Gastro - Appetite Flashcards
What are the 3 mechanisms through which thirst is regulated?
→ body fluid osmolality
→ blood volume is reduced
→ blood pressure is reduced
Which of the mechanisms is most potent?
→ plasma osmolality
→ change of 2-3% induces strong desire to drink
→ decrease of 10-15% in blood volume or arterial pressure is required to produce the same
What regulates osmolality?
ADH (anti-diuretic hormone) or vasopressin
What does ADH do?
acts on kidneys to regulate volume + osmolality of urine
Where in the kidneys does ADH act?
collecting duct, aquaporin 2 channel
How does low plasma ADH affect urine volume?
large volume of urine is excreted (water diuresis)
How does high plasma ADH affect urine volume?
small volume of urine is excreted (anti diuresis)
What receptors detect osmolality?
osmoreceptors
What are osmoreceptors?
Sensory receptors
Osmoregulation
Found in the hypothalamus
Where are osmoreceptors found?
in hypothalamus:
→ Organum vasculosum of the lamina terminalis (OVLT)
→ Subfornical Organ (SFO)
How do osmorecepetors stimulate ADH release?
→ Cells shrink when plasma more concentrated
→ Proportion of cation channels increases – membrane depolarizes
→ Send signals to the ADH producing cells to increase ADH
→ Fluid retention, Invokes drinking
How do osmorecepetors inhibit ADH release?
→ Cells are turgid/normal when plasma less concentrated
→ Proportion of cation channels decreases – membrane hype-polarises
→ No signals are sent to ADH producing cells, so ADH stays low
How is the sensation of thirst satisfied?
→ decreased by drinking even before sufficient water has been absorbed by the GI tract to correct plasma osmolality
→ Receptors in mouth, pharynx, oesophagus are involved
→ Relief of thirst sensation via these receptors is short lived.
→ Thirst is only completely satisfied once plasma osmolality is decreased or blood volume or arterial pressure corrected
Where is ADH stored?
posterior pituitary
What change in BP triggers the renin-angiotensin-aldosterone system?
decrease in blood pressure
What happens when BP decreases?
decrease in blood pressure causes JUXTAGLOMERULAR CELLS of renal afferent arterioles to produce RENIN
What does renin do?
renin is an enzyme that converts:
angiotensinogen —> angiotensin I
in the liver
What does angiotensin I do?
gets converted into angiotensin II by ACE in the lungs
What does angiotensin II cause?
→ vasoconstriction, increase in sympathetic activity
→ ADH secretion
→ H2O retention via Na+CL- absorption + K+ excretion
→ causes aldosterone to be released
→ Thirst
What else can stimulate aldosterone release?
increased potassium, decreased sodium levels
How is aldosterone released via angiotensin II? From where?
→ angiotensin II binds to intraglomerular messenger cells
→ cells contract + blood vessels around them contract
→ causes aldosterone to be released form zone glomerulosa of adrenal cortex
What does aldosterone do?
H2O retention via Na+CL- absorption + K+ excretion
What medications have an impact on the RAAS pathway?
→ ace inhibitors
→ direct renin inhibitors
Who studied body homeostasis in the 20th century?
→ Neuman 1902 – his weight was stable for a long time despite no conscious effort to balance out intake and expenditure
→ Passmore 1971 – most individual adults maintain a relatively stable weight over long periods
What does a reduction in fat mass result in?
increased food intake + reduced energy expenditure
What does adipose tissue expansion cause?
reduced food intake + increased energy expenditure
What systems are activated when weight is augmented? What is the result?
→ increased sympathetic nervous system activity
→ increased energy expenditure
→ decreased hunger/food intake
this all results in weight loss
What systems are activated when weight is reduced? What is the result?
→ decreased sympathetic nervous system activity
→ decreased energy expenditure
→ increased hunger/food intake
this all results in weight gain
What system mainly defend against the reduction of body fat?
central circuit
What system defends against rapid expansion?
yet to be discovered
What part of the body regulates appetite?
hypothalamus
What stimulants are necessary for hypothalamus to regulate appetite?
→ GHRELIN, PYY + other gut hormones
→ neural input from the periphery + other brain regions
→ LEPTIN
What parts of the hypothalamus are labelled here, 1-4?
1) paraventricular nucleus
2) ventromedial hypothalamus
3) lateral hypothalamus
4) arcuate nucleus
What is the arcuate nucleus?
→ in the medial basal area, near 3rd ventricle
→ brain involved in regulation of food intake
→ incomplete BBB, allows access to peripheral hormones
→ integrates peripheral and central feeding signals
→ has 2 significant neuronal populations
What are the 2 significant neuronal populations of the arcuate nucleus?
→ stimulatory (NPY/Agrp neuron)
→ inhibitory (POMC neuron)
What is the NPY / Agrp neuronal population responsible for?
→ makes peptides that could potentially stimulate food intake
→ e.g. increases neuropeptide Y signalling + reduces melanocortin signalling via the release of Agrp
What is NPY?
→ neuropeptide Y
→ released in many places in the body, found in high concentration in the arcuate nucleus
→ known as an orexigenic agent
What is Agrp?
→ Agouti-related protein
→ produced in the brain by the AgRP/NPY neuron
→ synthesized in neuropeptide Y (NPY)-containing cell bodies located in the ventromedial part of the arcuate nucleus
→ increases appetite + decreases metabolism + energy expenditure
What is the POMC neuronal population responsible for?
→ inhibits food intake, decreasing appetite, increasing metabolism + energy expenditure
→ produces peptides like POMC, then alpha-MSH to carry this out
What is POMC?
pro-opiomelanocortin
What is a melanocortin?
→ products of POMC cleavage
→ e.g. ACTH, MSH, alpha-MSH, etc.
What is the melanocortin system?
→ POMC neurones in the brain release alpha-MSH melanocortin
→ MC4 receptors in the Paraventricular Nucleus detect alpha-MSH
→ positive stimulation causes it to go on to suppress food intake
What is the paraventricular nucleus?
→ projects neurones into posterior pituitary to produce oxytocin, ADH
→ can also help regulate appetite + energy expenditure
How is the paraventricular nucleus involved with the arcuate nucleus?
→ ArGP causes increased feeding when it stimulates the paraventricular nucleus
→ alpha-MSH from POMC stimulates decreased feeding through MC4R
What parts of the arcuate nucleus have more NPY/ArGP neurones?
lateral
What parts of the arcuate nucleus have more POMC/CART neurones?
ventromedial
What is orexigenic?
agents that increase food intake
What is anoretic?
agents that decrease food intake
What is the benefits of the arcuate nucleus having access to the exposed BBB?
allows arcuate nucleus to interpret circulating factors, to see if feeding + appetite needs to be regulated
What receptors do the 2 neuronal populations of the arcuate nucleus have?
→ receptors for Leptin + Insulin
→ decrease in Leptin or Insulin signalling causes more NPY + ArGP
→ increase in Leptin or insulin signalling causes more POMC
What human CNS mutations can affect appetite?
→ No NPY or Agrp mutations associated with appetite discovered in humans
→ POMC deficiency and MC4-R mutations cause morbid obesity
Are mutations responsible for the prevalence of obesity?
Mutations not responsible for the prevalence of obesity - but useful to explain signaling
What higher parts of the brain are involved in appetite regulation?
→ amygdala
→ lateral + ventromedial hypothalamus
→ vagus nerve + brainstem
What is the role of the amygdala in appetite regulation?
regulates appetite through reward + motivation pathways
What is the role of the other parts of the hypothalamus in appetite regulation?
→ lateral = associated with orexigenic factors
→ ventromedial = associated with anoretic factors
What is the role of the vagus nerve + brainstem in appetite regulation?
neuronal info from digestive tract is relayed through vagus nerve to brainstem to the hypothalamus
What is the adipostat mechanism?
the body’s thermostat
how adipose tissue regulates the body’s adiposity and therefore appetite, feeding + energy expenditure
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.
What could be hypothesised about the adipostat mechanism in obesity?
problem with the regulation of it could be causing the obesity
What is the ob/ob mouse?
Why is it important?
→ obese mouse that ate excessively
→ lead to the discovery of leptin
What is leptin?
→ hormone made by adipocytes in adipose tissue + enterocytes in small intestine
→ circulates in plasma
→ acts upon the hypothalamus regulating appetite + food intake + thermogenesis / energy expenditure
→ meaning thin, discovered in 1994
→ missing in the ob/ob mouse
What does congenital leptin deficiency result in?
children will have normal body weight but insatiable hunger
will lead to excessive eating
results in them becoming obese
How can congenital leptin deficiency be treated?
leptin is effective in reducing body weight
What was the trend noticed by scientists concerning leptin in obesity?
high leptin levels were seen in those with high body fat
probably due to leptin resistance developed over time
What is leptin’s mechanism of action?
→ adipose tissue releases leptin
→ leptin stimulates hypothalamus
→ decreases food intake
→ increases energy expenditure + fat + glucose metabolism
What are the 3 things that can go wrong in leptin’s mechanisms to result in obesity?
→ absent leptin
→ regulatory defect in leptin levels
→ leptin resistance to high leptin levels
What is leptin circulation in plasma proportional to?
→ Leptin circulates in plasma in concentrations proportional to fat mass
→ low leptin = low body fat mass
→ high leptin = high body fat mass
Is leptin effective as a weight control drug?
no - usually obese people have sufficient leptin
What is the purpose of GI hormones? What produces them?
→ secreted by entero-endocrine cells in the stomach, pancreas & bowels
→ controls various function of digestive organs
Which GI hormones regulate appetite?
→ ghrelin
→ peptid YY
What GI hormones does the stomach release?
→ ghrelin
→ gastrin
What GI hormones does the pancreas release?
→ insulin → glucagon → somatostatin → pancreatic polypeptide → amylin
What GI hormones does the small intestine release?
→ cholecystokinin
→ secretin
→ GIP
→ motilin
What GI hormones does the large intestine release?
→ GLP-1
→ GLP-2
→ oxyntomodulin
→ PYY 3-36
What does ghrelin do?
→ stimulates + increases appetite
→ increases gastric emptying
How does ghrelin stimulate appetite?
Directly modulates neurons in the arcuate nucleus
→ Stimulates NPY/Agrp neurons
→ Inhibits POMC neurons.
When is Ghrelin levels the highest in the body? Why?
→ before a meal
→ help prepare for food intake by increasing gastric motility + acid secretion
What else is ghrenlin useful for?
Regulation of reward, taste sensation, memory, circadian rhythm
What is PPY?
→ peptide tyrosine tyrosine
→ released in terminal ileum + colon in response to food arrival
→ reduces appetite
How does PYY reduce appetite?
→ inhibits NPY release
→ stimulates POMC neurones
What comorbidities is obesity associated with?
→ depression → sleep apnoea → MI → bowel cancer → osteoarthritis → gout → peripheral vascular disease → diabetes → hypertension → stroke
