolarity is the number of osmoles of solute per liter solution, which is different than osmolality, which is the osmoles of solute per kilogram of solution
What secretes ADH, and what is special about them?
neurones in hypothalamus
- Antidiuretic hormone is made by the hypothalamus and is secreted into the blood by the pituitary gland.
these neurones express osmoreceptors that are exquisitely sensitive to blood osmolarity (respond to very small change)
Where are osmoreceptors located?
in the hypothalamus
in the organum vasculosum of the lamina terminalis
in the subfornical organ
What are osmoreceptors?
sensory receptors for osmoregulation
found in the hypothalamus
How are osmoreceptors triggered to release ADH?
cells shrink when plasma more concentrated=>
proportion of cation channels increases- membrane depolarises=>
send signals to the ADH producing cells to increase ADH=>
Fluid retention invokes drinking
(and vice versa)
How is ADH release regulated in these neurones?
- Under resting conditions, only a small proportion of the cation channels are active
- Hypertonic stimulation leads to cell shrinking and increases the proportion of active cation channels
- the resulting increase in positive charge influx depolarizes the membrane and increases neuronal action potential firing frequency
- under hypotonic conditions, the channels are inhibited and the loss of cation influx causes hyperpolarization and inhibits firing
How is thirst decreased?
decreased by drinking even before sufficient water has been absorbed by the GI tract to correct plasma osmolarity
receptors in mouth, pharynx, oesophagus are involved
relief of thirst sensation via these receptors are short lived
thirst is only completely satisfied once plasma osmolality has decreased or blood volume or arterial pressure corrected
What is thirst?
sensation that is best described as the desire to drink
Why is the reason for drinking not always a physiological need?
sometimes prompted by habit, ritual cravings (for alcohol, caffeine or other drugs)
and even a desire to consume a fluid that will give a warming or cooling sensation
Where is there a delay in absorption of water?
delay in absorption of water in the GI tract and correction of plasma osmolality
Why is it important that there are mechanisms in place to avoid excessive fluid intake?
important as although the kidney can deal with fluid overload=> there is a wastage of energy and interference of nutrient absorption (sodium drive)
What system controls blood pressure/ volume?
the renin-angiotensin-aldosterone system
Describe the enin-angiotensin-aldosterone system.
Renin is an aspartic protease protein & enzyme secreted by the kidneys…
- Renin activates the renin-angiotensin system by cleaving angiotensinogen, produced by the liver to yield angiotensin.
- When renal blood flow is reduced, juxtaglomerular cells in the kidneys convert the precursor prorenin into renin and secrete it directly into the circulation.
Angiotensinogen is a precursor protein produced in the liver and cleaved by renin to form angiotensin I.
Angiotensin-converting enzyme (ACE) produced in the lung, etc. cleaves two amino acids from angiotensin I to produce angiotensin ll approx. 30-60 minutes after the drop in blood pressure
Angiotensin Il is the major bioactive product of the renin-angiotensin system, binding to receptors on intraglomerular mesangial cells, causing these cells to contract along with the blood vessels surrounding them and causing the release of aldosterone.
Aldosterone is a mineralocorticoid released from the zona glomerulosa in the adrenal cortex.
Aldosterone has a major role in sodium conservation.
- It influences the reabsorption of sodium and excretion of potassium indirectly influencing water retention.
How is body mass regulated?
physiologically
humans regulate body mass in a way that changes in adipose tissue activate responses that favour the return to their previous weight
Describe body weight homeostasis.
Weight was stable for a long time despite no conscious effort to balance intake and expenditure
Most individual adults maintain a relatively stable weight over long periods
A reduction in fat mass increases food intake and reduces energy expenditure
Adipose tissue expansion reduces food intake and increases energy expenditure
What happens during weight augmented overfed state?
Increased sympathetic NS activity
Increased E expenditure
Decreased food intake/ hunger
Weight loss
What happens during weight reduced underfed state?
decreased sympathetic NS activity
Decreased E expenditure
Increased hunger/ food intake
Decreased thyroid function
Increased weight gain
Are there studies for the body’s mechanisms against weight gain/ loss?
yes for anti body reduction
yet to be discovered for anti weight gain
What part of the brain is critical in the regulation of food intake?
the hypothalamus is critical in the regulation of food intake
- contains neural circuits which produce a number of peptides that influence food intake
Describe appetite regulation.
What are appetite supressants called?
anorectic
What are appetite stimulants called?
orexigenic
What is the arcuate nucleus?
arcuate nucleus of the hypothalamus is an aggregation of neurons in the mediobasal hypothalamus adjacent to 3rd ventricle
brain area involved in the regulation of food intake
the most important site in the hypothalamic integration of energy balance
What does the arcuate nucleus do?
produces both appetite increasing (orexigenic) and appetite suppressant (anorectic) peptides
- one of the terminal fields of these orexigenic and anorexigenic neurones is the paraventricular nucleus
What is the PVN?
paraventricular nucleus of the hypothalamus lays adjacent to the 3rd ventricle
What is in the PVN?
contains neurones that project to the posterior pituitary
these projecting neurones secrete oxytocin and vasopressin affecting osmoregulation, appetite and stress reaction of the body
What does the lateral hypothalamus produce?
orexigenic peptides
What is the VMH and what is it associated with?
ventromedial hypothalamus which is associated with satiety
What do lesions of the VMH lead to?
obesity
there is a debate to what extent this is true
What in the VMH is suggested to regulate feeding behaviour?
melanocortins in the VMH
e.g., food intake decreases when arcuate nucleus pro-opiomelanocortin (POMC) neurons activate VMH brain-derived neurotrophic factor neurons
What structural adaptation of arcuate nucleus benefits it and why?
incomplete blood brain barrier, allows access to peripheral hormones
What feeding signals does the arcuate nucleus consider?
peripheral and central
What are the neuronal populations in the arcuate nucleus?
Stimulatory (NPY/ AGRP neuron)
Inhibitory (POMC neuron)
What are the stimultory NPY and AGRP neurons?
neuropeptide y= NPY
agouti-related peptide= AGRP
made by the NPY and AGRP neurons
What is the most important neuron of the inhibitory pathway?
pro-opiomelanocortin (POMC) neuron
Where is stimulating NPY and AGRP neuron found?
only in the hypothalamic arcuate nucleus
How do NPY and AGRP work?
NPY=> stimulating food intake by increasing neuropeptide Y signalling
AGRP=> reducing melanocortin signalling via the release of agouti-related peptide, an endogenous melanocortin receptor antagonist
What do the NPY and AGRP neurons also express and how are they activated? Furthermore what conditions cause certain food behaviours due to this mechanism?
also express receptors for leptin and insulin–> they’re activated by a decrease of leptin or insulin signalling
fasting, uncontrolled diabetes and genetic leptin deficiency
- food intake increases via this mechanism
What else are neurons in ARC responsible for?
integrating info and providing inputs to other nuclei in the hypothalamus
What is the most important nuclei in ARC?
the PVN (paraventricular nucleus)
What does POMC do to feeding?
decreases
What does NPY do to feeding?
increases
What does the function of the arcuate nucleus rely on?
on its diversity of neurons and its central role in homeostasis
What else, other than feeding, is the arcuate nucleus involved in?
fertility and CVD regulation
How does the melanocortin system work?
decreases food intake
alpha-MSH=> melanocyte stimulating hormone
What is the central melanocortin system?
a collection of the previously discussed CNS circuits such as:
- neuropeptide Y and agouti gene-related protein
- pro-opiomelanocortin
What are melanocortins?
products of the POMC gene
- a classic example is a-MSH
Why is the central melanocortin system important?
central regulator of E balance, involved in both feeding behaviour and E expenditure
How does a-MSH lead to decreased weight?
melanocortin-4 receptors (MC4R) expressed in PVN
- a-MSH stimulates MC4R and leads to reduction of appetite and weight
- ARGP inhibits
What are human CNS mutations affecting appetite?
No NPY or Agrp mutations associated with appetite in humans.
POMC deficiency and MC4-R mutations cause morbid obesity.
*Mutations not responsible for the prevalence of obesity - but useful to explain signalling.
What are signals for feeding from other brain regions? (3)
Higher centres
- Amygdala - emotion, memory.
Other parts of the hypothalamus, e.g. lateral hypothalamus
Vagus to brain stem to hypothalamus.
How does the amygdala play a role in appetite?
important role in controlling reward-related motivation pathways affecting appetite
What does the lateral hypothalamus do related to appetite?
produced appetite stimulant peptides
What is the ventromedial hypothalamus associated to in appetite?
ventromedial hypothalamus is associated with satiety
How is neuronal information from the digestive tract carried?
to the brainstem via the vagus nerve
What is brainstem linked to, and what is that linked to?
linked to the hypothalamus, which is linked to amygdala
What is the adipostat mechanism and what does it consist of?
keeps an individual’s fat mass within range despite changes in diet and activity
consists of 2 neuronal pathways in the hypothalamus
How does the adipostat mechanism work?
Circulating hormone produced by fat
Hypothalamus senses the concentration of hormone.
Hypothalamus then alters neuropeptides to increase or decrease food intake
Does the story of this mouse make sense?
leptin is missing in the ob/ ob mouse
What makes leptin?
Made by adipocytes in white adipose tissue & enterocytes in the small intestine
Where does leptin circulate?
in plasma
Where does leptin act?
Acts on the hypothalamus regulating appetite (intake) and thermogenesis (expenditure).
act on cell receptors in the arcuate and ventromedial nuclei in the hypothalamus
- consequently mediating feeding and thermogenesis
When is leptin high/ low?
low when low body fat
high when high body fat
What does leptin do (basic)?
hormone that decreases food intake, and increases thermogenesis
it helps with energy balance by inhibiting hunger
What is the primary function of leptin? And what are extra roles of leptin?
regulation of adipose tissue mass
- also plays a role in the development of atherosclerosis through the innate immune system
- low levels discovered in alzheimer’s disease and depression
- also facilitates surfactant production in the foetus
What is congenital leptin deficiency?
a condition that causes severe obesity
in these children leptin has been effective in reducing body weight
only few people known to have this defect
subjects carrying the mutations are of normal weight at birth, but they are constantly hungry and quickly gain weight
they had high body fat, but low serum leptin
When does leptin increase?
as body fat increases
What does leptin correlate with? And what does this mean?
serum leptin concs correlated with the % body fat
-> suggesting that most obese people are insensitive to endogenous leptin production
-> their leptin is high (in obese people)
What are the 3 mechanisms of leptin issues?
- insufficient production (aka low leptin)
- defective leptin receptor signalling- reduced/ normal leptin level despite high adipose tissue mass
- decreased sensitivity to leptin, resulting in an inability to detect satiety despite high energy stores and high levels
What is the mechanism of leptin?
Describe leptin resistance.
Leptin circulates in plasma in concentrations proportional to fat mass
Overweight humans have ↑leptin
Obesity due to leptin resistance - hormone is present but
doesn’t signal effectively
Leptin is ineffective as a weight control drug.
Why do we feel less hungry after a meal?
Hormonal signals from the gut
bulk in stomach- limited so not really
nutrients in circulation- limited so not really
What are the GI hormones?
aka gut hormones
a group of hormones secreted by enteroendocrine cells in the stomach, pancreas, and small intestine
control various functions of digestive organs such as motility and appetite regulation
What are the 2 main gut hormones?
Ghrelin and Peptide YY
they regulate appetite
What does Ghrelin do?
stimulates appetite, increases gastric emptying
What does Peptide YY do?
inhibits food intake
When are serum levels of ghrelin highest?
before melas
- helps prepare for food intake by increasing gastric motility and acid secretion
How is ghrelin linked to the hypothalamus?
Directly modulates neurons in the arcuate nucleus
* Stimulates NPY/Agrp neurons.
* Inhibits POMC neurons.
Does ghrelin decrease or increase appetite?
increase
What is ghrelin involved with?
regulation of reward, taste sensation, memory and circadian rhythm
What hormone does this graph relate to and how can you tell?
Ghrelin, highest before meals, and decreases after meals
between meals there is a diurnal rhythm, and slowly increases during the day
How is ghrelin measured?
radioimmunoassay in plasma samples
What happens to humans who get iv ghrelin?
there was a clear cut increase in E consumption by every individual from a free-choice buffet during ghrelin compared with saline infusion
What is PYY and what does it do? And how is it secreted? and what does it stimulate and inhibit?
Peptide tyrosine tyrosine
Short peptide released in the terminal ileum (TI) and colon in response to
Reduces appetite – can be digested or injected IV
Food arriving to the TI and colon results in PYY release
Stimulates POMC neurons
Inhibits NPY release
How many AA long is PYY?
36
What encodes peptide tyrosine tyrosine?
PYY gene
Is PYY anorexigenic or orexigenic?
anorexigenic
What foods increase release of PYY?
dietary fibres, whole grains, consumed and enzymatic breakdown of crude fish proteins
What do dietary fibres, whole grains, consumed and enzymatic breakdown of crude fish proteins do to satiety?
induce satiety
via stimulation of POMC and inhibition of NPY release
What is amount of PYY released from the GI tract proportional to?
calorie content of a meal
What is the effect of PYY on food intake and hunger in humans?
What co-morbidities is obesity associated with? (10)
depression
stroke
sleep apnoea
bowel cancer
osteoarthritis
gout
peripheral vascular disease
diabetes
hypertension
myocardial infarction
What does thi figure demonstrate?
Does this summary make sense?
Y/ N
