Endocrine control of food intake Flashcards
what allows the brain to access peripheral hormones?
the incomplete brain barrier located at the arcuate nucleus location (cricumventricular organ)
arcuate nucleus is at the hypothalamus
solitary nucleus is in the medulla (below)
what integrates central and peripheral feeding signals?
arcuate nucleus
what are the two main neuronal populations?
stimulatory- increase appetite (NPY/Agrp)
inhibitory- decrease appetite (POMC)
what are the stimulatory neurones of the arcuate nucleus?
where do these neurone goes
NPY/Agrp
goes to the lateral hypothalamus
what are the inhibitory neurones of the arcuate nucleus and where do they go?
POMC
goes to the ventromedial nucleus
where do there arcuate nucleus neurones travel
the arcuate itself is in the hypothalamus
the neurones extend to other hypothalamic regions (lateral hypothalamus and ventromedial nucleus) and extra-hypothalamic regions
which nucleus do BOTH Agrp/NPY and POMC neurone axons extend to?
what does this nucleus contain?
paraventricular nucleus
MC4R
what is the effect of Agrp neurone on MC4R (Melanocortin 4 receptor)?
Agrp (an appetite stimulatory) would inhibit MC4R to increase appetite
(MCR4 is the target for alpha MSH of POMC to stop feeling hungry all time i.e. is anti-hunger)
what is the effect of POMC neurone on MC4R
POMC is cleaved into alpha-MSH which stimulates MC4R to decrease appetite
what defects lead to morbid obesity?
what is the effect of a POMC deficiency?
POMC deficiency and MC4R mutations
POMC def leads to lack of cortisol
[no known NPY/Agrp mutations]
what does the ob/ob mouse show about the importance of leptin?
The effects of missing leptin:
- recessive mutations led to obesity, diabetes, infertility and stunted growth, low immune function, decreased body temp
- There were abnormalities comparable to a starved animals
- The mouse eats a lot thinking it has no fat in the body
leptin levels according to body fat
low BF-
high BF-
low BF- low leptin
high BF- high leptin
effect of leptin administration
decreased food intake
increased thermogenesis
restores LH pulsatility therefore enabling normal puberty and menstrual cycles
why is leptin an ineffective weight control drug
obesity is due to leptin resistance so leptin has no efficacy on the receptor despite having high leptin
leptin is anti-starvation rather than anti-obesity
what is the effect of leptin on the neurones
activates POMC–> increase satiety
inhibits NPY/Agrp–> decrease appetite
what are the effects of an absence of leptin
o Hyperphagia, lowered energy expenditure and sterility – like effects of starvation.
- ammenorhoea
o Leptin is an anti-starvation hormone and so presence of leptin tells the brain that one has sufficient fat reserves for normal functioning (but high leptin has little effect).
how does the circulation of insulin compare to body fat
proportional
where are insulin receptors found
what is the effect of central administration of insulin
- receptors in the hypothalamus
- central administration reduces food intake
what regulates the release of gut hormones?
content of the gut and therefore mechanoreceptors
what enables Ghrelin to cross the BBB?
28aa gastric hormone with fatty acid group attached
what enzyme adds the fatty group to Ghrelin?
GOAT
Ghrelin O-Acyltransferase
–> this activates ghrelin
what are the effects of ghrelin on hormones and appetite?
- on neurones
- overall effects
stimulates NYP/Agrp–> stimulates appetite
inhibits POMC –> decreases satiety
- increases appetite
- drives hunger for food just before a meal
- therefore increased intake
- ghrelin falls after a meal
what do L- cells secrete?
the appetite reducers:
PYY
GLP-1 (from preproglucagon gene)
glucagon is also secreted by alpha cells of the pancreas
what is the correlation between PYY and calories?
PYY aims to reduce appetite:
more calories in the food –>more PYY released by the L cells
how is PYY activated?
- process
- enzyme involved
cleaved at position 1 and 2 at N-terminal
- tyrosine 1
- proline 2
to form PYY3-36
- this is done by DPP4 (di-peptidyl peptidase 4)
- DPP4 is also involved in the metabolism of GLP-1 (incretins)
what is the effect of PYY?
- inhibits NPY neurones–> decreased appetite
- stimulates POMC –> increased satiety
overall reduced hunger
“a meal has been had”
when is GLP-1 released?
post-prandial
what is the effect of GLP-1?
incretin effect:
in stimulating glucose-stimulated insulin release to reduce food intake
gut hormone summary
increase appetite- Ghrelin
decrease appetite- PYY, GLP-1
saxenda
liraglutide
long-acting glucagon-like peptide-1 receptor agonist
reduces food intake
what is the dosage of Saxenda/liraglutide for T2DM
double
GLP-1 agonists
how is GLP-1 inhibited quickly?
by metabolism by:
DPP-4 (gliptins)
causes inactivation
why is PYY3-36 a hard target for drug manipulation?
narrow therapeutic window
Genetics hypotheses for obesity prevalence [2]
o Thrifty gene hypothesis: SURVIVAL
- Specific genes are selected for to increase metabolic efficiency and fat storage.
- It makes evolutional sense to put on weight.
- Thin humans didn’t survive famines so didn’t pass genes on to modern humans.
o Drifty gene hypothesis (ADAPTIVE drift):
- There is a normal distribution of body weight – the fat people were eaten, the thin starved.
- However, 10k-20k years ago, humans learned to defend themselves and so obesity was not selected against so obesity was a neutral change (whilst the thin still starved).
environment only plays a role in obesity when one is genetically prone to obesity
describe the pathway that stimulates hunger or satiety
- mechanoreceptors in the stomach detect stretch
- low stretch means increased hunger due to decreased receptor firing
- VAGUS carries signal to SOLITARY nucleus in the medulla
- solitary nucleus to the ARCUATE nucleus in the hypothalmaus
- the arcuate sends orexinogenic projections to the LATERAL HYPOTHALAMUS to stimulate appetite (Agrp/NPY) nb involved in wakefulness
- the arcuate sends anorexigenic projections to the VENTROMEDIAL nucleus to increase satiety (POMC)
