Gut Brain Relationship

8/13/2019 Gut Brain Relationship

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Gut-Brain Interrelationships and Control ofFeeding BehaviorIntroduction to the Gut-Brain Connection

Hypothalamic Control of Feeding Behavior Orexigenic Peptides Neuropeptide tyrosine NP! "gouti-related peptide "g#P $elanin-concentrating hormone $CH Orexins Galanin G"%"norexigenic Peptides PO$C-&erived $elanocortins

Cocaine- and "mphetamine-#egulated 'ranscript C"#' Galanin-li(e peptide G"%P Corticotropin-releasing factor )C#F or C#H* and related peptides

Hypothalamic %ipid $eta+olism and ,nergy Homeostasis

Gastrointestinal Hormones G%P- and GIP Oxyntomodulin Cholecysto(inin Ghrelin and O+estatin

Pancreatic polypeptide Protein tyrosine tyrosine P!!

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Introduction to Gut-Brain Interactions'he +rain in particular the hypothalamus plays highly critical roles in the regulation of energymeta+olism nutrient partitioning and the control of feeding +ehaviors5 'he gastrointestinal tract isintimately connected to the actions of the hypothalamic-pituitary axis via the release of peptides thatexert responses 8ithin the +rain as 8ell as through neuroendocrine and sensory inputs from the gut5

'reat headaches effectively using panadol fever ta+lets 5 "lthough a complete discussion of theinterrelationships +et8een the gut and the +rain in the control of energy homeostasis and regulation offeeding is +eyond the intended scope of this page focus 8ill +e placed on +riefly revie8ing the currentliterature5 'he primary centers in the +rain involved in the control of appetite are the hypothalamic-

pituitary axis and the +rain stem5 'he role of these +rain regions in appetite control are discussed in thesection +elo8 on Hypothalamic Control of Feeding Behavior5

'he consumption of food initiates a cascade of neuronal and hormonal responses 8ithin and +y the

gastrointestinal system that impact responses in the central nervous system5 'he +rain initiatesresponses to feeding even +efore the ingestion of food5 'he very sight and smell of food stimulatesexocrine and endocrine secretions in the gut as 8ell as increasing gut motility5 Ingestion of foodstimulates mechanoreceptors leading to distension and propulsion to accommodate the food5 "s thefood is propelled through the gut regions of the intestines secrete various hormones that circulate to the

+rain and impact hypothalamic responses as discussed in the sections +elo85 'he mechanoreceptorresponses are transmitted via afferent nerve signals along the vagus nerve to the dorsal vagal complexin the medulla and terminating in the nucleus of the solitary tract )N'9 for the latin term nucleustractus solitarii *5 Pro:ections from the N'9 enter the visceral sensory complex of the thalamus 8hichmediates the perception of gastrointestinal fullness and satiety5 9everal hormones released from the gutin response to food inta(e exert anorexigenic )appetite suppressing* responses in the +rain particularly

in the hypothalamus5 'hese hormones include glucagon-li(e peptide- )G%P- * cholecysto(inin)CC;* peptide tyrosine tyrosine )P!!* pancreatic polypeptide )PP* and oxyntomodulin )O


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Hypothalamic Control of Feeding Behavior'he hypothalamus is located +elo8 the thalamus and :ust a+ove the +rain stem and is composed ofseveral domains )nuclei* that perform a variety of functions5 'he hypothalamus forms the ventral

portion of the region of the +rain called the diencephalon5 "natomically the hypothalamus is dividedinto three +road domains termed the posterior tu+eral and anterior regions5 ,ach of these three regions

is further su+divided into medial and lateral areas5 'he various nuclei of the hypothalamus constitutethe functional domains of the various hypothalamic areas5 'he primary nuclei of the hypothalamus thatare involved in feeding +ehaviors and satiety )the sensation of +eing full* include the arcuate nucleus ofthe hypothalamus )"#C also a++reviated "#H* the dorsomedial hypothalamic nucleus )&$H or&$N* and the ventromedial hypothalamic nucleus )=$H or =$N* all of 8hich are located in thetu+eral medial area5 'he "#C is involved in control of feeding +ehavior as 8ell as secretion of various

pituitary releasing hormones the &$H is involved in stimulating gastrointestinal activity and the=$H is involved in satiety5 ,arly experiments involving lesions in the hypothalamus demonstrated thatthe lateral hypothalamic area )%H"* is responsi+le for transmitting orexigenic signals )desire for foodinta(e* and loss of this region results in starvation5 'he medial hypothalamic nuclei )=$H and to alesser extent the &$H* are responsi+le for the sensations of satiety and lesions in these regions of the

hypothalamus result in hyperphagia )excessive hunger* and o+esity5"ppetite is a complex process that results from the integration of multiple signals at the hypothalamus5'he hypothalamus receives neural signals hormonal signals such as leptin cholecysto(inin )CC;* andghrelin and nutrient signals such as glucose free fatty acids amino acids and volatile fatty acids5 'hiseffect is processed +y a specific se>uence of neurotransmitters +eginning 8ithin the "#C andorexigenic cells containing neuropeptide ! )NP!* and "gouti-related peptide )"g#P* responsiveneurons and anorexigenic cells containing pro-opiomelanocortin PO$C )yielding the neurotransmitter?-$9H* and cocaine and amphetamine-regulated transcript )C"#'* responsive neurons5 'hese socalled first order neurons act on second order orexigenic neurons )containing either melaninconcentrating hormone $CH or orexin* or act on anorexigenic neurons )expressing corticotropinreleasing hormone C#H* to alter feed inta(e5 In addition satiety signals from the liver andgastrointestinal tract signal through the vagus nerve to the nucleus of the solitary tract )N'9 for thelatin term nucleus tractus solitarii * to cause meal termination and in com+ination 8ith thehypothalamus integrate the various signals to determine the feeding response5 'he activities of theseneuronal path8ays are also influenced +y numerous factors such as nutrients fasting and disease tomodify appetite and hence impact on gro8th and reproduction5

Hormonal circuits from the gut )stomach small intestine and pancreas* and fat )adipose tissue* thatimpact the sensations of hunger and satiety that are exerted via hypothalamic neuroendocrine path8ays5Ghrelin from the stomach leptin from adipose tissue insulin from the pancreas and peptide tyrosinetyrosine )P!!* from the small intestine +ind to receptors on orexigenic and@or anorexigenic neurons inthe "#C of the hypothalamus5 'he effects of these peptide hormone-receptor interactions are release ofeither the orexigenic neuropeptides NP! and "g#P or the anorexigenic neuropeptides C"#' and thePO$C-derived peptide ?-$9H5 'hese neuropeptides from the "#C travel along axons to secondaryneurons in other areas of the hypothalamus such as the paraventricular nucleus )P=N*5 'he ultimateeffects of these signaling cascades are changes in the sensation of hunger and satiety in the N'95%,P#B is the large form of the leptin receptor )see the "dipose 'issue page for descriptions of leptinand leptin receptors*5 GH9# is the gro8th hormone secretagogue receptor to 8hich ghrelin +inds5$C4# and $CA# are melanocortin 4 receptor and melanocortin A receptor respectively5 ! # and !2#
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are the NP! receptors and 2 respectively )see the next section +elo8 for more information on NP!receptors5

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europeptide !" P! NP! is a hypothalamic neuroendocrine protein that is a mem+er of a family of structurally related proteins identified as the pancreatic polypeptide )PP* family of hormones5 In addition to NP! thisfamily is composed of t8o gut hormones pancreatic polypeptide )PP* and peptide tyrosine-tyrosine)P!!* +oth of 8hich are discussed +elo85 ,ach of these peptide hormones contains 40 amino acidsconsisting of numerous tyrosines )hence the ! peptides nomenclature* and an ?-amidation at the C-terminus5 'he three-dimensional structure of these hormones includes a hairpin-li(e motif referred to asthe pancreatic polypeptide fold )PP-fold*5 'he PP-fold is re>uired for interaction of the hormones 8ithspecific G-protein coupled receptors )GPC#s*5

'he PP family of proteins +ind to a family of receptors that 8ere originally characteri ed as NP!receptors5 'here are four NP! receptors in humans and they are designated as ! !2 !A and ! 5 "nadditional receptor identified as !0 is found in mice and ra++its5 Comparisons of the amino acidse>uences of the four human ! receptors sho8 that receptors ! !A are more closely related to eachother than to the receptors !2 and ! 5 #eceptors ! !2 and ! preferentially +ind NP! and P!!8hereas !A exhi+its highest affinity for PP5 "lthough the ! receptor is expressed and +inds ligand itis a truncated protein5 'he !2 receptor is involved in anorexigenic responses )suppression of appetite*8hereas the ! and ! receptors have +een sho8n to induce orexigenic responses )stimulation ofappetite*5 'he !2 receptors are thus referred to as inhi+itory receptors 8ith respect to the activity of

NP! and they are a+undantly expressed on NP! neurons in the arcuate nucleus )"#C* of thehypothalamus5

NP! is expressed throughout the mammalian +rain 8ith highest levels found in the "#C of thehypothalamus5 NP! is one of the most potent orexigenic factors produced +y the human +ody5 Dithinthe "#C there are t8o neuronal populations that exert opposing actions on the desire for food inta(e5

Neurons that co-express NP! and another neuropeptide called agouti-related peptide )"g#P* stimulatefood inta(e 8hereas neurons that co-express PO$C and cocaine and amphetamine-regulatedtranscript )C"#'* suppress the desire for food inta(e5 'he role of NP! in appetite control can +edemonstrated +y central administration of NP! 8hich results in a mar(edly increased desire for foodinta(e5 'he ! and ! receptors mediate the +ul( of the effects of NP! on the hypothalamic-pituitary-thyroid axis5 Dithin the ventromedial nucleus )=$N* of the hypothalamus +inding of NP! to the !receptor results in inhi+ition of neuronal function )via hyperpolari ation* 8hich results in interference8ith the satiety role of the =$N5 'he ma:ority of hypothalamic !2 receptors are found on NP!-containing neurons5 Conversely !2 receptor activation in the "#C results in inhi+ition of the actions of

NP! 8hich accounts for the anorexigenic actions associated 8ith !2 activation5

Of significance to dieting and 8eight loss is the fact that 8hen people lose excess 8eight the level of NP! increases 8hich li(ely is a contri+uting factor to the ina+ility of most people to (eep the 8eightoff5 'his phenomenon has +een demonstrated in mice fed a high-fat diet5 'hese mice 8ill +ecomeo+ese have increased fat mass and increased circulating levels of leptin 5 Dhen the animals are placedon a calorie-restricted diet they lose the excess fat and leptin levels decline5 Ho8ever the level ofexpression of the NP! gene is o+served to +e significantly increased5 'his and other data indicate that
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NP! is also one of the most important hypothalamic-derived neuropeptides mediating the effects ofleptin on overall energy homeostasis5 Dhereas losing excess 8eight is associated 8ith increasedexpression of NP! the levels of the anorexigenic peptides PO$C and C"#' do not change5

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#gouti-related peptide" #gRP"s the name implies agouti-related peptide )"g#P* is a protein 8ith se>uence homology to the agouti

protein 8hich controls coat color in rodents5 "g#P is a protein of 42 amino acids encoded onchromosome 0>225 "g#P is expressed primarily in the "#C and is found to co-locali e 8ith neuronsthat also produce NP!5 "lthough expression of "g#P is restricted to the "#C "g#P fi+ers pro:ect toseveral +rain areas as 8ell as to multiple areas 8ithin the hypothalamus including the paraventricularnucleus )P=N or P=H* and perifornical lateral hypothalamus )PF%H*5 In addition all of these "g#Pnerve terminals contain NP!5 'he P=N is a region of the hypothalamus that integrates neuropeptidesignals from numerous regions of the +rain and hypothalamus )e5g5 the "#C* as 8ell as the +rainstem5

'he perifornical lateral hypothalamus is a su+domain of the %H" that is involved in arousal and food-see(ing +ehaviors5

"g#P together 8ith NP! represent a distinct set of "#C-expressed orexigenic peptides5 "g#P isclassically referred to as a mem+er of the central melanocortin system 8hich in addition to "g#Pcomprises ?-melanocyte stimulating hormone ?-$9H )see +elo8 for description of ?-$9H actions*and t8o melanocortin receptors identified as melanocortin receptor-4 )$C4#* and melanocortinreceptor-A )$CA#*5 Dhereas ?-$9H is an agonist of +oth $C4# and $CA# "g#P serves toantagoni e the actions of ?-$9H at these same receptors 8ith highest antagonist activity on $CA#5 Inaddition to antagoni ing the effect of ?-$9H at the $C4# and $CA# "g#P suppresses the +asalactivity of the $CA# thus defining "g#P as an inverse agonist5

'he close functional relationship +et8een "g#P and NP! is demonstrated +y the fact that theexpression of these t8o peptides is similarly modulated under identical physiological conditions suchas negative energy +alance or increased energy demand that occurs during food deprivation5 &uring

periods of fasting +oth "g#P and NP! levels rise and evidence indicates that this is due primarily to adrop in the level of the peripheral hormones leptin and insulin and a rise in ghrelin 5 "lso "g#P li(e

NP! sho8s a strong circadian rhythm in its expression rising at the onset of natural feeding cycles5 "sto +e expected the expression of +oth "g#P and NP! are conversely suppressed under conditions of

positive energy +alance5 In studies in experimental animals manipulations in diet also result inalterations in the levels of "g#P expression5 "g#P gene expression is higher in rats on a lo8-energydiet compared to a fat-rich diet or in conditions 8here glucose utili ation is reduced5 In fact +oth "g#Pand NP! are suppressed +y a single in:ection of glucose5 On the other hand in:ections of thecompound Intralipid )8hich increases circulating lipids* does not result in changes in "g#P levels5

'he strong orexigenic effects of "g#P can +e demonstrated +y in:ecting the peptide into the +rain ofexperimental animals5 Central in:ection of "g#P has a potent stimulatory effect on food inta(e 8hichcan also +e seen using a $CA# antagonist5 'hese results confirm the function of "g#P as an antagonistof ?-$9H5 'he food inta(e stimulation exerted +y in:ection of "g#P is similar to that seen +y centralin:ection of NP! 8ith differences +eing that the duration of the effect 8ith "g#P is much longer thanthat exerted +y NP!5 Ho8ever the long-term effect does not involve the $CA# 8hich indicates that"g#P li(ely induces long-term changes to the neural signaling path8ays do8nstream of this receptor5Chronic administration of "g#P results in increased daily food inta(e 8hile simultaneously decreasing
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oxygen consumption and the capacity of +ro8n adipose tissue to expend energy5 'hese chronic effectsresult in increased fat mass accumulation all of 8hich are effects similar to those seen 8ith chronicadministration of NP!5 In complimentary studies using transgenic mice that overexpress the "g#Pgene it has +een sho8n that increased levels of "g#P result in increased feeding +ehavior and foodinta(e5 'hese mice exhi+it hyperphagia and o+esity in addition to increased +ody lengthhyperinsulinemia late-onset hyperglycemia and pancreatic-islet hyperplasia5 'hese results are similar

to those seen in mice that ectopically express the NP! gene and are also evident in mice that har+or a$CA# (noc(-out5

'here exists an antagonism +et8een the actions of "g#P )and NP!* and the melanocortins incontrolling eating and +ody 8eight5 'his is evident from studies sho8ing changes in endogenous "g#Pthat are opposite to those seen 8ith the melanocortin peptides5 In addition +rain mapping sho8s that"g#P neurons interact 8ith PO$C neurons in the "#C through the inhi+itory neurotransmitter E-amino +utyric acid )G"B"*5 Both "g#P and NP! axons that co-locali e G"B" pro:ect onto PO$Cexpressing cells in the "#C and the "g#P-stimulated release of G"B" results in inhi+ition of theactivity of the PO$C neurons an effect also seen 8ith NP!5 Peripheral hormones that act on the "#Cand there+y affect the actions of "g#P and NP! are leptin and ghrelin5 %eptin +inds to its receptor

present on "G#P and NP! neurons and inhi+its their firing resulting in reduced G"B" release onto

PO$C neurons5 'his leptin-induced reduction in G"B" action at PO$C neurons is a disinhi+ition andis in part the mechanism +y 8hich leptin decreases feeding +ehaviors5 Conversely ghrelin +inding itsreceptor activates "g#P and NP! neurons resulting in an increase in G"B" release 8ith resultantinhi+ition of PO$C neurons5

Given that "g#P and NP! 8hich are activated under similar conditions and have compara+le effectsindicates that they very li(ely evolved to ensure the signaling of hunger during food scarcity and toena+le the +ody to endure long periods of negative energy +alance5

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Melanin-Concentrating Hormone" MCH$elanin-concentrating hormone )$CH* 8as originally identified as a / amino acid cyclic peptide thatinduced the lightening of the s(in in fish5 9u+se>uently the peptide 8as identified in rodents to +eoverexpressed in response to fasting and also elevated in genetically o+ese mice ) ob/ob mice*5 Inhumans and other mammals $CH is expressed exclusively in the lateral hypothalamus and onaincerta )region of gray matter cells in the su+thalamus +elo8 the thalamus*5 In humans there are t8o G-

protein coupled receptors )GPC#s* that +ind $CH identified as $CH # and $CH2#5 #odentsho8ever do not possess the $CH2# gene5 $CH # is a typical GPC# that couples to the activation of

+oth G > and G i type G-proteins5 'he G > class of G-protein activates phospholipase C-E )P%CE*

resulting in increases in intracellular Ca 2 5 'he G i class represses adenylate cyclase activity resulting indecreased c"$P production5 ,xpression of $CH # is seen throughout the +rain 8ith highest levels inthe cortex hippocampus amygdala and nucleus accum+ens5 $CH # expression is also seen in

peripheral tissues such as adipose tissue intestines lymphocytes and the pituitary5 'he pattern ofcentral nervous system expression of $CH and $CH # suggests that this peptide-receptor system isinvolved in a host of physiological functions 8ithin the +rain5

Involvement of $CH in the regulation of feeding +ehaviors and energy homeostasis has +een sho8n inmice 8here either the $CH gene or the $CH # gene have +een (noc(ed out5 "dditional information
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on the function of $CH in feeding and energy consumption has +een o+tained 8ith the use of selective pharmacological $CH # antagonists5 In mice lac(ing the $CH gene the prominent phenotype ishypophagia )reduced desire for food inta(e* and lean +ody mass5 'hese results indicate that $CH is animportant orexigenic )appetite stimulating* hormone5 In contrast central administration of $CH resultsin increased food inta(e in mice5 Dhen the $CH # gene is (noc(ed out mice are hyperphagichyperactive and lean5 Dhen $CH # antagonists are administered peripherally animals exhi+it

decreased $CH-induced food inta(e5 In addition if $CH # antagonists are chronically administeredthere is o+served a decrease in +ody 8eight in rats that had diet-induced o+esity5 $CH # antagonistshave +een sho8n to modulate leptin secretion and insulin release 8hich suggests that the 8eight lossassociated 8ith systemic antagonist administration is due to +oth central and peripheral effects5 $anystudies indicate that $CH # antagonists modulate energy homeostasis and thus the anti-o+esityeffects are due primarily to increased energy expenditure and not to suppression of feeding +ehaviors5

In addition to modulation of feeding +ehaviors and energy expenditure the $CH system has +eensho8n to +e involved in affective disorders such as anxiety and depression5 $ice in 8hich the $CH #gene has +een (noc(ed out exhi+it less anxiety-li(e +ehaviors than 8ild-type mice5 "dministration of$CH # antagonists have also +een sho8n to have anxiolytic )reducing anxiety* properties5 'hesestudies indicate that the $CH system is important in the modulation of stress responses5 $CH #

antagonists have also +een sho8n to +e efficacious in animal models of depressive +ehavior althoughthe precise mechanism for the antidepressant effects are not yet clearly defined5

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The $re%ins'he orexins constitute t8o neuroendocrine peptides derived from the same gene5 'hese peptides aredesignated orexin " and orexin B5 'he orexins are also called the hypocretins as the peptides 8ereindependently isolated5 One group used a su+tractive c&N" screening approach to enrich for c&N"sfrom the hypothalamous )identified as hypocretins* and another group 8as screening for ligands thatactivated orphan G-protein coupled receptors )GPC#s* that 8ould induce transient calcium currents inGPC#-expressing cells5 'he latter group demonstrated that the identified ligands induced orexigenic)appetite stimulating* responses and thus named the peptides orexin " and orexin B5 Orexin "corresponds to hypocretin )HC#'- * and orexin B corresponds to hypocretin 2 )HC#'-2*5

Isolation of the human orexin gene located on chromosome >2 demonstrated that the encoded protein 8as a pre-proprotein that contained the amino acid se>uences of +oth orexin " and orexin B5'he prepro-protein contains a 42 amino acid leader se>uence typical of secreted proteins5 'he orexin

prepro-protein is 4 amino acids in length 8ith the 44 amino acid orexin " peptide encoded +y aminoacids 4410 and the 2 amino acid orexin B peptide encoded +y amino acids 0/1/05 Both orexin " andorexin B peptides are C-terminally amidated5 'he N-terminal glutamine residue of orexin " is cycli edinto a pyroglutamyl residue and the peptide contains t8o intrachain disulfide +onds5 'he amino acidse>uences of verte+rate orexin " peptides are 33 conserved and those of verte+rate orexin B

peptides are /4 conserved5 Overall the full-length prepro-proteins are conserved across variousverte+rate species5 9tructurally +oth orexin " and orexin B are highly conserved and this structuralconservation explians the a+ility of the orexin receptors to +ind +oth peptides5 'here are t8o orexinreceptors identified as O< # and O< 2# )also identified as HC#'# and HC#'#2 respectively*5

O< # exhi+its an order of magnitude higher affinity for orexin " compared to orexin B 8hereas O< 2#

has +een sho8n to +ind +oth peptides 8ith e>ual affinity5 'he orexin receptors are typical GPC#s 8ith


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O< # coupling to the G > su+class of G-proteins and O< 2# coupling to +oth the G > and G i class of G-

protein5 'he G > class of G-protein activates phospholipase C-E )P%CE* resulting in increases in

intracellular Ca 2 5 'he G i class represses adenylate cyclase activity resulting in decreased c"$P

production5

'he cell +odies of orexin expressing neurons are found in the lateral and posterior hypothalamic areas8ith axonal pro:ections throughout the +rain5 ,xpression of the orexin receptors is also 8idelydistri+uted throughout the central nervous system5 'his distri+ution of orexin and orexin receptorexpression is suggestive of important roles in the emotional and motivational aspects of feeding

+ehavior5 Indeed as their name implies in:ection of orexin peptides into the +rain 8as sho8n toincrease food consumption in rats5 Ho8ever in addition to increased feeding +ehavior centraladministration of orexins increases 8a(efulness and suppresses #,$ sleep5 'hese latter o+servationsdemonstrate that orexins play a causative role in the regulation of sleep-8a(e cycles5 9u+se>uentresearch demonstrated that loss of orexin function results in a condition in animals that mimics thesleep disorder in humans (no8n as narcolepsy5 Dhen the orexin gene is (noc(ed out in mice theyexhi+it increased #,$ sleep during dar( periods 8hen they are normally a8a(e5 In addition these micehave fre>uent episodes of sudden collapse during dar( cycles that resem+les cataplexy in humans5

Cataplexy often accompanies narcolepsy in humans5 In human narcolepsy patients there is a significantreduction in the amount of detecta+le orexin " and orexin B as 8ell as an 3 1 33 reduction in thenum+er of neurons that contain detecta+le prepro-orexin m#N"5 Ho8ever no mutation has +een foundin either the prepro-orexin or orexin receptor genes except for one rare early onset severe case 8herethere 8as a mutation in the signal peptide of prepro-orexin that impaired protein traffic(ing and

processing5 'here is an association +et8een certain H%" alleles and narcolepsy that suggests thereduced orexin levels may result from selective autoimmune destruction of orexin neurons5 &ogs thathar+or a null mutation in the O< 2# gene exhi+it a narcolepsy phenotype that is highly similar to human

narcolepsy5

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Galanin" G#&Galanin )G"%* is a 2/ amino acid peptide 8hose name is derived from the fact that it contains an N-terminal glycine residue and a C-terminal alanine5 G"% is expressed in the gut and the +rain 8ith 8idedistri+ution throughout the hypothalamus including the P=N the PF%H and "#C5 'he expression ofG"% in the hypothalamus is directly correlated to its role in energy homeostasis and the control offeeding +ehaviors5 In addition to regulating feeding G"% serves as a gro8th and prolactin-releasingfactor to the lactotroph especially in states of high estrogen exposure is involved in learning andmemory through effects in the hippocampus and is involved in pain and sei ures5 "dditionally G"%exerts affective responses such as mood disorders and anxiety5 G"% exerts these myriad effects via

+inding to three distinct G protein-coupled receptors )GPC#s* identified as G"%# G"%#2 andG"%#45 'he highest levels of expression of G"%# are seen in hypothalamic nuclei that includes theP=N and supraoptic nucleiJ G"%#2 in the "#C &$H and P=NJ and G"%#4 in the P=N =$H and&$H5 Dhen G"% is in:ected into the third ventricle of the +rain or into the P=N it elicits a strongorexigenic )increased feeding* response 8ith a preference for fat over protein and car+ohydrates5 'hefeeding +ehavior responses to G"% exposure are primarily due to +inding G"%# in thehypothalamus5


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"lthough G"% is an orexigenic peptide it has mar(ed differences in its responses to food deprivationand inta(e and the signals it induces compared to those of NP! and "g#P in terms of theirresponsiveness to endocrine and physiological signals5 In:ection of G"% results in a stimulatory effecton feeding +ehavior yet the response is smaller and of shorter duration than that induced +y NP!5 'hefeeding response elicited +y G"% has little impact on food preference 8hether for car+ohydrate or fat8hereas the responses to NP! result in a preference for car+ohydrates5 In addition G"%-induced

feeding is greatly attenuated 8hen fat is removed from the diet5 'he primary function of G"% 8hen ananimal is consuming a high-fat diet is to restore car+ohydrate +alance through +ehavioral andmeta+olic actions under conditions 8here car+ohydrate inta(e and meta+olism are suppressed5 'headrenal steroid corticosterone only transiently inhi+its G"% gene expression in P=N neurons and hasno effect on feeding responses of G"%5 In contrast this steroid hormone has a potent stimulatory effecton NP! and "g#P and on NP!-induced feeding5 "lthough insulin suppresses +oth G"% and NP!expression leptin strongly inhi+its NP! gene expression and release yet produces little or no change in

+asal G"% expression in the "#C and only a small suppression of G"% expression in the P=N5 'hedifferential responsiveness of G"% neurons to leptin is li(ely due to the lo8 concentration of leptinreceptors on G"% neurons5 'he lo8 leptin receptor level on G"% neurons compared to NP! neuronsalso explains their different responses to food restriction 8hich reduces leptin levels5 Food restrictiondoes little to the level of G"% expression 8hile mar(edly enhancing NP! gene expression5 &ifferencein G"% and NP! expression are also found under conditions of altered nutrient meta+olism5"dministration of inhi+itors of fatty acid oxidation suppress G"% expression +ut have no effect on

NP!5 Conversely administration of inhi+itors of glucose oxidation do not alter G"% expression +utresult in elevated expression of NP!5 'hese nutrient differences are also o+served in experimentalanimals fed different diets5 G"% expression in the P=N is stimulated +y a high-fat diet 8hereas NP!expression in the "#C is unaffected or reduced +y fat consumption5 'hese differences in response tofat-rich diets are also seen 8ith fat accumulation and are li(ely the result of differences in responses toleptin5 'he a+ility of G"% to exert its stimulation of feeding responses may +e due to its interactions8ith other peptide systems5 'he opioids are +elieved to have some role in mediating G"%-inducedfeeding since the opioid receptor agonist naloxone attenuates the G"% feeding response5 G"% mayalso induce feeding via an inhi+ition of the anorexigenic melanocortin systyem )PO$CJ see +elo8*5'his is suggested +y evidence that PO$C neurons in the "#C are innervated +y G"% expressingneurons as 8ell as expressing the G"%# gene5 ,vidence indicates that G"% has a direct inhi+itoryaction on "#C neurons expressing G"%# as 8ell as modulating the secretory activity of PO$Cneurons5

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P$MC-'erived Melanocortins'he PO$C-derived melanocortin peptides include ?-$9H K-$9H E-$9H "C'H

-2A

and "C'H- 4

1 NH 2 )desacetyl-?-$9H*5 'he PO$C-derived melanocortins +elong to a family of peptides referred to

as the melanocortin system5 'his system includes the PO$C-derived melanocotins 8hich exhi+itagonist activities the antagonist peptide "g#P the melanocortin receptors )$C#* and themelanocortin receptor accessory proteins )$#"Ps*5 'he $C# family of receptors consists of fiveidentified mem+ers termed $C # through $C #5

'he melanocortin system has +een sho8n to +e critical in the regulation of food inta(e and energyexpenditure via a num+er of different assay systems involving +oth humans and animals5 It is importantto note that although K-$9H and E-$9H are found to +e produced in human +rain they are not found in


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rodent +rain or pituitary5 Ho8ever 8hen administered into the +rain of animals the melanocortins ?-$9H K-$9H and "C'H -2A inhi+it the inta(e of food5 'he actions of $9H peptides in feeding

+ehavior is exerted primarily via peptide +inding to the $CA# and to a lesser extent to the $C4#5Genetic mutations in humans as 8ell as in animals that disrupt the expression and processing )thisincludes the proteases that process the PO$C precursor* of PO$C peptides and $C#s are associated8ith changes in energy +alance and can lead to o+esity and type 2 dia+etes5 In humans there have +een

mutations identified in prohormone convertase @4 )PC @4* and car+oxypeptidase , )CP,* as 8ell asin the ?-$9H degrading en yme prolylcar+oxypeptidase )P#CP* that are associated 8ith energyim+alance and a propensity for o+esity5 In mice a mutation in the CP, gene also results in thedevelopment of late-onset o+esity5 In genome-8ide screens for gene polymorphisms associated 8ith anincreased ris( of developing type 2 dia+etes the $CA# gene 8as identified5 $utations in the $CA#gene are the most fre>uent causes of severe o+esity in humans5

In mice a+lation of the PO$C gene )PO$C-null* results in via+le animals even though they haveminimal adrenal tissue and undetecta+le glucocorticoids due to the lac( of "C'H5 'hese animalsdevelop o+esity +ut do not +ecome dia+etic5 "lthough not dia+etic these mice do have a disruption inthe regulation of glucagon secretion in response to experimental hypoglycemia5 'his indicates thatPO$C-derived peptides are involved in the regulation of glucagon5 In humans a rare PO$C-null

mutation has +een descri+ed5 Lnli(e the situation in the PO$C-null mice humans 8ith a lac( ofPO$C expression are una+le to survive 8ithout glucocorticoid supplementation from +irth5 Individualsthat survive have red hair dramatically increased desire for food inta(e and high propensity foro+esity5 'hese conditions are the same as those seen in PO$C-null mice5 "nother PO$C mutation thathas +een identified in humans resulting in o+esity is a point mutation in the cleavage site +et8een K-$9H and K-endorphin5 'he conse>uences of this mutation suggests that K-$9H may +e a significantendogenous anorectic agonist that activates the $CA#5

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Cocaine- and #mphetamine-RegulatedTranscript" C#RT'he cocaine- and amphetamine-regulated transcript )C"#'* peptides are neuroendocrine peptidesinvolved in feeding +ehavior drug re8ard systems stress cardiovascular functions and +oneremodeling5 ,xpression of the C"#' gene is essentially confined to hypothalamic neuroendocrineneurons and lim+ic system circuits involved in re8ard processes5 C"#' peptides are found areas of the

+rain involved in the control of feeding +ehaviors including regions of the hypothalamus such as the=$N lateral hypothalamus )%H* P=N N'9 "#C and the nucleus accum+ens5

'he human C"#' gene )sym+ol M C"#'P' for C"#' prepro-peptide* is located on chromosome> 21> A and is composed of three exons5 'he gene is transcri+ed into t8o alternatively spliced

m#N"s that encode proC"#' peptides of different lengths identified as proC"#' - / and proC"#' - 325 Ho8ever only the proC"#' - / peptide is found in humans5 'he proC"#' proteincontains a signal se>uence typical of secreted proteins and is re>uired for insertion of the protein intovesicles and su+se>uent processing5 'he active portions of the C"#' peptides are located do8nstreamof the alternatively spliced region and thus +oth proC"#' - / and proC"#' - 32 encode the same

+iologically active hormones5 'he proC"#' proteins contain several sites for post-translational processing +y prohormone convertases5 In humans 8here only the short form proC"#' - / peptide is present the processing yields C"#' peptides identified as C"#' A2- / and C"#' A/- /5 In rodents
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8here +oth C"#' m#N" transcripts yield proC"#' proteins the nomenclature of the processed peptide reflects the amino acid num+ering of the longer 32 amino acid pro-protein and are identifiedas C"#' - 32 and C"#' 02- 325 'here is a high degree of interspecies conservation of the activeC"#' peptide se>uences 8ith the human rat homology +eing / 5 " definitive C"#' receptor has asyet not +een isolated5 Ho8ever several lines of evidence indicate that C"#' peptides +ind 8ith highaffinity and specificity to a cell surface protein)s* that triggers signaling events typical of a GPC# class

receptor5 In cell culture assays addition of C"#' peptides results in phosphorylation of extracellularsignal-regulated (inase ),#;* as 8ell as the transcription factor cyclic "$P response element +inding protein )C#,B*5 'hese results indicate that the C"#' receptor is a GPC# that activates the G i@o class

of G-proteins5

" role for C"#' peptides in the regulation of feeding +ehaviors 8as demonstrated in animal models8here intracere+rovascular )icv* in:ection results in decreased food inta(e5 'hese types of resultsindicate that C"#' peptides are anorexigenic )decrease appetite*5 Dithin the "#C of the hypothalamusC"#'-peptide containing neurons are surrounded +y NP! expressing nerve terminals5 'he distri+utionof C"#' and NP! in the "#C suggests that these t8o neuropeptides may exhi+it cross-tal( in theregulation of feeding since NP! is an orexigenic )appetite stimulating* hormone and C"#' is ananorexigenic hormone5 Dhen animals are food-deprived the level of C"#' m#N" in the "#Cdecreases5 Conversely 8hen leptin is administered to animals the level of C"#' m#N" in the "#Cincreases5 In addition in animals 8ith disrupted leptin signaling the level of C"#' m#N" is nearlyundetecta+le in the "#C5 'he functions of C"#' peptides in inhi+iting the desire for food inta(e mayinvolve circuits that include the serotonin-A receptor and $&$" receptors5 $&$" is 4 A-methylenedioxy- N -methyl-amphetamine more commonly (no8n as ecstasy 5 Dhen C"#' m#N"levels are experimentally reduced the anorectic effects of $&$" as 8ell as serotonin-A receptoractivation are a+olished5 In addition mice in 8hich the C"#'P' gene has +een (noc(ed out exhi+itincreased desire for feeding and gain 8eight5

9everal human studies have also indicated that C"#' peptides function in appetite control5 In an Italianfamily 8here several mem+ers are o+ese it 8as found that a missense mutation 8as present in their

C"#' gene5 'his mutation changed a %eu at position 4A to a Phe and resulted in deficiency of C"#' peptide in the +lood5 If this mutant human gene is expressed in a mouse pituitary tumor cell line theexpressed protein is poorly processed and secreted5 In another study of mor+idly o+ese individuals inFrance a single nucleotide polymorphism )9NP* 8as identified in the C"#' gene at position 14038here a ' 8as replaced 8ith a C5 In a study examining the promoter region of the C"#' gene fromseveral hundred individuals it 8as found that a polymorphism resides approximately 0(+ upstreamthat may +e associated 8ith o+esity5

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Galanin-li(e peptide" G#&PGalanin-li(e peptide )G"%P* is a 03 amino acid peptide that is structurally related to galanin hence thederivation of its name5 "mino acids /12 of G"%P are identical to the first 4 amino acids of G"%5'he structural and se>uence similarities +et8een G"%P and G"% explain the fact that G"%P functions

+y +inding 8ith high affinity to G"% receptors5 Ho8ever there are differences in affinities of the t8o peptides for the different G"% receptors5 G"% +inds all three receptor su+types )G"%# G"%#2 andG"%#4* 8ith similar affinities 8hereas G"%P +inds 8ith highest affinity to G"%#4 follo8ed +yG"%#2 8ith G"%# +inding 8ith least affinity5 ,xpression of G"%P is almost exclusively found in


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the hypothalamic "#C and G"%P neurons pro:ect to the P=N +ut not the lateral hypothalamus5

Central in:ection studies revealed the anorexigenic effects of G"%P as 8ell as its responsiveness to theeffects of leptin5 Ho8ever it should +e noted that there are differences in the responses to G"%Pin:ection 8hen comparing rats and mice5 In:ection of G"%P into mice results in the inhi+ition offeeding responses and also leads to an increase in energy expenditure and fat oxidation in +ro8nadipose tissue resulting in a hyperthermic effect5 In contrast in:ection of G"%P into rat +rains results in

an orexigenic response5'he leptin receptor is expressed on most G"%P neurons and expression of G"%P in the "#C isinduced +y leptin5 In contrast G"%P expression in the "#C is significantly reduced in leptin-deficient)ob/ob * and leptin receptor-deficient ) db/db * mice5 Food deprivation results in reduced circulatinglevels of leptin and this in turn reduces the rapid entry of circulating G"%P into the +rain5 Fastingresults in a decrease in +oth the level of G"%P m#N" as 8ell as the num+er of G"%P expressingneurons5 %eptin administration 8ill restore G"%P expression in fasted animals as 8ell as in leptin-deficient ) ob/ob * mice5

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Corticotropin-releasing factor )CRF* andrelated peptidesCorticotropin-releasing factor )C#F also (no8n as corticotropin-releasing hormone C#H* +elongs toan interacting family of proteins that includes C#F at least t8o different C#F receptor su+types )C#Fand C#F2* a C#F-+inding protein )C#F-BP* and the urocortins 8hich are endogenous C#F receptorligands5 'here are three (no8n urocortins identified as urocortin 2 and 4 )Lcn Lcn2 Lcn4*5 'heurocortins are also identified +y #oman numeral designations urocortin I II and III5 C#F is a A amino

acid peptide that is found 8idely expressed in the +rain5 C#F-expressing neurons are a+undant in thehypothalamic P=N 8here they control the pituitary-adrenal axis regulating the release of "C'H andglucocorticoids5

Lcn is a A3 amino acid peptide that is expressed primarily in the lateral hypothalamus and supraopticnucleus 8ith urocortin-containing neurons pro:ecting to the =$H5 Lcn2 is a A4 amino acid peptideand is expressed in the mouse hypothalamus in the P=N and "#C5 In humans increased Lcn2expression is also seen in cardiac myocytes during heart failure5 Lcn4 is a 4 amino acid peptide 8hoseexpression is found in the rostral perifornical area lateral to the P=N 8ith Lcn4 neurons pro:ectingthroughout the hypothalamus and the lim+ic system5 Lcn4 expression is also high in pancreatic K-cells8here it stimulates insulin as 8ell as glucagon secretion5

C#F and the urocortins function through t8o G protein-coupled receptors C#F and C#F25 C#F andLcn +ind 8ith high affinity to the C#F 5 In contrast Lcn2 and Lcn4 +ind 8ith much higher affinitythan C#F to C#F2 and are therefore are li(ely to +e the endogenous ligands of this receptor5 Inaddition to +inding to t8o receptors C#F and urocortins also +ind to C#F-BP 8hich is expressed inassociation 8ith C#F-expressing neurons in many +rain areas including the hypothalamus5 C#F-BPacts as an inhi+itor of +oth C#F and the urocortins there+y modulating the +iological actions of these

peptides5

Hypothalamic expression of C#F is negatively regulated +y the circulating level of cortisosterone suchthat C#F m#N" and protein levels are highest 8hen corticosterone levels are declining5 In rodents


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8ho feed during the dar( cycle corticosterone levels rise at the onset of feeding and C#F levelsdecrease5 Glucocorticoids also negatively regulate C#F expression5 'his effect of glucocorticoids onC#F expression supports a permissive role for the adreanl steroids in promoting +ody fat accrual5&ia+etes leads to increased C#F expression in the P=N and this effect is can +e further enhanced +ythe administration of insulin5 ,xpression of C#F is also stimulated in states of positive energy +alanceand is reduced in states of negative energy +alance such as food deprivation5 Circulating nutrients also

affect the level of C#F expression5 Dhen glucose levels rise C#F levels decline 8ith the oppositeoccurring 8hen glucose levels fall5 In contrast to the changes in C#F levels in response to serumglucose changes excess fat consumption does not appear to alter C#F expression5

Central administration of C#F results in suppression of spontaneous feeding responses demonstratingits anorexigenic properties5 'he C#F-mediated suppression of feeding occurs along 8ith a stimulationsympathetic nervous system activity and resting oxygen consumption 8hich results in increased fatmo+ili ation and oxidation and raises +lood glucose 8hile inhi+iting insulin secretion5 Centraladministration of Lcn also suppresses feeding and its effect is strongest in the P=N and more potentand longer-lasting than that of C#F5 Lcn2 administration also suppresses food inta(e as 8ell asresulting in delayed gastric emptying and decreased heat-induced edema5 Chronic administration ofC#F +ut not Lcn increases +ro8n adipose tissue mass and raises circulating levels of corticosterone

and lipids 8hile reducing the levels of glucose5 ,xperimental evidence indicates that C#F2 mediatesthe anorectic effects of these ligands 8hile C#F mediates their meta+olic effects5 $ice lac(ing theC#F2 receptor exhi+it a +lunted response to the feeding-inhi+itory effects of urocortin and selectiveC#F2 receptor antagonists +loc( the suppressive effects of urocortins and C#F on food inta(e and

+ody 8eight5

'he role of C#F as an anorexigenic hormone may involve the NP! melanocortin and C"#' systemsacting in a do8nstream fashion5 'he C#F neurons in the hypothalamus co-locali e 8ith +oth the NP!! receptor and the $CA#5 In addition C#F expression in the P=N is stimulated +y centraladministration of a melanocortin agonist +ut is inhi+ited +y an $CA# antagonist5 'here is anantagonistic relationship +et8een C#F and NP! demonstraetd +y the fact that administration of C#Fand Lcn result in a reduction in +oth NP! expression and NP!-mediated feeding5 "lsoadministration of C#F antagonists result in increased NP!-induced feeding responses5 In contrast to theC#F-NP! antagonism central administration of C"#' activates C#F neurons in the P=N indicatingthat C#F may mediate the anorectic effect of C"#'5 %eptin is also involved in the effects of C#F andthe urocortins as demonstrated +y the fact that the anorexigenic actions of leptin are attenuated in the

presence of C#F antagonists5 %eptin also facilitates the upta(e of Lcn into the +rain there+y potentiating its anorexigenic actions5

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Hypothalamic &ipid Meta+olism and ,nergyHomeostasisHypothalamic Fatty #cid Meta+olism

Dithin the central nervous system the meta+olism of fatty acids is primarily for the purposes ofmem+rane function and the central regulation of energy meta+olism5 Fats do not serve as a ma:orsource of energy 8ithin the +rain this need is o+tained from the oxidation of glucose and (etone


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+odies5 "lthough (etone +odies are essentially derived from fatty acids )via the acetyl-Co" derivedfrom K-oxidation* these compounds arrive in the +rain from the +lood +eing produced 8ithin the liver5"l+umin-+ound fatty acids gain access into the +rain across the +lood-+rain +arrier )BBB* +y +oth

passive diffusion and protein carrier-mediated transport via F"'@C&40 and F"'P 5 For information onfatty acid transport into cells visit the Fatty "cid Oxidation page5

Once fatty acids are ta(en up +y cells in the +rain they are activated through the action the various fatty

acyl-Co" synthetases5 "lthough fatty acyl-Co"s are su+strates for K-oxidation the rates ofmitochondrial fat oxidation are extremely lo8 in the +rain5 'he fates of fatty acyl-Co"s in the +rainare conversion into various structural entities including phospholipids triacylglyceridesdiacylglycerides and fatty acyl-carnitine species as 8ell as lipid-derived signaling molecules5 9tudiesusing palmitic acid have demonstrated that the ma:ority of palmitate is incorporated into the neutrallipid fraction principally consisting of triacylglycerides and non-esterified free fatty acids5 In additionin contrast to non-neural tissues the desaturation and elongation of palmitate 8ithin the +rainrepresents a very minor fate of the fat5 Instead palmitate is converted into fatty acids of less than 0car+on atoms5 'he largest pool of lipid derived from palmitate is phospholipid of 8hich the primaryspecies is phosphatidylcholine5

"lthough K-oxidation of fatty acids represents a minor if at all source of the "'P pool in neurons it isan important meta+olic path8ay determining the ultimate fate of fatty acids that enter the +rain5 "s aresult of fatty acid oxidation a num+er of a>ueous +yproducts are detected in the +rain such as fattyacyl-Co"s fatty acyl-carnitines (etone +odies and various amino acids5 Dhen using in vitro assays8ith palmitate it is found that the ma:ority of the car+ons from this fatty acid end up in the amino acidsglutamate glutamine aspartate asparagine and G"B"5 In addition numerous organic acids includingcitrate malate K-hydroxy+utyrate and acetyl Co" result from palmitate oxidation5 By far citraterepresents the largest +yproduct of fatty acid oxidation in the +rain5 'hese fates of fatty acids that enterthe +rain have +een 8or(ed out 8ith the use of a selective carnitine palmitoyltransferase )CP'- *inhi+itor5 "s discussed in the Fatty "cid Oxidation page regulation of the rate of fatty acid entry intothe mitochondria for oxidation is exerted +y malonyl-Co"-mediated inhi+ition of CP'- 5 Indeedinhi+ition of mitochondrial CP'- is emerging as a via+le target for the central regulation of feeding

+ehaviors and energy homeostasis5 Inhi+ition of +rain CP'- decreases the entry of fatty acid car+onsinto the a>ueous meta+olic pools +ut does not alter the distri+ution into various long-chain acyl-Co"compounds and triacylglycerides5

Fatty acids specifically long-chain fatty acids via the formation of long-chain fatty acyl-Co"s havevery recently +een sho8n to exert anorexigenic effects via the hypothalamus5 For example 8hen oleicacid is in:ected into cere+ral ventricles there is a resultant decrease in feeding +ehavior in la+oratoryanimals5 'he decreases in feeding +ehavior are associated 8ith declines in the expression and release of

NP! and "g#P in the hypothalamus5 In addition to reducing feeding +ehaviors central administrationof oleic acid is associated 8ith increased peripheral glucose homeostasis5 Oleic acid must +e convertedto its Co" derivative for these effects to +e exerted since it has +een sho8n that +loc(ade of fatty acyl-

Co" synthetase activity a+olishes the oleic acid-regulated glucose homeostasis5 $itochondrial CP'-activity has also +een sho8n to play a role in the central effects of fatty acids5 For example the -car+on fatty acid octanoic acid does not exert any anorexigenic effects and mitochondrial upta(e ofoctanoyl-Co" does not re>uire CP'- 5 "dditionally inhi+ition of hypothalamic CP'- leads to anincrease in cytosolic long-chain acyl-Co" content and results in anorexigenic effects5

Humans express three different CP'- genes identified as CP'- " CP'- B and CP'- C5 'he CP'- Bgene is not expressed in the hypothalamus and the level of hypothalamic CP'- " expression isminimal5 In addition the +inding affinity of CP'- " for malonyl-Co" is relatively lo85 'he CP'- Cgene is +rain specific and +inding of malonyl-Co" to the CP'- C protein is of similar affinity to that of
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the CP'- B isoform5 In experiments in mice it has +een sho8n that deletion of CP'- C results inreduced feeding +ehavior and lo8ered +ody 8eight similar to studies in 8hich hypothalamic malonyl-Co" levels are elevated5 'hese results point to the fact that hypothalamic malonyl-Co" levels li(ely

play a ma:or role in the control of feeding +ehaviors5 Ho8ever the precise mechanisms +y 8hichmalonyl-Co" and cytosolic long-chain fatty acyl-Co" interactions result in reduced appetite are notfully characteri ed5 In the CP'- C (noc(-out mice experiments although the animals exhi+ited

reduced feeding +ehavior they +ecame o+ese more >uic(ly on a high-fat diet than control animals eventhough they ate less5 "lso the +rain specific CP'- C isoform does not cataly e carnitine transferaseactivity5 'herefore precisely ho8 the inhi+ition of hypothalamic CP'- C leads to long-chain acyl-Co"accumulation remains unclear5

Hypothalamic Malonyl-Co# Regulation

"s indicated a+ove the +rain does not readily oxidi e fatty acids for energy production5 Ho8ever thema:or en ymes of the fatty acid +iosynthetic path8ay such as acetyl-Co" car+oxylase )"CC* and fattyacid synthase )F"9* are expressed in neuronal regions of the hypothalamus that are involved in energyhomeostasis5 =arious hormones and meta+olic fuels affect hypothalamic malonyl-Co" levels andmalonyl-Co" is considered a (ey satiety inducing signal in the +rain5 &uring periods of fastinghypothalamic levels of malonyl-Co" rapidly decrease and act as a signal of hunger5 Conversely duringfeeding hypothalamic levels of malonyl-Co" rapidly rise and act as a signal to stop eating5 'hereforean understanding of the regulation of hypothalamic malonyl-Co" levels is of significance especially8ith respect to efforts to control feeding +ehaviors in humans5

"s descri+ed in the %ipid 9ynthesis page the production of malonyl-Co" is cataly ed +y "CC5 'hereare t8o isoforms of "CC "CC and "CC2 )sometimes referred to as the "CC? and "CCK isoformsrespectively*5 ,xpression of "CC predominates in the liver 8hereas expression of "CC2

predominates in tissues 8ith a high oxidative capacity5 'hese differences in expression have led to thesuggestion that the malonyl-Co" produced +y "CC2 is preferentially involved in the regulation of fattyacid oxidation 8hereas malonyl-Co" produced +y "CC is preferentially involved in the regulation

of fatty acid synthesis5Both isoforms of "CC are allosterically activated +y citrate and inhi+ited +y palmitoyl-Co" and othershort- and long-chain fatty acyl-Co"s5 Citrate triggers the polymeri ation of "CC 8hich leads tosignificant increases in its activity5 "lthough "CC2 does not undergo significant polymeri ation)presuma+ly due to its mitochondrial association* it is allosterically activated +y citrate5 Glutamate andother dicar+oxylic acids can also allosterically activate +oth "CC isoforms5 "CC activity is alsoregulated +y phosphorylation5 Both "CC and "CC2 contain at least eight sites that undergo

phosphorylation5 'he sites of phosphorylation in "CC2 have not +een as extensively studied as those in"CC 5 Phosphorylation of "CC at three serine residues )9 / 9 233 and 9 2 * +y "$P; leads toinhi+ition of the en yme5 Glucagon-stimulated increases in c"$P and su+se>uently to increased P;"activity also lead to phosphorylation of "CC 8here "CC2 is a +etter su+strate for P;" than is "CC 5

'he role of "CC in regulating malonyl-Co" synthesis in the hypothalamus leading to anorexigeniceffects has +een demonstrated in studies on leptin 5 'he anorexigenic effects of leptin involve theactivation of "CC leading to increased malonyl-Co" levels in the "#C5 Dhen the activity of "CC2 isinhi+ited in the "#C leptin is una+le to reduce food inta(e and su+se>uent +ody 8eight +ecause it isno longer a+le to alter malonyl-Co" content 8ithin the "#C5 'his latter effect occurs even thoughleptin still induces an inhi+ition of "$P; indicating that malonyl-Co"-mediated effects on appetiteand feeding +ehaviors are do8nstream of any effects of "$P;5 'hese experimental results in animalsdemonstrate that "CC activity is an important regulator of feeding +ehaviors via the a+ility of "CC2 toregulate hypothalamic malonyl-Co" levels5 Potential differences in a+ility of "CC and "CC2 to elicit
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decreases in appetite are difficult to assess since deletion of "CC in mice results in em+ryoniclethality5

Hypothalamic Malonyl-Co# 'ecar+o%ylase )MC'*

'he intracellular levels of malonyl-Co" represent a +alance +et8een its synthesis from acetyl-Co" +y"CC and its utili ation in fatty acid synthesis +y F"9 as 8ell as +y its degradation to acetyl-Co" viathe action of malonyl-Co" decar+oxylase )$C&*5 Indeed $C& is involved in regulating malonyl-Co"levels in multiple tissues5 Inhi+ition of $C& results in reduced rates of fatty acid oxidation in highlyoxidative tissues such as the heart5 "s 8ell $C& inhi+ition leads to reduced triacylglyceride content inlipid synthesi ing tissues such as the liver5 Dhen hypothalamic $C& levels are experimentallyincreased in la+oratory animals there is a dramatic increase in food inta(e 8eight gain and ultimatelyresults in o+esity5

'ranscriptional regulation of the $C& gene is exerted +y PP"#? a ma:or transcription factor involvedin the regulation of fatty acid oxidation5 Hypothalamic PP"#? has +een sho8n to play a role in theregulation of appetite presuma+ly via enhanced expression of $C& 8ith the use of pirinixic acid8hich is a PP"#? agonist5 "s discussed +elo8 inhi+ition of fatty acid synthase )F"9* the rate-limiting

en yme inde novo

lipogenesis decreases appetite and promotes 8eight loss5 "dministration of pirinixic acid results in normali ation of malonyl-Co" levels in mice that have hypothalamic-specific(noc(-out of F"95 'he PP"#?-mediated increase in $C& results in reduced levels of malonyl-Co" inthe hypothalamus5 'his is associated 8ith increased food inta(e in the F"9 (noc(-out micedemonstrating that malonyl-Co" levels are indeed responsi+le for the hypophagic effects o+served inthe F"9 (noc(-out mice5

Hypothalamic Fatty #cid ynthase )F# *

"s indicated a+ove the intracellular levels of malonyl-Co" 8ill decline as it is incorporatred into denovo synthesi ed fatty acids via the action of F"95 'he role of F"9 in the regulation of feeding

+ehavior and appetite has +een demonstrated 8ith the use of the F"9 inhi+itors C and cerulenin as8ell as in F"9 (noc(-out mice )as indicated a+ove*5 Inhi+ition of F"9 causes potent anorexigeniceffects that are associated 8ith a reduction in hypothalamic NP! expression and increases inintracellular malonyl-Co" content5 $ice 8ith F"9 deleted specifically in the "#C and P=N regions ofthe hypothalamus exhi+it reduced appetite and 8eigh significantly less than control animals5

'he anorexigenic effects of F"9 inhi+ition 8ith the use of C may not +e due entirely to alterations inmalonyl-Co" content5 'he anorexigenic effects of C have also +een associated 8ith increases inglucose meta+olism 8hich results in increased levels of "'P5 Increases in "'P lead to inhi+ition of"$P; activity 8hich in turn results in reduced "$P;-mediated phosphorylation and inhi+ition of"CC5 'herefore there 8ill +e increased levels of malonyl-Co" demonstrating that malonyl-Co" isli(ely to +e the primary signaling molecule responsi+le for the hypophagic effects of C 5 F"9

inhi+itors such as C also activate the mammalian target of rapamycin )m'O#* and since m'O#and "$P; activities are inversely related they are li(ely to +e reciprocally involved in the regulationof appetite5

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Gastrointestinal Hormones and Peptides'here are more than 43 peptides currently identified as +eing expressed 8ithin the digestive tractma(ing the gut the largest endocrine organ in the +ody5 'he regulatory peptides synthesi ed +y the gutinclude hormones peptide neurotransmitters and gro8th factors5 Indeed several hormones andneurotransmitters first identified in the central nervous system and other endocrine organs have

su+se>uently +een found in endocrine cells and@or neurons of the gut5 =isit the Peptide Hormones pageto see a more complete list of gastrointestinal peptides and hormones and their modes of action5 'hefollo8ing discussion 8ill focus on the gut peptides 8ith the +est demonstrated roles in the control ofappetite and feeding +ehavior via their interactions 8ith signals produced in the hypothalamic-pituitaryaxis5

Hormone %ocation $a:or "ction

Cholecysto(inin )CC;* enteroendocrine I cells

predominantly in the

duodenum :e:unum

stimulates gall+ladder contraction and +ileflo8 increases secretion of digestiveen ymes from pancreas vagal nerves inthe gut express CC; receptors

Ghrelin

primary site is


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and increases energy consumptionJ has8ea( affinity for G%P- receptor as 8ellas glucagon receptor may mimicglucagon actions in liver and pancreas

Pancreatic polypeptidePP pancreas

inhi+its pancreatic +icar+onate and protein secretion

Peptide tyrosine tyrosineP!!

enteroendocrine % cells predominantly in theileum and colon

reduced gut motility delays gastricemptying inhi+ition of gall+laddercontraction induces satiety via actions inthe arcuate nucleus )"#C* of thehypothalamus

=asoactive intestinal peptide )=IP* pancreas

smooth muscle relaxationJ stimulates pancreatic +icar+onate secretion

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G&P-. and GIP'he glucagon gene encodes a precursor protein identified as preproglucagon5 &epending on the tissueof expression coupled 8ith the presence of specific proteases called prohormone convertases

preproglucagon can +e processed into several different +iological peptides in addition to glucagon5 'heglucagon-li(e peptides )principally glucagon-li(e peptide- G%P- * and glucose-dependentinsulinotropic peptide )GIP* are gut hormones that constitute the class of molecules referred to as theincretins 5 Incretins are molecules associated 8ith food inta(e-stimulation of insulin secretion from the

pancreas5

G%P- is derived from the product of the glucagon gene5 'his gene encodes a preproprotein that isdifferentially cleaved dependent upon the tissue in 8hich it is synthesi ed5 For example in pancreatic?-cells prohormone convertase 2 action leads to the release of glucagon5 In the gut prohormoneconvertase @4 action leads to release of several peptides including G%P- 5 Lpon nutrient ingestionG%P- is secreted from intestinal enteroendocrine %-cells that are found predominantly in the ileumand colon 8ith some production from these cell types in the duodenum and :e:unum5 Bioactive G%P-consists of 2 formsJ G%P- ) -4 * and G%P- ) -40*amide 8here the latter form constitutes the ma:ority) 3 * of the circulating hormone5

9tructure of the mammalian preproglucagon product sho8n in the middle5 On the top half are the processing results that occur 8hen the GCG gene is expressed in the gastrointestinal system and the +rain5 9ho8n on the +ottom half are the processing results that occur 8hen GCG gene is expressed inthe pancreas5 G#PPMglicentin-related pancreatic peptide5 IPMintervening peptide5 G%P-2Mglucagon-li(e peptide-25 Glicentin )composed of amino acids 10/* is found in the small intestine +ut the
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ma:ority is processed to G#PP and oxyntomodulin5 $PGFMma:or proglucagon fragment comprisesamino acids 21 and is found in the pancreas5

'he primary physiological responses to G%P- are glucose-dependent insulin secretion inhi+ition ofglucagon secretion and inhi+ition of gastric acid secretion and gastric emptying5 'he latter effect 8illlead to increased satiety 8ith reduced food inta(e along 8ith a reduced desire to ingest food5 'he actionof G%P- at the level of insulin and glucagon secretion results in significant reduction in circulating

levels of glucose follo8ing nutrient inta(e5 'his activity has significance in the context of dia+etes 5 'heglucose lo8ering activity of G%P- is highly transient as the half-life of this hormone in the circulationis less than 2 minutes5 #emoval of +ioactive G%P- is a conse>uence of N-terminal proteolysiscataly ed +y dipeptidyl peptidase I= )&PP I= or &PPA*5 &PPA is also (no8n as the lymphocytesurface antigen C&20 and has numerous activities unrelated to incretin inactivation )see &PPA page formore information on &PPA*5

"ll of the effects of G%P- are mediated follo8ing activation of the G%P- receptor )G%P- #*5 'heG%P- # is a typical seven-transmem+rane spanning receptor coupled to G-protein activation increasedc"$P production and activation of P;"5 Ho8ever there are also P;"-independent responses initiatedthrough the G%P- #5 Other ma:or responses to the actions of G%P- include pancreatic K-cell

proliferation and expansion concomitant 8ith a reduction of K-cell apoptosis )death*5 In addition G%P- activity results in increased expression of the glucose transporter-2 )G%L'-2* and gluco(inase genes

in pancreatic cells5

Glucose-dependent insulinotropic peptide )GIP* is derived from a 4-amino acid proprotein encoded +y the GIP gene and circulates as a +iologically active A2-amino acid peptide5 GIP is synthesi ed +yenteroendocrine ;-cells 8hose locations are primarily in the duodenum and proximal :e:unum5 'heoriginal activity associated 8ith GIP 8as the inhi+ition of gastric acid secretion and 8as thusoriginally called gastric inhi+itory peptide5 Ho8ever su+se>uent research demonstrated that this guthormone possessed potent stimulation of glucose-dependent insulin secretion5 In addition GIP hassignificant effects on fat meta+olism exerted at the level of adipocytes5 'hese actions includestimulation of lipoprotein lipase activity leading to increased upta(e and incorporation of fatty acids +y

adipocytes5 Dhereas GIP exerts positive effects on pancreatic K-cell proliferation and survival similarto that sho8n for G%P- the hormone does not affect glucagon secretion nor gastric emptying5 %i(eG%P- GIP is inactivated through the action of &PP-A5

'he GIP receptor )GIP#* is a seven-transmem+rane G-protein coupled receptor found on pancreatic K-cells5 #esponses to GIP have +een sho8n to +e defective in type 2 dia+etic patients5 Interestingly ingene (noc(-out mice it has +een sho8n that loss of the GIP# is correlated to resistance to o+esity evenif the animals are fed a high fat diet5

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$%yntomodulinOxyntomodulin )O


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43 minutes5 'he amount of O


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referring to the alimentary tract )the gut* and CC; B referring to the +rain5 Ho8ever +oth receptors are

found 8idely expressed in the CN9 as 8ell as the periphery5 'he CC; B receptor exhi+its e>ual affinity

for CC; and another gut peptide gastrin5 Gastrin is involved in the production and release of Hthere+y generating gastric acid5

Lpon +inding its receptors in the gut CC; induces contractions of the gall+ladder and release of

pancreatic en ymes and also inhi+its gastric emptying5 Dithin the +rain )specifically the medianeminence and ventromedial nucleus of the hypothalamus =$H* CC; actions elicit +ehavioralresponses and satiation5 'he CC;- receptor is +elieved to +e the receptor primarily responsi+le foralterations in feeding +ehavior5 ,vidence for this comes from the Otsu(a %ong ,vans 'o(ushima Fattyrat 8hich has a null mutation in the CC;- receptor5 'hese rats are hyperphagic and develop o+esityeven on a fat restricted diet5 'he situation is not entirely conclusive since (noc(-out of the CC;-receptor in mice does not result in a similar phenotype5 Ho8ever the a+ility of CC; to regulate foodinta(e has +een clearly demonstrated in numerous studies5 For example central administration of CC;results in reduced food inta(e5 Of significance to appetite control this effect is enhanced 8ith co-administration of leptin 5 'he synergistic effects of CC; and leptin may +e due to the fact that theirreceptors are co-locali ed to the same sensory vagal afferent neurons5

In humans the correlations +et8een CC; and o+esity are gro8ing5 9tudies have sho8n that the fastinglevels of CC; are lo8er in mor+idly o+ese individuals than in lean individuals5 In addition the post-feeding responses to CC; in mor+idly o+ese individuals in attenuated compared to lean individuals5'he primary appetite suppressing effects of CC; are exerted via its inhi+itory actions on NP! neurons)orexigenic neurons* in the &$H and the N'95

Lsing genome 8ide screens for polymorphisms in genes associated 8ith o+esity and@or increasedfeeding +ehaviors have sho8n a correlation to the CC; H4 haplotype5 Polymorphisms in the CC;-receptor gene may also predispose an individual to o+esity5 "lthough CC; is (no8n to +e involved insatiation it may have limited use as a therapeutic for the treatment of o+esity at least 8hen used alone5'his is due to the fact that 8hen studied in la+oratory animals administration of CC; resulted inreduced meal si e +ut the animals increased their fre>uency of food inta(e such that the overalloutcome 8as no net change in +ody 8eight5 Ho8ever given the synergistic actions of CC; and leptincom+ination therapies of these t8o hormones may prove useful5

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Ghrelin and $+estatinGro8th hormone secretagogues )GH9s* 8ere originally characteri ed +y small synthetic molecules thatacted upon the pituitary and hypothalamus leading to amplification of the pulsatile release of gro8th

hormone5 Ghrelin 8as first discovered +ased upon its a+ility to interact 8ith the GH9 receptor )GH9#*and stimulate the release of gro8th hormone5 Indeed ghrelin 8as found to +e the endogenous ligandfor the GH9#5 'he name ghrelin is derived from gro8th- hormone rel ease5 'he specific receptor to8hich ghrelin +inds and activates is identified as GH9# type a )GH9# a*5

'he ghrelin gene )sym+ol M GH#%* is located on chromosome 4p201p2 and is composed of exonsand encodes the ghrelin preproprotein that can undergo differential processing to yield mature ghrelin

peptide or o+estatin5 O+estatin exerts its effect in exact opposition to that of ghrelin5 'he nameo+estatin is derived from a contraction of o+ese and statin )to suppress*5 Dhereas treatment of animals8ith ghrelin results in increased appetite and food inta(e o+estatin treatment suppresses food inta(e5
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Ghrelin is produced and secreted +y the uired for its activity as for full-length ghrelin5 'he formation of des-ghrelin is the

conse>uence of alternative splicing due to an intron that reside +et8een the glutamines at positions 4and A )Q 4 and Q A* of the preproghrelin se>uence5

'he ma:or effect of ghrelin is exerted 8ithin the central nervous system at the level of the arcuatenucleus 8here it stimulates the release of neuropeptide ! )NP!* and agouti-related protein )"g#P*5'he actions of NP! and "g#P enhance appetite and thus food inta(e5 Dithin the hypothalamus ghrelinaction results in activation of "$P; leading to reduced intracellular levels of long-chain fatty acids5'he reduction in fatty acid levels appears to +e the molecular signal leading to increased expression of

NP! and "g#P5 Ho8ever it is important to note that the signaling events triggered +y ghrelin +indingto GH9# a are complex5 'here is activation of a G-protein coupled to P%C-E activation 8ith resultantactivation of P;C and an additionally coupled G-protein activates P;"5

'he secretion of ghrelin is the inverse of that of insulin5 'he primary mechanisms that are coupled to production of ghrelin are fasting hypoglycemia and leptin 5 Conversely inhi+ition of ghrelin production is exerted +y food inta(e hyperglycemia and o+esity5 'he action of ghrelin at the level ofincreasing the release of NP! is the exact opposite to that of leptin 8hich inhi+its NP! release5"dditional effects of ghrelin include inhi+ition of the expression of pro-inflammatory cyto(inesinfluences exocrine and endocrine functions of the pancreas controls gastric acid secretion and gastricmotility influences sleep patterns memory and anxiety-li(e +ehavioral responses5

O+estatin exerts its effect in exact opposition to that of ghrelin5 #elease of o+estatin suppresses foodinta(e and gastric emptying activity5 %i(e ghrelin 8hich is post-translationally modified o+estatin isalso modified +ut its modification is an amidation5 O+estatin 8as found to +ind to an orphan G-proteincoupled receptor )GPC#* identified as GP#4/5 ,vidence indicates that GP#4/ is also the inc-sensingreceptor )Rn#* that responds to Rn 2 in the processes of tissue repair5 GP#4/ is expressed in livergastrointestinal tract adipose tissue and pancreas5 "ctivation of the receptor results in increased c"$Pand conse>uent activation of P;" medicated signaling path8ays5 Dithin the pancreas GP#4/ has +eensho8n to regulate the expression of insulin receptor su+strate-2 )I#9-2* and pancreatic and duodenalhomeo+ox- )P&uired for increased insulin secretion5'here is some controversy as to 8hether or not GP#4/ is indeed the o+estatin receptor5 It is possi+lethat activation of GP#4/ +y preparations of o+estatin 8ere due to inc present in the assays5

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Pancreatic Polypeptide" PPPancreatic polypeptide 8as the first mem+er of the PP-fold family to +e isolated and characteri ed5 It8as originally found as an impurity in preparations of insulin from chic(en pancreas5 9u+se>uently it8as sho8n to +e produced and secreted +y type F cells 8ithin the periphery of pancreatic islets5 'hestimulus for the release of PP is the ingestion of food and the level of release is proportional to the

caloric inta(e5 Increased circulating levels of PP can +e detected in the +lood for up to 0 hoursfollo8ing ingestion of food5 Humoral signals that are involved in food inta(e-mediated secretion of PPinclude ghrelin cholecysto(inin )CC;* motilin and secretin5 "dditionally adrenergic stimulationsecondary to either hypoglycemia or exercise results in increased release of PP5 'he actions of PPinclude delaying gastric emptying inhi+ition of gall+ladder contraction and attenuation of pancreaticexocrine secretions5 'hese gut actions of PP are associated 8ith the mechanism referred to as the ileal

+ra(e 8hich is manifest 8ith the slo8ing of the passage of nutrients through the gut5

PP induces an anorexigenic response 8ithin the +rainstem )area postremus "P* and vagus5 'heseresponses are mediated via activation of the !A receptor 8hich +inds PP 8ith highest affinity5 Inaddition to its expression in the "P the !A receptor is also expressed in regions of the hypothalamusincluding the "#C5 'herefore additional anorexigenic responses to PP can +e induced 8ithin thehypothalamus5 'hus PP plays an important role in the regulation of satiety )the sensation of +eing full*5In o+ese individuals there is a reduced level of PP secretion in response to food inta(e 8hereas inanorexia nervosa there is increased PP release follo8ing consumption of food5 PP may also play a rolein the pathogenesis of Prader-Dilli syndrome )PD9* 5 'his disorder is characteri ed +y short staturereduced intellect and hyperphagia )excessive hunger and a+normally large food inta(e*5 In patients8ith PD9 there is a reduced secretion of PP in response to food inta(e as 8ell as a reduced +asal levelof circulating PP5

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Protein Tyrosine Tyrosine" P!!P!! is produced +y and secreted from intestinal enteroendocrine %-cells of the ileum and colon5"dditional gut hormones that are secreted along 8ith P!! include G%P- and oxyntomodulin )O


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released in response to the ingestion of food is proportional to the caloric inta(e5 "nimal and humanstudies of anorectic conditions indicate that P!! has a critical role in satiety5 Dithin the CN9 P!!exerts its effects on satiety via actions in the hypothalamus specifically the "#C of the hypothalamus5'he "#C is in close proximity to the deficient +lood-+rain +arrier of the median eminence of thehypothalamus thus allo8ing this region to respond rapidly to the release of a gut hormone into thecirculation5 ,vidence confirming the role of P!! 4-40 in inducing anorexia has +een o+tained in mice

+y direct in:ection of the peptide into the "#C5 P!! 4-40 has +een sho8n to exert the inhi+ition on foodinta(e in a !2-dependent manner5 "lthough it 8as proposed that P!! 4-40 might exert its anorexigenic

effects +y activating !2 receptors on PO$C neurons in the "#C the P!! 4-40 -induced inhi+ition of

food inta(e has +een sho8n to still occur in PO$C (noc(out mice5 Given the role of P!! in appetitesuppression it is thought that distur+ances in P!! release in response to food inta(e may play a role inthe development of o+esity5 Indeed in o+ese humans there is a +lunted P!! response follo8ing foodinta(e compared to lean humans5 Current therapeutic interventions designed to com+at o+esity involvestudies of the efficacy of P!! at suppressing appetite5

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#eturn to 'he $edical Biochemistry Page

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Gut Brain Relationship