Regulation of food intake ; a complex circuitry between different areas of the brain

1. signal transduction pathwaysinvolved in the regulation of foodintakeor whydoes Homer Simpson loves to eat an excess of donuts

2. Regulation of foodintake; a complexcircuitrybetweendifferent areas of the brain Signal transduction

3. With respect to regulation, a general distinction is made betweenhomeostatic (metabolite input) and hedonicregulation (reward input)

4. Rememberthat warm bloodedanimals, withhighlydevelopedbrains, have twobigworries; how to keep warm and how to keep the brainturning over

5. A simplified version of homeostaticregulation of foodintake; focus on signalsfrom the digestive system (ghrelin, CCK, PYY), adipose tissue (leptin) and the pancreas (insulin)

6. 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

7. ghrelinsignalshunger (orexigen, stimulatesfoodintake), whereasleptin, insulin, CCK and PYY signal satiety (anorexigen, inhibitfoodintake).Theirtargets are neurons in the arcuate nucleus, of which POMPC/CARTprovide an orexic signal and AgRP/NPY neurons drive the anorexicresponse NTS, nucleus tractus solitarius

8. Neuro-anatomy of homeostaticregulation of foodintake; opposing actions of AgRP/NPY and POMC/CART containingneurons

9. Nature of neurotransmittersinvolved in homeostaticregulation of foodintake 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)

10. Neuro-anatomy of hedonicregulation of foodintake; reward (or pleasure) seeking areas of the brain control orexigenicneurons of LHA

11. Neurotransmittorsinvolved in hedonicregulation of foodintake 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

12. So what’swrongwith 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 30 30 BMI = weight (kg)/height (m)2 BMI body mass index (IMC indice de masse corporelle)

13. In the following lectures wewill 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)