Download 1 Food intake regulation

signal transduction pathways involved in the regulation of food intake
or
why does Homer Simpson loves to eat an excess of donuts
Regulation of food intake; a complex circuitry between different
areas of the brain
Signal
transduction
With respect to regulation, a general distinction is made
between homeostatic (metabolite input) and hedonic regulation
(reward input)
Remember that warm
blooded animals, with highly
developed brains, have two
big worries; how to keep
warm and how to keep the
brain turning over
A simplified version of
homeostatic regulation of
food intake; focus on
signals from the digestive
system (ghrelin, CCK, PYY),
adipose tissue (leptin) and
the pancreas (insulin)
Nature of the different hormones and neurotransmittor
CCK, cholecystokinin (P06307) (chole=bile, cysto=pouch, kinin=move the bile bladder) is a
peptide hormone produced in the small intestine in response to feeding. It causes the
release of digestive enzymes from the (exocrine) pancreas, bile from the galbladder and
release of H+ in parietal cells of the stomach. In the central nervous system it acts as an
anorexigen (hunger suppressant).
PYY, peptide tyrosine-tyrosine (P10082) , released by by cells in the ileum and colon in
response to feeding and acts as an anorexigen
Insulin, (P01308) peptide hormone released by b-cells in the islet of Langerhans of the
(endocrine) pancreas (hence its name insulin) in response to elevated levels of blood
glucose. It acts as an anorexigen.
Leptin, (P41159) peptide hormone released by adipose tissue in response to triglyceride
loading. Mice lacking the peptide or its receptor are obese. Leptin comes from leptos,
meaning thin.
Ghrelin, (Q9UBU3) is a polypeptide hormone produced by cells lining the fundus of the
stomach and en by epsilon cells of the pancreas. It has an orexigenic effect (stimulates
food intake. It is also produced in the arcuate nucleus where it stimulates secretion of growth
hormone by the anterior pituitary gland, hence its name Ghre meaning growth
ghrelin signals hunger
(orexigen, stimulates
food intake), whereas
leptin, insulin, CCK
and PYY signal satiety
(anorexigen, inhibit
food intake).
NTS, nucleus tractus solitarius
Their targets are
neurons in the
arcuate nucleus, of
which POMPC/CART
provide an orexic
signal and AgRP/NPY
neurons drive the
anorexic response
Neuro-anatomy of homeostatic regulation of food intake; opposing actions of
AgRP/NPY and POMC/CART containing neurons
Nature of neurotransmitters involved in homeostatic regulation
of food intake
CART, cocaine and amphetamine regulated transcript (Q16568) , discovered as
a cocaine- and amphetamine-inducible gene, propeptide, converted by
prohormone convertase into at least two active peptides (CART 55-102 and
CART 62-102)
POMC, pro-opiomelanocortin (P01189) , precursor peptide, converted by
prohormone convertases, yielding as many as 10 active peptides amongst
which a- and b-MSH (melanocortin) but also b-endorphine, hence its name
(voir ressource 08, à partir de page 28 (section troisième transit); « vers la voie de la sécrétion
contrôlée »)
NPY , neuropeptide Y (P01303) , short neuropeptide isolated from the
hypothalamus and resembling peptide YY produced by the digestive tract,
hence its name.
AgRP, agouti-related protein (O00253) , sequence similarity with Agouti
signalling peptide, a hormone that controls coat pigmentation in Augoutis
(rodents). Acts as an antagonist of the melanocortin-3 and -4 receptor
(blocks action of a-MSH)
Neuro-anatomy of hedonic regulation of food intake; reward (or pleasure)
seeking areas of the brain control orexigenic neurons of LHA
Neurotransmittors involved in hedonic regulation of food intake
Dopamine, tyrosine-derived neurotransmitter
endocannabinoids ,
-anandamide (arachidonoyl ethanolamide, AEA)
(meaning “bliss”), binds CB1 and CB2
-2-arachidonoyl glycerol (2-AG)
-2-arachidonoyl glyceryl ethere (noladin ether), binds CB1 anb CB2
-N-arachidonoyl –dopamine (NADA), binds CB1
-Virodhamine (O-arachidonoyl-ethanolamine, OEA), binds CB1 and CB2
anandamide
endogenous opioids,
-enkephalin short peptide cleaved from proenkephalin protein (act on m- and d-receptor)
examples tyr-gly-gly-phe-leu (leu-enkephalin) or tyr-gly-gly-phe-met (met-enkephalin)
-endorphins, short peptides cleaved from pro-opiomelanocortin protein (act on m-receptor
-dynorphin short peptide cleaved from prodynorphin protein (act on k-receptor
GABA, g-aminobutyric acid, amino-acid derived neurotransmitter
So what’s wrong with obese people?
30
30
BMI = weight (kg)/height (m)2
BMI body mass index
(IMC indice de masse corporelle)
-In most cases a polygenic disorder
which still has to be understood
further
-In some (severe) cases a lack of
MC4-R signalling, an excess of
ghrelin, a lack of leptin or a
dysfunctioning of insulin signalling
-In some cases a disorder
associated with a syndrome such as
Prader-Willi, Bardet-Biedl or
Alstrôm
In the following lectures we will look into more detail how
insulin, leptin and ghrelin signal in the arcuate nucleus
Receptor tyrosine
kinase (insulin)
7 TM receptor (ghrelin)
Cytokine receptor (leptin)