10/15/2011. TÁMOP–4.1.2-08/2/A/KMR-2009-0006 1 Development of Complex Curricula for Molecular Bionics and InfobionicsPrograms within a consortial* framework** Consortium leader PETER PAZMANYCATHOLIC UNIVERSITY Consortium members SEMMELWEISUNIVERSITY, DIALOG CAMPUS PUBLISHER The Project has been realisedwith the support of the European Union and has been co-financed by the European Social Fund *** **Molekuláris bionika és Infobionika Szakok tananyagának komplex fejlesztése konzorciumi keretben ***A projekt az Európai Unió támogatásával, az Európai Szociális Alap társfinanszírozásával valósul meg. PETER PAZMANY CATHOLIC UNIVERSITY SEMMELWEIS UNIVERSITY sote_logo.jpg dk_fejlec.gif INFOBLOKK 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 2 Peter Pazmany Catholic University Faculty of Information Technology REGULATION OF FEEDING www.itk.ppke.hu (Táplálkozás szabályozás) ZSOLT LIPOSITS BEVEZETÉS A FUNKCIONÁLIS NEUROBIOLÓGIÁBA INTRODUCTION TO FUNCTIONAL NEUROBIOLOGY INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 3 www.itk.ppke.hu ENERGY INTAKE =ENERGY EXPENDITURE ENERGY INTAKE ‹ENERGY EXPENDITURE ENERGY INTAKE ›ENERGY EXPENDITURE LEANNORMALOBESE INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 4 www.itk.ppke.hu OBESITY TYPE 2 DIABETES heart disease (cardiovascular disease) blindness (retinopathy) nerve damage (neuropathy) kidney damage (nephropathy) INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 5 www.itk.ppke.hu Satiety hormones Leptin Insulin PYY CCK Hunger hormone Ghrelin Brain GI TRACT SIGNALLING Schwartz et al, 2005 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 6 www.itk.ppke.hu HYPOTHALAMUS PVN GHRELIN INSULIN LEPTIN GLUCOCORTICOIDS SEX STEROIDS THYROID HORMONES CCK PYY ARC DM INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 7 www.itk.ppke.hu NPY AGRP . -MSH CART ARC PVN SECOND ORDER EFFECTOR NEURONS TRH CRH OXY VAS PITUITARY-ADRENAL &THYROID AXES POSTERIOR PITUITARY AUTONOMIC CENTERS OREXIN MCH INSULIN GHRELIN LEPTIN GLUCOCORTICOIDS METABOLIC SIGNALS FIRST ORDER SENSOR NEURONS OREXIGENIC ANOREXIGENIC OUTFLOWS NTS FOOD INTAKE ENERGY EXPENDITURE WATER, ELECTROLYTE ADAPTATION INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 8 www.itk.ppke.hu diakep Posterior pituitary Anterior pituitary Autonomic centers INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 9 www.itk.ppke.hu NPY/AGRP Barsh & Schwartz, 2002 Untitled-1 a-MSH/CART Jobst et al., 2004 The sensor system INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 10 www.itk.ppke.hu Hypothalamus CINGULUM DA E/NE 5-HT PLASTICITY ADAPTATION ENDOCRINE AXES SALT AND WATER BALANCE AUTONOMIC REGULATION INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 11 www.itk.ppke.hu ARCUATE NUCLEUS PARAVENTRICULAR NUCLEUS SUPRACHIASMATIC NUCLEUS PREFRONTAL CORTEX VENTRAL TEGMENTAL AREA DORSAL TEGMENTAL NUCLEUS NUCLEUS ACCUMBENS Lateral view of the transparent rodent brain NUCLEUS OF THE SOLITARY TRACT DORSAL VAGAL NUCLEUS INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 12 www.itk.ppke.hu The relation of various hypothalamic lesions to adiposity in the ratA. W. Hetherington, S. W. Ranson The Journal of Comparative Neurology76:475-499(1942) Weight gain Lesion of VMH Destruction of satiety centre Hypothalamic lesions and adiposity in the ratA. W. Hetherington, S. W. Ranson The AnatomicalRecord 78: 149-172 (1940) Lesion of LH Disruption of feeding centre Weight loss INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 13 www.itk.ppke.hu CAUDAL Hypothalamic nuclei regulating food intake and energy expenditure ROSTRAL SON INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 14 www.itk.ppke.hu PVN SCN DMH VMH ARH ME Thyrotropin-releasinghormone Corticotropin-relasinghormone Oxytocin Vasopressin Somatostatin Galanin CART Nesfatin Vasopressin VIP Gastrin-releasing peptide Neuropeptide-Y RFRP Orexin MCH PACAP NPY AGRP .-MSH CART LHA CRH TRH ADRENAL & THYROID AXES NTS Visceral afferents AUTONOMIC CENTERS EFFECTOR RELAY SENSORS LEPTINGHRELININSULINIL -6 GLUCOSE CCK PFC ACCUMBENS VTA REWARD ADDICTION INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 15 www.itk.ppke.hu PVN VMH ARH LHA Hahn et al, Nat Neurosci.1998, NPYAGRP Fekete et al, J Neurosci. 2000;20:9224-34 MSH CART mch MCH orexin OREXIN DMH crh-trh TRH CRH PVN INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 16 www.itk.ppke.hu PVN VMH ARH LHA DMH OREXIGENIC NEUROMESSENGERS Neuropeptide Y (NPY) Agouti-related protein(AGRP) Melanin-concentrating hormone (MCH) Orexin Endocannabinoids Galanin ANOREXIGENIC NEUROMESSENGERS .-melonocyte stimulating hormone (.-MSH) Cocaine and amphetamine-regulated transcript (CART) Thyrotropin-releasing hormone (TRH) Corticotropin-releasing hormone (CRH) Glucagon-like peptide (GLP-1) Urocortin TRASNMITERS Serotonin GABA Dopamine Norepinephrine Epinephrine Glutamate Histamine METABOLIC SIGNALS Leptin Ghrelin Insulin Glucose CCK Thyroid hormones Estradiol Testosterone Glucocorticoids INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 17 www.itk.ppke.hu NEUROMODULATORS PERIPHERAL SIGNALS ANOREXIGENIC MESSENGERS OREXIGENIC MESSENGERS Führer et al, Obesity,2008,16:945-50 FOOD INTAKE ENERGY EXPENDITURE Hypothalamic kaleidoscope kaleidoscope.gif INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 18 www.itk.ppke.hu Monitoring and processing of metabolic signals by hypothalamic nuclei INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 19 www.itk.ppke.hu FAT LEPTIN STOMACH GHRELIN Elmquistet al., J Comp Neurol, 1998, 395:535–47 LEPTIN RECEPTOR mRNA Hrabovszky et al, 2010, unpublished GHRELIN RECEPTOR mRNA GHSR arc vmn VMH ARH VMH ARH INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 20 www.itk.ppke.hu NPY AGRP POMC CART AGRP NPY orexigenic Effect of fasting on the expression of orexigenic and anorexigenic peptide mRNAs in the arcuate nucleus CART MSH anorexigenic Lechan RM, Fekete C. Prog Brain Res. 2006,153:209-35. INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 21 www.itk.ppke.hu Effects of central leptin, insulin and glucose administration on the peptidergic neurons of the arcuate nucleus NPY FED FAST FAST+LEPTIN FAST+INSULIN FAST+GLUCOSE AGRP FED FAST FAST+LEPTIN FAST+INSULIN FAST+GLUCOSE MSH FED FAST FAST+LEPTIN FAST+INSULIN FAST+GLUCOSE CART FED FAST FAST+LEPTIN FAST+INSULIN FAST+GLUCOSE Fekete et al., Endocrinology,2006,147:520-9 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 22 www.itk.ppke.hu crh-trh TRH CRH PVN PITUITARY BRAIN ADRENAL THYROID ACTH FSH T4/T3 GC Basal oxygen consumption Fat stores Lipogenesis Lipolysis Thermogenesis Mitochondrial uncoupling WAT BAT Gluconeogenesis Lipolysis Glucose uptake inhibition INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 23 www.itk.ppke.hu Origin, chemical nature and regulatory effects of synaptic afferents to CRH and TRH neurons INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 24 www.itk.ppke.hu PVNEM ULTRASTRUCTURE OF PARVICELLULAR NEURONS PVNneurop MEem CELL BODIES I N P U T O U T P U T Liposits Zs, Crit. Rev. Neurobiol. 1993;7:89-162 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 25 www.itk.ppke.hu PVNpnmtem ADRENERGICINPUT TO THE PVN Y C1-3proj Liposits Z, PhelixC,PaullWK: Histochemistry,1986;84:105-20. INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 26 www.itk.ppke.hu CRHpnmtlm CATECHOLAMINERGIC NEURONAL INPUTTOCRHNEURONS Y LipositsZ, PhelixC, PaullWK: Histochemistry. 1986;84:201-5. INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 27 www.itk.ppke.hu Glutamatergicinnervationof hypophysiotropicCRHneurons VGLUT-2 + CRH WittmannG, et al.: Brain Res. 2005;1039:53-62. INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 28 www.itk.ppke.hu A/NA 5-HT MC GLU CRH GABA CRH Peptides and transmitters in boutonssynapsingwith CRHneurons LipositsZ: ProgHistochemCytochem. 1990;21:1-98. MiklosIHand Kovacs KJ.,Neuroscience. 2002;113:581-92. WittmannG,et al., Endocrinology. 2005;146(7):2985-91. CART POMC NPY Lipositset al, 1987 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 29 www.itk.ppke.hu GABA-ergicinnervationof hypophysiotrophicTRHneurons FeketeC, et al.: Brain Res. 2002;957:251-8. fig1 fig2 Axo-somatic Axo-dendritic INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 30 www.itk.ppke.hu .-MSH/CART A/NA 5-HT GAL NPY/AGRP GLU TRH GABA Synaptic modulators of TRH neurons Liposits Z, et al., Histochemistry. 1987;88(1):1-10.,WittmannG, et al., Brain Res. 2004;1002:43-50., FeketeC, et al.,J Neurosci. 2000;20:1550-8., FeketeC, et al., J Neurosci. 2000;20:9224-34., FeketeC, et al.: Brain Res. 2002;957:251-8.,WittmannG,et al.:Brain Res. 2005;1039:53-62. Fekete et al, 2000 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 31 www.itk.ppke.hu Impact of feeding-related systems on hypophysiotrophicCRH and TRH neuron populations INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 32 www.itk.ppke.hu Innervationof PVN and hypophysiotrophicCRHneurons byNPYandPOMCaxons CRHACTH POMC CRHnpy NPY Liposits Z, SieversL, PaullWK., Histochemistry. 1988;88:227-34. INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 33 www.itk.ppke.hu Quantitative analysis of quadruple-labeling immunofluorescence(PNMT/DBH/NPY/CRH) in intact rats Type of NPY-IR bouton Percentage of CRH neurons contacted (%) Average number of NPY-IR varicosities per innervated CRH neuron Percentage of all NPY-IR boutons in contact with CRH neurons (%) Single-labeled NPY 89.0 5.3 5.3 0.8 36.6 3.1 DBH/NPY 82.8 6.2 3.5 0.8 22.2 3.0 PNMT/DBH/NPY 94.2 1.1 5.5 0.4 41.2 5.6 All NPY 100 12.9 2.0 100 NPY from ARC NPYfrom NA/A CRH 64% Origin of NPYinnervationof CRHneurons Füzesiet al, Endocrinology, 2007,148:5442-50 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 34 www.itk.ppke.hu Colocalizationof NPYand PNMTin axons innervating TRH neurons NPY-ergicinnervation of TRH neurons WittmannG.et al., NeurosciLett. 2002;324:69-73 Originof NPY-ergicafferentstoTRHneurons NPY from ARC NPY from C1-C2 TRH 75% 25 % INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 35 www.itk.ppke.hu NPY from ARC NPY from C1-C2 TRH 75% NPY from ARC NPY from NA/A cells CRH 64% NPY input to CRH and TRH neurons INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 36 www.itk.ppke.hu AGRP CART POMC NPY NPY AGRP POMC CART Impact of fastingon the expression of feeding-related peptide mRNAs orexigenic Lechan RM, Fekete C. Prog Brain Res. 2006;153:209-35. TRH CRH anorexigenic compositenpyCRH FED FAST TRH mRNA CRH mRNA FED FAST INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 37 www.itk.ppke.hu Effects of AGRPon the TRH mRNAlevels in the PVN of WT and MC4-R KOmice WT control WT AGRP MC4-R KO control MC4-R KO AGRP Fekete C. et al., Endocrinology. 2004;145:4816-21. INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 38 www.itk.ppke.hu The novel glutamatergic phenotype of TRH and CRH neurons INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 39 www.itk.ppke.hu VGLUT-2 IMMUNOREACTIVITY IN AXONS OF MEDIAN EMINENCE PS Hrabovszky et al., Neuroscience. 2007, 23;144:1383-92. vglut2 kep ME III. INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 40 www.itk.ppke.hu Localization ofVGLUT-2 mRNA and retrogradelytransportedFluoroGoldin the hypothalamus PVH VMH SON HrabovszkyE,et al., Neuroscience. 2007,23;144:1383-92. VGLUT-2 mRNA FluoroGold VGLUT-2 mRNA FluoroGold INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 41 www.itk.ppke.hu CRHTRHLHRHSS VPOXY + VGLUT-2 + VGLUT-2 mRNA CRH mRNA VGLUT-2-IR TRH-IR VGLUT-2-IR CRH-IR Expression of VGLUT-2 mRNA in neurosecretorysystems HrabovszkyE,et al: Endocrinology. 2004;145:4018-21. HrabovszkyE,et al: Endocrinology. 2005 ;146:341-7. HrabovszkyE,et al: EurJ Neurosci. 2005;21:2120-6. HrabovszkyE,et al: NeurochemInt. 2006;48:753-61. INTRODUCTION TO FUNCTIONAL NEUROBIOLOGY : Regulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 42 www.itk.ppke.hu Neurosecretory Hormone + Glutamate Para-or autocrine release regulator? Hormone + Glutamate Synaptic co-modulator? portalcapillary INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 43 www.itk.ppke.hu TARGET Retrograde endocannabinoid signaling in hypothalamic feeding centers endocannabinoids endocannabinoids CB1 CB1 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 44 www.itk.ppke.hu CB1-IRinnervationof the arcuatenucleus Asymmetricsynapse Symmetricsynapse CB1-IR Nissl CB1 AGRP CB1 a-MSH WittmannG. et al., J. Comp. Neurol, 2007 ,10;503:270-9. INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 45 www.itk.ppke.hu Excitatory Inhibitory Localization of CB1 receptor in excitatoryand inhibitory pre-synaptic terminals of parvicellularneurons in PVN CB1 WittmannG. et al., J. Comp. Neurol, 2007 ,10;503:270-9. PVN INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 46 www.itk.ppke.hu GABA - GABA - GABA - GLU + GLU + TRH neuron Modulation of excitatory and inhibitory synapticinputs toTRHneuronsby endogenous cannabinoids Innervationof TRH neuronsby CB1-IR axons Deli et al. et al.: Endocrinology, 2009,150:98-103 CB1 CB1 CB1 CB1 CB1 EC EC EC TRH CB1 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 47 www.itk.ppke.hu 0 5 10 15 20 25 30 35 40 2-AG content (pmol/mg tissue) C G * Effect of ghrelin on the endocannabinoid content of the Fig1 Fig2 Cooperation between ghrelinand endocannabinoidsignaling mechanisms 0 0.2 0.4 0.6 0.8 1 1.2 C G ** C G WT CB1-KO Effect of ghrelin on food intake in WT and CB1 KO mice Kolaet al., PLoS One. 2008 Mar 12;3(3):e1797. INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 48 www.itk.ppke.hu Organization and specific features of the human hypothalamic feeding centers INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 49 www.itk.ppke.hu Reciprocal connection between.-MSH-and NPY-producing neurons in the infundibularnucleus of the human hypothalamus Menyhért J. et al., Brain Res. 2006;1076:101-5. A B C INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 50 www.itk.ppke.hu .-MSHcells do not express CARTin humans Menyhért J. et al., Endocrinology, 2007,148:4276-81 INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 51 www.itk.ppke.hu NPY-IRand .-MSH-IRinnervationof the CRH-IRneurons in the paraventricular nucleus of the humanhypothalamus A B C Mihály E. et al., 2007, unpublished MihalyE. et al., J Comp Neurol. 2002;446:235-43. .-MSH NPY INTRODUCTION TO FUNCTIONAL NEUROBIOLOGYRegulation of feeding 10/15/2011. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 52 www.itk.ppke.hu NPY AGRP CART .-MSH CRH TRH PVN INF OREXIGENIC ANOREXIGENIC Characteristics of neuronal networks regulating feeding in humans