Diapositive 1

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signal transduction pathways involved in the
regulation of food intake or why does Homer
Simpson loves to eat an excess of donuts
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Regulation of food intake a complex circuitry
between different areas of the brain
Signal transduction
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With respect to regulation, a general distinction
is made between homeostatic (metabolite input)
and hedonic regulation (reward input)
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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
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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)
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Nature of the different hormones and
neurotransmittor
CCK, cholecystokinin (P06307) (cholebile,
cystopouch, kininmove 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
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ghrelin signals hunger (orexigen, stimulates food
intake), whereas leptin, insulin, CCK and PYY
signal satiety (anorexigen, inhibit food
intake).Their targets are neurons in the
arcuate nucleus, of which POMPC/CARTprovide an
orexic signal and AgRP/NPY neurons drive the
anorexic response
NTS, nucleus tractus solitarius
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Neuro-anatomy of homeostatic regulation of food
intake opposing actions of AgRP/NPY and
POMC/CART containing neurons
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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)
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Neuro-anatomy of hedonic regulation of food
intake reward (or pleasure) seeking areas of the
brain control orexigenic neurons of LHA
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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 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
anandamide
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So whats wrong with obese people?

• 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

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BMI weight (kg)/height (m)2
BMI body mass index (IMC indice de masse
corporelle)
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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)