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Gut-Brain Interrelationships and Control of Feeding Behavior


Introduction 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 energy meta+olism nutrient partitioning and the control of feeding +ehaviors5 'he gastrointestinal tract is intimately connected to the actions of the hypothalamic-pituitary axis via the release of peptides that exert responses 8ithin the +rain as 8ell as through neuroendocrine and sensory inputs from the gut5 'reat headaches effectively using panadol fever ta+lets5 "lthough a complete discussion of the interrelationships +et8een the gut and the +rain in the control of energy homeostasis and regulation of feeding is +eyond the intended scope of this page focus 8ill +e placed on +riefly revie8ing the current literature5 'he primary centers in the +rain involved in the control of appetite are the hypothalamicpituitary axis and the +rain stem5 'he role of these +rain regions in appetite control are discussed in the section +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 initiates responses to feeding even +efore the ingestion of food5 'he very sight and smell of food stimulates exocrine and endocrine secretions in the gut as 8ell as increasing gut motility5 Ingestion of food stimulates mechanoreceptors leading to distension and propulsion to accommodate the food5 "s the food 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 mechanoreceptor responses are transmitted via afferent nerve signals along the vagus nerve to the dorsal vagal complex in the medulla and terminating in the nucleus of the solitary tract )N'9 for the latin term nucleus tractus solitarii*5 Pro:ections from the N'9 enter the visceral sensory complex of the thalamus 8hich mediates the perception of gastrointestinal fullness and satiety5 9everal hormones released from the gut in 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<$ or O<!*5 " single orexigenic )appetite stimulating* hormone ghrelin is (no8n to +e released +y cells of the gut5 +ac( to the top

Hypothalamic Control of Feeding Behavior


'he hypothalamus is located +elo8 the thalamus and :ust a+ove the +rain stem and is composed of several 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 divided into 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 constitute the functional domains of the various hypothalamic areas5 'he primary nuclei of the hypothalamus that are involved in feeding +ehaviors and satiety )the sensation of +eing full* include the arcuate nucleus of the 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 the tu+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 that the lateral hypothalamic area )%H"* is responsi+le for transmitting orexigenic signals )desire for food inta(e* and loss of this region results in starvation5 'he medial hypothalamic nuclei )=$H and to a lesser extent the &$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;* and ghrelin and nutrient signals such as glucose free fatty acids amino acids and volatile fatty acids5 'his effect is processed +y a specific se>uence of neurotransmitters +eginning 8ithin the "#C and orexigenic cells containing neuropeptide ! )NP!* and "gouti-related peptide )"g#P* responsive neurons and anorexigenic cells containing pro-opiomelanocortin PO$C )yielding the neurotransmitter ?-$9H* and cocaine and amphetamine-regulated transcript )C"#'* responsive neurons5 'hese so called first order neurons act on second order orexigenic neurons )containing either melanin concentrating hormone $CH or orexin* or act on anorexigenic neurons )expressing corticotropin releasing hormone C#H* to alter feed inta(e5 In addition satiety signals from the liver and gastrointestinal tract signal through the vagus nerve to the nucleus of the solitary tract )N'9 for the latin term nucleus tractus solitarii* to cause meal termination and in com+ination 8ith the hypothalamus integrate the various signals to determine the feeding response5 'he activities of these neuronal path8ays are also influenced +y numerous factors such as nutrients fasting and disease to modify appetite and hence impact on gro8th and reproduction5

Hormonal circuits from the gut )stomach small intestine and pancreas* and fat )adipose tissue* that impact the sensations of hunger and satiety that are exerted via hypothalamic neuroendocrine path8ays5 Ghrelin from the stomach leptin from adipose tissue insulin from the pancreas and peptide tyrosine tyrosine )P!!* from the small intestine +ind to receptors on orexigenic and@or anorexigenic neurons in the "#C of the hypothalamus5 'he effects of these peptide hormone-receptor interactions are release of either the orexigenic neuropeptides NP! and "g#P or the anorexigenic neuropeptides C"#' and the PO$C-derived peptide ?-$9H5 'hese neuropeptides from the "#C travel along axons to secondary neurons in other areas of the hypothalamus such as the paraventricular nucleus )P=N*5 'he ultimate effects 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 leptin and 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#

are the NP! receptors - and 2 respectively )see the next section +elo8 for more information on NP! receptors5 +ac( to the top

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! this family 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 acids consisting of numerous tyrosines )hence the ! peptides nomenclature* and an ?-amidation at the Cterminus5 'he three-dimensional structure of these hormones includes a hairpin-li(e motif referred to as the pancreatic polypeptide fold )PP-fold*5 'he PP-fold is re>uired for interaction of the hormones 8ith specific G-protein coupled receptors )GPC#s*5 'he PP family of proteins +ind to a family of receptors that 8ere originally characteriBed as NP! receptors5 'here are four NP! receptors in humans and they are designated as !- !2 !A and !C5 "n additional receptor identified as !0 is found in mice and ra++its5 Comparisons of the amino acid se>uences of the four human ! receptors sho8 that receptors !- !A are more closely related to each other than to the receptors !2 and !C5 #eceptors !- !2 and !C preferentially +ind NP! and P!! 8hereas !A exhi+its highest affinity for PP5 "lthough the !C receptor is expressed and +inds ligand it is a truncated protein5 'he !2 receptor is involved in anorexigenic responses )suppression of appetite* 8hereas the !- and !C receptors have +een sho8n to induce orexigenic responses )stimulation of appetite*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 the hypothalamus5 NP! is expressed throughout the mammalian +rain 8ith highest levels found in the "#C of the hypothalamus5 NP! is one of the most potent orexigenic factors produced +y the human +ody5 Dithin the "#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* stimulate food inta(e 8hereas neurons that co-express PO$C and cocaine and amphetamine-regulated transcript )C"#'* suppress the desire for food inta(e5 'he role of NP! in appetite control can +e demonstrated +y central administration of NP! 8hich results in a mar(edly increased desire for food inta(e5 'he !- and !C receptors mediate the +ul( of the effects of NP! on the hypothalamic-pituitarythyroid axis5 Dithin the ventromedial nucleus )=$N* of the hypothalamus +inding of NP! to the !receptor results in inhi+ition of neuronal function )via hyperpolariBation* 8hich results in interference 8ith 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 8eight off5 'his phenomenon has +een demonstrated in mice fed a high-fat diet5 'hese mice 8ill +ecome o+ese have increased fat mass and increased circulating levels of leptin5 Dhen the animals are placed on a calorie-restricted diet they lose the excess fat and leptin levels decline5 Ho8ever the level of expression of the NP! gene is o+served to +e significantly increased5 'his and other data indicate that

NP! is also one of the most important hypothalamic-derived neuropeptides mediating the effects of leptin on overall energy homeostasis5 Dhereas losing excess 8eight is associated 8ith increased expression of NP! the levels of the anorexigenic peptides PO$C and C"#' do not change5 +ac( to the top

#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 on chromosome -0>225 "g#P is expressed primarily in the "#C and is found to co-localiBe 8ith neurons that also produce NP!5 "lthough expression of "g#P is restricted to the "#C "g#P fi+ers pro:ect to several +rain areas as 8ell as to multiple areas 8ithin the hypothalamus including the paraventricular nucleus )P=N or P=H* and perifornical lateral hypothalamus )PF%H*5 In addition all of these "g#P nerve terminals contain NP!5 'he P=N is a region of the hypothalamus that integrates neuropeptide signals 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 foodsee(ing +ehaviors5 "g#P together 8ith NP! represent a distinct set of "#C-expressed orexigenic peptides5 "g#P is classically referred to as a mem+er of the central melanocortin system 8hich in addition to "g#P comprises ?-melanocyte stimulating hormone ?-$9H )see +elo8 for description of ?-$9H actions* and t8o melanocortin receptors identified as melanocortin receptor-4 )$C4#* and melanocortin receptor-A )$CA#*5 Dhereas ?-$9H is an agonist of +oth $C4# and $CA# "g#P serves to antagoniBe the actions of ?-$9H at these same receptors 8ith highest antagonist activity on $CA#5 In addition to antagoniBing the effect of ?-$9H at the $C4# and $CA# "g#P suppresses the +asal activity 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 the expression of these t8o peptides is similarly modulated under identical physiological conditions such as 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 a drop in the level of the peripheral hormones leptin and insulin and a rise in ghrelin5 "lso "g#P li(e NP! sho8s a strong circadian rhythm in its expression rising at the onset of natural feeding cycles5 "s to +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 in alterations in the levels of "g#P expression5 "g#P gene expression is higher in rats on a lo8-energy diet compared to a fat-rich diet or in conditions 8here glucose utiliBation is reduced5 In fact +oth "g#P and NP! are suppressed +y a single in:ection of glucose5 On the other hand in:ections of the compound 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 of experimental animals5 Central in:ection of "g#P has a potent stimulatory effect on food inta(e 8hich can also +e seen using a $CA# antagonist5 'hese results confirm the function of "g#P as an antagonist of ?-$9H5 'he food inta(e stimulation exerted +y in:ection of "g#P is similar to that seen +y central in:ection of NP! 8ith differences +eing that the duration of the effect 8ith "g#P is much longer than that 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 receptor5 Chronic administration of "g#P results in increased daily food inta(e 8hile simultaneously decreasing

oxygen consumption and the capacity of +ro8n adipose tissue to expend energy5 'hese chronic effects result in increased fat mass accumulation all of 8hich are effects similar to those seen 8ith chronic administration of NP!5 In complimentary studies using transgenic mice that overexpress the "g#P gene it has +een sho8n that increased levels of "g#P result in increased feeding +ehavior and food inta(e5 'hese mice exhi+it hyperphagia and o+esity in addition to increased +ody length hyperinsulinemia 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 $CA# (noc(-out5 'here exists an antagonism +et8een the actions of "g#P )and NP!* and the melanocortins in controlling eating and +ody 8eight5 'his is evident from studies sho8ing changes in endogenous "g#P that are opposite to those seen 8ith the melanocortin peptides5 In addition +rain mapping sho8s that "g#P neurons interact 8ith PO$C neurons in the "#C through the inhi+itory neurotransmitter Eamino +utyric acid )G"B"*5 Both "g#P and NP! axons that co-localiBe G"B" pro:ect onto PO$C expressing cells in the "#C and the "g#P-stimulated release of G"B" results in inhi+ition of the activity of the PO$C neurons an effect also seen 8ith NP!5 Peripheral hormones that act on the "#C and 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 and is in part the mechanism +y 8hich leptin decreases feeding +ehaviors5 Conversely ghrelin +inding its receptor activates "g#P and NP! neurons resulting in an increase in G"B" release 8ith resultant inhi+ition of PO$C neurons5 Given that "g#P and NP! 8hich are activated under similar conditions and have compara+le effects indicates that they very li(ely evolved to ensure the signaling of hunger during food scarcity and to ena+le the +ody to endure long periods of negative energy +alance5 +ac( to the top

Melanin-Concentrating Hormone" MCH


$elanin-concentrating hormone )$CH* 8as originally identified as a -/ amino acid cyclic peptide that induced the lightening of the s(in in fish5 9u+se>uently the peptide 8as identified in rodents to +e overexpressed in response to fasting and also elevated in genetically o+ese mice )ob/ob mice*5 In humans and other mammals $CH is expressed exclusively in the lateral hypothalamus and Bona incerta )region of gray matter cells in the su+thalamus +elo8 the thalamus*5 In humans there are t8o Gprotein coupled receptors )GPC#s* that +ind $CH identified as $CH-# and $CH2#5 #odents ho8ever do not possess the $CH2# gene5 $CH-# is a typical GPC# that couples to the activation of +oth G> and Gi type G-proteins5 'he G> class of G-protein activates phospholipase C-E )P%CE* resulting in increases in intracellular Ca2F5 'he Gi class represses adenylate cyclase activity resulting in decreased c"$P production5 ,xpression of $CH-# is seen throughout the +rain 8ith highest levels in the 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 of central nervous system expression of $CH and $CH-# suggests that this peptide-receptor system is involved in a host of physiological functions 8ithin the +rain5 Involvement of $CH in the regulation of feeding +ehaviors and energy homeostasis has +een sho8n in mice 8here either the $CH gene or the $CH-# gene have +een (noc(ed out5 "dditional information

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 is hypophagia )reduced desire for food inta(e* and lean +ody mass5 'hese results indicate that $CH is an important orexigenic )appetite stimulating* hormone5 In contrast central administration of $CH results in increased food inta(e in mice5 Dhen the $CH-# gene is (noc(ed out mice are hyperphagic hyperactive and lean5 Dhen $CH-# antagonists are administered peripherally animals exhi+it decreased $CH-induced food inta(e5 In addition if $CH-# antagonists are chronically administered there is o+served a decrease in +ody 8eight in rats that had diet-induced o+esity5 $CH-# antagonists have +een sho8n to modulate leptin secretion and insulin release 8hich suggests that the 8eight loss associated 8ith systemic antagonist administration is due to +oth central and peripheral effects5 $any studies indicate that $CH-# antagonists modulate energy homeostasis and thus the anti-o+esity effects 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 +een sho8n 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 'hese studies 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 although the precise mechanism for the antidepressant effects are not yet clearly defined5 +ac( to the top

The $re%ins
'he orexins constitute t8o neuroendocrine peptides derived from the same gene5 'hese peptides are designated orexin " and orexin B5 'he orexins are also called the hypocretins as the peptides 8ere independently isolated5 One group used a su+tractive c&N" screening approach to enrich for c&N"s from the hypothalamous )identified as hypocretins* and another group 8as screening for ligands that activated orphan G-protein coupled receptors )GPC#s* that 8ould induce transient calcium currents in GPC#-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 -G>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 amino acids 4410C and the 2H amino acid orexin B peptide encoded +y amino acids 0/1/05 Both orexin " and orexin B peptides are C-terminally amidated5 'he N-terminal glutamine residue of orexin " is cycliBed into a pyroglutamyl residue and the peptide contains t8o intrachain disulfide +onds5 'he amino acid se>uences of verte+rate orexin " peptides are -33I conserved and those of verte+rate orexin B peptides are /4I conserved5 Overall the full-length prepro-proteins are GCI conserved across various verte+rate species5 9tructurally +oth orexin " and orexin B are highly conserved and this structural conservation explians the a+ility of the orexin receptors to +ind +oth peptides5 'here are t8o orexin receptors 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

O<-# coupling to the G> su+class of G-proteins and O<2# coupling to +oth the G> and Gi class of Gprotein5 'he G> class of G-protein activates phospholipase C-E )P%CE* resulting in increases in intracellular Ca2F5 'he Gi class represses adenylate cyclase activity resulting in decreased c"$P production5 'he cell +odies of orexin expressing neurons are found in the lateral and posterior hypothalamic areas 8ith axonal pro:ections throughout the +rain5 ,xpression of the orexin receptors is also 8idely distri+uted throughout the central nervous system5 'his distri+ution of orexin and orexin receptor expression is suggestive of important roles in the emotional and motivational aspects of feeding +ehavior5 Indeed as their name implies in:ection of orexin peptides into the +rain 8as sho8n to increase food consumption in rats5 Ho8ever in addition to increased feeding +ehavior central administration of orexins increases 8a(efulness and suppresses #,$ sleep5 'hese latter o+servations demonstrate that orexins play a causative role in the regulation of sleep-8a(e cycles5 9u+se>uent research demonstrated that loss of orexin function results in a condition in animals that mimics the sleep disorder in humans (no8n as narcolepsy5 Dhen the orexin gene is (noc(ed out in mice they exhi+it increased #,$ sleep during dar( periods 8hen they are normally a8a(e5 In addition these mice have 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 significant reduction in the amount of detecta+le orexin " and orexin B as 8ell as an H3I1-33I reduction in the num+er of neurons that contain detecta+le prepro-orexin m#N"5 Ho8ever no mutation has +een found in either the prepro-orexin or orexin receptor genes except for one rare early onset severe case 8here there 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 the reduced orexin levels may result from selective autoimmune destruction of orexin neurons5 &ogs that har+or a null mutation in the O<2# gene exhi+it a narcolepsy phenotype that is highly similar to human narcolepsy5 +ac( to the top

Galanin" G#&
Galanin )G"%* is a 2/ amino acid peptide 8hose name is derived from the fact that it contains an Nterminal glycine residue and a C-terminal alanine5 G"% is expressed in the gut and the +rain 8ith 8ide distri+ution throughout the hypothalamus including the P=N the PF%H and "#C5 'he expression of G"% in the hypothalamus is directly correlated to its role in energy homeostasis and the control of feeding +ehaviors5 In addition to regulating feeding G"% serves as a gro8th and prolactin-releasing factor to the lactotroph especially in states of high estrogen exposure is involved in learning and memory through effects in the hippocampus and is involved in pain and seiBures5 "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 and G"%#45 'he highest levels of expression of G"%#- are seen in hypothalamic nuclei that includes the P=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 strong orexigenic )increased feeding* response 8ith a preference for fat over protein and car+ohydrates5 'he feeding +ehavior responses to G"% exposure are primarily due to +inding G"%#- in the hypothalamus5

"lthough G"% is an orexigenic peptide it has mar(ed differences in its responses to food deprivation and inta(e and the signals it induces compared to those of NP! and "g#P in terms of their responsiveness to endocrine and physiological signals5 In:ection of G"% results in a stimulatory effect on feeding +ehavior yet the response is smaller and of shorter duration than that induced +y NP!5 'he feeding response elicited +y G"% has little impact on food preference 8hether for car+ohydrate or fat 8hereas 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 an animal is consuming a high-fat diet is to restore car+ohydrate +alance through +ehavioral and meta+olic actions under conditions 8here car+ohydrate inta(e and meta+olism are suppressed5 'he adrenal steroid corticosterone only transiently inhi+its G"% gene expression in P=N neurons and has no effect on feeding responses of G"%5 In contrast this steroid hormone has a potent stimulatory effect on 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 'he differential responsiveness of G"% neurons to leptin is li(ely due to the lo8 concentration of leptin receptors on G"% neurons5 'he lo8 leptin receptor level on G"% neurons compared to NP! neurons also explains their different responses to food restriction 8hich reduces leptin levels5 Food restriction does little to the level of G"% expression 8hile mar(edly enhancing NP! gene expression5 &ifference in 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 +ut result in elevated expression of NP!5 'hese nutrient differences are also o+served in experimental animals 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 to fat-rich diets are also seen 8ith fat accumulation and are li(ely the result of differences in responses to leptin5 'he a+ility of G"% to exert its stimulation of feeding responses may +e due to its interactions 8ith other peptide systems5 'he opioids are +elieved to have some role in mediating G"%-induced feeding since the opioid receptor agonist naloxone attenuates the G"% feeding response5 G"% may also 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"% expressing neurons as 8ell as expressing the G"%#- gene5 ,vidence indicates that G"% has a direct inhi+itory action on "#C neurons expressing G"%#- as 8ell as modulating the secretory activity of PO$C neurons5 +ac( to the top

P$MC-'erived Melanocortins
'he PO$C-derived melanocortin peptides include ?-$9H K-$9H E-$9H "C'H--2A and "C'H---41 NH2 )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$C-derived melanocotins 8hich exhi+it agonist activities the antagonist peptide "g#P the melanocortin receptors )$C#* and the melanocortin receptor accessory proteins )$#"Ps*5 'he $C# family of receptors consists of five identified mem+ers termed $C-# through $CC#5 'he melanocortin system has +een sho8n to +e critical in the regulation of food inta(e and energy expenditure via a num+er of different assay systems involving +oth humans and animals5 It is important to note that although K-$9H and E-$9H are found to +e produced in human +rain they are not found in

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 $C4#5 Genetic mutations in humans as 8ell as in animals that disrupt the expression and processing )this includes the proteases that process the PO$C precursor* of PO$C peptides and $C#s are associated 8ith 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 as in the ?-$9H degrading enByme prolylcar+oxypeptidase )P#CP* that are associated 8ith energy im+alance and a propensity for o+esity5 In mice a mutation in the CP, gene also results in the development of late-onset o+esity5 In genome-8ide screens for gene polymorphisms associated 8ith an increased 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$C-null* results in via+le animals even though they have minimal adrenal tissue and undetecta+le glucocorticoids due to the lac( of "C'H5 'hese animals develop o+esity +ut do not +ecome dia+etic5 "lthough not dia+etic these mice do have a disruption in the regulation of glucagon secretion in response to experimental hypoglycemia5 'his indicates that PO$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( of PO$C expression are una+le to survive 8ithout glucocorticoid supplementation from +irth5 Individuals that survive have red hair dramatically increased desire for food inta(e and high propensity for o+esity5 'hese conditions are the same as those seen in PO$C-null mice5 "nother PO$C mutation that has +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 significant endogenous anorectic agonist that activates the $CA#5 +ac( to the top

Cocaine- and #mphetamine-Regulated Transcript" C#RT


'he cocaine- and amphetamine-regulated transcript )C"#'* peptides are neuroendocrine peptides involved in feeding +ehavior drug re8ard systems stress cardiovascular functions and +one remodeling5 ,xpression of the C"#' gene is essentially confined to hypothalamic neuroendocrine neurons 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 C>-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"#'--H/ and proC"#'---325 Ho8ever only the proC"#'--H/ peptide is found in humans5 'he proC"#' protein contains a signal se>uence typical of secreted proteins and is re>uired for insertion of the protein into vesicles and su+se>uent processing5 'he active portions of the C"#' peptides are located do8nstream of the alternatively spliced region and thus +oth proC"#'--H/ 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"#'--H/ peptide is present the processing yields C"#' peptides identified as C"#' A2-H/ and C"#' A/-H/5 In rodents

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 identified as C"#' CC--32 and C"#' 02--325 'here is a high degree of interspecies conservation of the active C"#' peptide se>uences 8ith the human rat homology +eing /-I5 " definitive C"#' receptor has as yet not +een isolated5 Ho8ever several lines of evidence indicate that C"#' peptides +ind 8ith high affinity 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 extracellular signal-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 Gi@o class of G-proteins5 " role for C"#' peptides in the regulation of feeding +ehaviors 8as demonstrated in animal models 8here intracere+rovascular )icv* in:ection results in decreased food inta(e5 'hese types of results indicate that C"#' peptides are anorexigenic )decrease appetite*5 Dithin the "#C of the hypothalamus C"#'-peptide containing neurons are surrounded +y NP! expressing nerve terminals5 'he distri+ution of C"#' and NP! in the "#C suggests that these t8o neuropeptides may exhi+it cross-tal( in the regulation of feeding since NP! is an orexigenic )appetite stimulating* hormone and C"#' is an anorexigenic hormone5 Dhen animals are food-deprived the level of C"#' m#N" in the "#C decreases5 Conversely 8hen leptin is administered to animals the level of C"#' m#N" in the "#C increases5 In addition in animals 8ith disrupted leptin signaling the level of C"#' m#N" is nearly undetecta+le in the "#C5 'he functions of C"#' peptides in inhi+iting the desire for food inta(e may involve circuits that include the serotonin-A receptor and $&$" receptors5 $&$" is 4 Amethylenedioxy-N-methyl-amphetamine more commonly (no8n as NecstasyN5 Dhen C"#' m#N" levels are experimentally reduced the anorectic effects of $&$" as 8ell as serotonin-A receptor activation are a+olished5 In addition mice in 8hich the C"#'P' gene has +een (noc(ed out exhi+it increased desire for feeding and gain 8eight5 9everal human studies have also indicated that C"#' peptides function in appetite control5 In an Italian family 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 the expressed protein is poorly processed and secreted5 In another study of mor+idly o+ese individuals in France a single nucleotide polymorphism )9NP* 8as identified in the C"#' gene at position 1403H 8here a ' 8as replaced 8ith a C5 In a study examining the promoter region of the C"#' gene from several hundred individuals it 8as found that a polymorphism resides approximately -C0(+ upstream that may +e associated 8ith o+esity5 +ac( to the top

Galanin-li(e peptide" G#&P


Galanin-li(e peptide )G"%P* is a 03 amino acid peptide that is structurally related to galanin hence the derivation 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 and G"%#4* 8ith similar affinities 8hereas G"%P +inds 8ith highest affinity to G"%#4 follo8ed +y G"%#2 8ith G"%#- +inding 8ith least affinity5 ,xpression of G"%P is almost exclusively found in

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 the effects of leptin5 Ho8ever it should +e noted that there are differences in the responses to G"%P in:ection 8hen comparing rats and mice5 In:ection of G"%P into mice results in the inhi+ition of feeding responses and also leads to an increase in energy expenditure and fat oxidation in +ro8n adipose 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 is induced +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 circulating levels of leptin and this in turn reduces the rapid entry of circulating G"%P into the +rain5 Fasting results in a decrease in +oth the level of G"%P m#N" as 8ell as the num+er of G"%P expressing neurons5 %eptin administration 8ill restore G"%P expression in fasted animals as 8ell as in leptindeficient )ob/ob* mice5 +ac( to the top

Corticotropin-releasing factor )CRF* and related peptides


Corticotropin-releasing factor )C#F also (no8n as corticotropin-releasing hormone C#H* +elongs to an 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 receptor ligands5 'here are three (no8n urocortins identified as urocortin - 2 and 4 )Lcn- Lcn2 Lcn4*5 'he urocortins 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 the hypothalamic P=N 8here they control the pituitary-adrenal axis regulating the release of "C'H and glucocorticoids5 Lcn- is a A3 amino acid peptide that is expressed primarily in the lateral hypothalamus and supraoptic nucleus 8ith urocortin-containing neurons pro:ecting to the =$H5 Lcn2 is a A4 amino acid peptide and is expressed in the mouse hypothalamus in the P=N and "#C5 In humans increased Lcn2 expression is also seen in cardiac myocytes during heart failure5 Lcn4 is a 4H amino acid peptide 8hose expression is found in the rostral perifornical area lateral to the P=N 8ith Lcn4 neurons pro:ecting throughout the hypothalamus and the lim+ic system5 Lcn4 expression is also high in pancreatic K-cells 8here 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 and Lcn- +ind 8ith high affinity to the C#F-5 In contrast Lcn2 and Lcn4 +ind 8ith much higher affinity than C#F to C#F2 and are therefore are li(ely to +e the endogenous ligands of this receptor5 In addition to +inding to t8o receptors C#F and urocortins also +ind to C#F-BP 8hich is expressed in association 8ith C#F-expressing neurons in many +rain areas including the hypothalamus5 C#F-BP acts 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 such that C#F m#N" and protein levels are highest 8hen corticosterone levels are declining5 In rodents

8ho feed during the dar( cycle corticosterone levels rise at the onset of feeding and C#F levels decrease5 Glucocorticoids also negatively regulate C#F expression5 'his effect of glucocorticoids on C#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 +y the administration of insulin5 ,xpression of C#F is also stimulated in states of positive energy +alance and 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 opposite occurring 8hen glucose levels fall5 In contrast to the changes in C#F levels in response to serum glucose changes excess fat consumption does not appear to alter C#F expression5 Central administration of C#F results in suppression of spontaneous feeding responses demonstrating its anorexigenic properties5 'he C#F-mediated suppression of feeding occurs along 8ith a stimulation sympathetic nervous system activity and resting oxygen consumption 8hich results in increased fat mo+iliBation and oxidation and raises +lood glucose 8hile inhi+iting insulin secretion5 Central administration of Lcn- also suppresses feeding and its effect is strongest in the P=N and more potent and longer-lasting than that of C#F5 Lcn2 administration also suppresses food inta(e as 8ell as resulting in delayed gastric emptying and decreased heat-induced edema5 Chronic administration of C#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 mediates the anorectic effects of these ligands 8hile C#F- mediates their meta+olic effects5 $ice lac(ing the C#F2 receptor exhi+it a +lunted response to the feeding-inhi+itory effects of urocortin and selective C#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"#' systems acting in a do8nstream fashion5 'he C#F neurons in the hypothalamus co-localiBe 8ith +oth the NP! !C receptor and the $CA#5 In addition C#F expression in the P=N is stimulated +y central administration of a melanocortin agonist +ut is inhi+ited +y an $CA# antagonist5 'here is an antagonistic relationship +et8een C#F and NP! demonstraetd +y the fact that administration of C#F and Lcn- result in a reduction in +oth NP! expression and NP!-mediated feeding5 "lso administration of C#F antagonists result in increased NP!-induced feeding responses5 In contrast to the C#F-NP! antagonism central administration of C"#' activates C#F neurons in the P=N indicating that C#F may mediate the anorectic effect of C"#'5 %eptin is also involved in the effects of C#F and the 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 +ac( to the top

Hypothalamic &ipid Meta+olism and ,nergy Homeostasis


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

+odies5 "lthough (etone +odies are essentially derived from fatty acids )via the acetyl-Co" derived from 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 on fatty 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 of mitochondrial fat oxidation are extremely lo8 in the +rain5 'he fates of fatty acyl-Co"s in the +rain are conversion into various structural entities including phospholipids triacylglycerides diacylglycerides and fatty acyl-carnitine species as 8ell as lipid-derived signaling molecules5 9tudies using palmitic acid have demonstrated that the ma:ority of palmitate is incorporated into the neutral lipid fraction principally consisting of triacylglycerides and non-esterified free fatty acids5 In addition in contrast to non-neural tissues the desaturation and elongation of palmitate 8ithin the +rain represents a very minor fate of the fat5 Instead palmitate is converted into fatty acids of less than -0 car+on atoms5 'he largest pool of lipid derived from palmitate is phospholipid of 8hich the primary species is phosphatidylcholine5 "lthough K-oxidation of fatty acids represents a minor if at all source of the "'P pool in neurons it is an important meta+olic path8ay determining the ultimate fate of fatty acids that enter the +rain5 "s a result of fatty acid oxidation a num+er of a>ueous +yproducts are detected in the +rain such as fatty acyl-Co"s fatty acyl-carnitines (etone +odies and various amino acids5 Dhen using in vitro assays 8ith palmitate it is found that the ma:ority of the car+ons from this fatty acid end up in the amino acids glutamate glutamine aspartate asparagine and G"B"5 In addition numerous organic acids including citrate malate K-hydroxy+utyrate and acetyl Co" result from palmitate oxidation5 By far citrate represents the largest +yproduct of fatty acid oxidation in the +rain5 'hese fates of fatty acids that enter the +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 into the mitochondria for oxidation is exerted +y malonyl-Co"-mediated inhi+ition of CP'--5 Indeed inhi+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+ons into 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 have very recently +een sho8n to exert anorexigenic effects via the hypothalamus5 For example 8hen oleic acid is in:ected into cere+ral ventricles there is a resultant decrease in feeding +ehavior in la+oratory animals5 '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 administration of oleic acid is associated 8ith increased peripheral glucose homeostasis5 Oleic acid must +e converted to its Co" derivative for these effects to +e exerted since it has +een sho8n that +loc(ade of fatty acylCo" 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 Hcar+on fatty acid octanoic acid does not exert any anorexigenic effects and mitochondrial upta(e of octanoyl-Co" does not re>uire CP'--5 "dditionally inhi+ition of hypothalamic CP'-- leads to an increase 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'--B gene is not expressed in the hypothalamus and the level of hypothalamic CP'--" expression is minimal5 In addition the +inding affinity of CP'--" for malonyl-Co" is relatively lo85 'he CP'--C gene is +rain specific and +inding of malonyl-Co" to the CP'--C protein is of similar affinity to that of

the CP'--B isoform5 In experiments in mice it has +een sho8n that deletion of CP'--C results in reduced feeding +ehavior and lo8ered +ody 8eight similar to studies in 8hich hypothalamic malonylCo" 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 8hich malonyl-Co" and cytosolic long-chain fatty acyl-Co" interactions result in reduced appetite are not fully characteriBed5 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 even though they ate less5 "lso the +rain specific CP'--C isoform does not catalyBe carnitine transferase activity5 '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 oxidiBe fatty acids for energy production5 Ho8ever the ma:or enBymes of the fatty acid +iosynthetic path8ay such as acetyl-Co" car+oxylase )"CC* and fatty acid synthase )F"9* are expressed in neuronal regions of the hypothalamus that are involved in energy homeostasis5 =arious hormones and meta+olic fuels affect hypothalamic malonyl-Co" levels and malonyl-Co" is considered a (ey satiety inducing signal in the +rain5 &uring periods of fasting hypothalamic levels of malonyl-Co" rapidly decrease and act as a signal of hunger5 Conversely during feeding hypothalamic levels of malonyl-Co" rapidly rise and act as a signal to stop eating5 'herefore an understanding of the regulation of hypothalamic malonyl-Co" levels is of significance especially 8ith respect to efforts to control feeding +ehaviors in humans5 "s descri+ed in the %ipid 9ynthesis page the production of malonyl-Co" is catalyBed +y "CC5 'here are t8o isoforms of "CC "CC- and "CC2 )sometimes referred to as the "CC? and "CCK isoforms respectively*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 the suggestion that the malonyl-Co" produced +y "CC2 is preferentially involved in the regulation of fatty acid oxidation 8hereas malonyl-Co" produced +y "CC- is preferentially involved in the regulation of fatty acid synthesis5 Both isoforms of "CC are allosterically activated +y citrate and inhi+ited +y palmitoyl-Co" and other short- and long-chain fatty acyl-Co"s5 Citrate triggers the polymeriBation of "CC- 8hich leads to significant increases in its activity5 "lthough "CC2 does not undergo significant polymeriBation )presuma+ly due to its mitochondrial association* it is allosterically activated +y citrate5 Glutamate and other dicar+oxylic acids can also allosterically activate +oth "CC isoforms5 "CC activity is also regulated +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 )9G/ 9-233 and 9-2-C* +y "$P; leads to inhi+ition of the enByme5 Glucagon-stimulated increases in c"$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 anorexigenic effects has +een demonstrated in studies on leptin5 'he anorexigenic effects of leptin involve the activation of "CC leading to increased malonyl-Co" levels in the "#C5 Dhen the activity of "CC2 is inhi+ited in the "#C leptin is una+le to reduce food inta(e and su+se>uent +ody 8eight +ecause it is no longer a+le to alter malonyl-Co" content 8ithin the "#C5 'his latter effect occurs even though leptin still induces an inhi+ition of "$P; indicating that malonyl-Co"-mediated effects on appetite and feeding +ehaviors are do8nstream of any effects of "$P;5 'hese experimental results in animals demonstrate that "CC activity is an important regulator of feeding +ehaviors via the a+ility of "CC2 to regulate hypothalamic malonyl-Co" levels5 Potential differences in a+ility of "CC- and "CC2 to elicit

decreases in appetite are difficult to assess since deletion of "CC- in mice results in em+ryonic lethality5 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 utiliBation in fatty acid synthesis +y F"9 as 8ell as +y its degradation to acetyl-Co" via the 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 highly oxidative tissues such as the heart5 "s 8ell $C& inhi+ition leads to reduced triacylglyceride content in lipid synthesiBing tissues such as the liver5 Dhen hypothalamic $C& levels are experimentally increased in la+oratory animals there is a dramatic increase in food inta(e 8eight gain and ultimately results in o+esity5 'ranscriptional regulation of the $C& gene is exerted +y PP"#? a ma:or transcription factor involved in the regulation of fatty acid oxidation5 Hypothalamic PP"#? has +een sho8n to play a role in the regulation of appetite presuma+ly via enhanced expression of $C& 8ith the use of pirinixic acid 8hich is a PP"#? agonist5 "s discussed +elo8 inhi+ition of fatty acid synthase )F"9* the rate-limiting enByme in de novo lipogenesis decreases appetite and promotes 8eight loss5 "dministration of pirinixic acid results in normaliBation 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" in the hypothalamus5 'his is associated 8ith increased food inta(e in the F"9 (noc(-out mice demonstrating that malonyl-Co" levels are indeed responsi+le for the hypophagic effects o+served in the 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 de novo synthesiBed 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 CGC and cerulenin as 8ell as in F"9 (noc(-out mice )as indicated a+ove*5 Inhi+ition of F"9 causes potent anorexigenic effects that are associated 8ith a reduction in hypothalamic NP! expression and increases in intracellular malonyl-Co" content5 $ice 8ith F"9 deleted specifically in the "#C and P=N regions of the hypothalamus exhi+it reduced appetite and 8eigh significantly less than control animals5 'he anorexigenic effects of F"9 inhi+ition 8ith the use of CGC may not +e due entirely to alterations in malonyl-Co" content5 'he anorexigenic effects of CGC have also +een associated 8ith increases in glucose meta+olism 8hich results in increased levels of "'P5 Increases in "'P lead to inhi+ition of "$P; activity 8hich in turn results in reduced "$P;-mediated phosphorylation and inhi+ition of "CC5 'herefore there 8ill +e increased levels of malonyl-Co" demonstrating that malonyl-Co" is li(ely to +e the primary signaling molecule responsi+le for the hypophagic effects of CGC5 F"9 inhi+itors such as CGC also activate the mammalian target of rapamycin )m'O#* and since m'O# and "$P; activities are inversely related they are li(ely to +e reciprocally involved in the regulation of appetite5 +ac( to the top

Gastrointestinal Hormones and Peptides


'here are more than 43 peptides currently identified as +eing expressed 8ithin the digestive tract ma(ing the gut the largest endocrine organ in the +ody5 'he regulatory peptides synthesiBed +y the gut include hormones peptide neurotransmitters and gro8th factors5 Indeed several hormones and neurotransmitters 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 page to see a more complete list of gastrointestinal peptides and hormones and their modes of action5 'he follo8ing discussion 8ill focus on the gut peptides 8ith the +est demonstrated roles in the control of appetite and feeding +ehavior via their interactions 8ith signals produced in the hypothalamic-pituitary axis5 Hormone %ocation enteroendocrine I cells predominantly in the duodenum :e:unum primary site is <@"-li(e enteroendocrine cells of the stomach oxyntic )acid secreting* glands minor synthesis in intestine pancreas and hypothalamus enteroendocrine % cells predominantly in the ileum and colon $a:or "ction stimulates gall+ladder contraction and +ile flo8 increases secretion of digestive enBymes from pancreas vagal nerves in the gut express CC;- receptors

Cholecysto(inin )CC;*

Ghrelin

regulation of appetite )increases desire for food inta(e* energy homeostasis glucose meta+olism gastric secretion and emptying insulin secretion

Glucagon-li(e peptide-)G%P--* Glucose-dependent insulinotropic polypeptide )GIP* originally called gastric inhi+itory polypeptide

potentiates glucose-dependent insulin secretion inhi+its glucagon secretion inhi+its gastric emptying

enteroendocrine ; cells of the duodenum and proximal :e:unum

inhi+its secretion of gastric acid enhances insulin secretion

O+estatin

primary site is stomach minor synthesis in intestine

derived from pro-ghrelin protein acts in opposition to ghrelin action on appetite contains all of the amino acids of glucagon )see Figure +elo8*J inhi+its meal-stimulated gastric acid secretion similar to G%P-- and G%P-2 actionJ induces satiety decreases 8eight gain

Oxyntomodulin

enteroendocrine % cells predominantly in the ileum and colon

and increases energy consumptionJ has 8ea( affinity for G%P-- receptor as 8ell as glucagon receptor may mimic glucagon actions in liver and pancreas Pancreatic polypeptideO PP pancreas inhi+its pancreatic +icar+onate and protein secretion reduced gut motility delays gastric emptying inhi+ition of gall+ladder contraction induces satiety via actions in the arcuate nucleus )"#C* of the hypothalamus smooth muscle relaxationJ stimulates pancreatic +icar+onate secretion

Peptide tyrosine tyrosineO P!!

enteroendocrine % cells predominantly in the ileum and colon

=asoactive intestinal peptide )=IP* +ac( to the top

pancreas

G&P-. and GIP


'he glucagon gene encodes a precursor protein identified as preproglucagon5 &epending on the tissue of expression coupled 8ith the presence of specific proteases called prohormone convertases preproglucagon can +e processed into several different +iological peptides in addition to glucagon5 'he glucagon-li(e peptides )principally glucagon-li(e peptide-- G%P--* and glucose-dependent insulinotropic peptide )GIP* are gut hormones that constitute the class of molecules referred to as the incretins5 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 is differentially cleaved dependent upon the tissue in 8hich it is synthesiBed5 For example in pancreatic ?-cells prohormone convertase 2 action leads to the release of glucagon5 In the gut prohormone convertase -@4 action leads to release of several peptides including G%P--5 Lpon nutrient ingestion G%P-- is secreted from intestinal enteroendocrine %-cells that are found predominantly in the ileum and colon 8ith some production from these cell types in the duodenum and :e:unum5 Bioactive G%P-consists of 2 formsJ G%P--)G-4G* and G%P--)G-40*amide 8here the latter form constitutes the ma:ority )H3I* 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 in the pancreas5 G#PPMglicentin-related pancreatic peptide5 IPMintervening peptide5 G%P-2Mglucagonli(e peptide-25 Glicentin )composed of amino acids -10/* is found in the small intestine +ut the

ma:ority is processed to G#PP and oxyntomodulin5 $PGFMma:or proglucagon fragment comprises amino acids G21-CH and is found in the pancreas5 'he primary physiological responses to G%P-- are glucose-dependent insulin secretion inhi+ition of glucagon secretion and inhi+ition of gastric acid secretion and gastric emptying5 'he latter effect 8ill lead to increased satiety 8ith reduced food inta(e along 8ith a reduced desire to ingest food5 'he action of G%P-- at the level of insulin and glucagon secretion results in significant reduction in circulating levels of glucose follo8ing nutrient inta(e5 'his activity has significance in the context of dia+etes5 'he glucose lo8ering activity of G%P-- is highly transient as the half-life of this hormone in the circulation is less than 2 minutes5 #emoval of +ioactive G%P-- is a conse>uence of N-terminal proteolysis catalyBed +y dipeptidyl peptidase I= )&PP I= or &PPA*5 &PPA is also (no8n as the lymphocyte surface antigen C&20 and has numerous activities unrelated to incretin inactivation )see &PPA page for more information on &PPA*5 "ll of the effects of G%P-- are mediated follo8ing activation of the G%P-- receptor )G%P--#*5 'he G%P--# is a typical seven-transmem+rane spanning receptor coupled to G-protein activation increased c"$P production and activation of P;"5 Ho8ever there are also P;"-independent responses initiated through 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 -C4-amino acid proprotein encoded +y the GIP gene and circulates as a +iologically active A2-amino acid peptide5 GIP is synthesiBed +y enteroendocrine ;-cells 8hose locations are primarily in the duodenum and proximal :e:unum5 'he original activity associated 8ith GIP 8as the inhi+ition of gastric acid secretion and 8as thus originally called gastric inhi+itory peptide5 Ho8ever su+se>uent research demonstrated that this gut hormone possessed potent stimulation of glucose-dependent insulin secretion5 In addition GIP has significant effects on fat meta+olism exerted at the level of adipocytes5 'hese actions include stimulation 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 similar to that sho8n for G%P-- the hormone does not affect glucagon secretion nor gastric emptying5 %i(e G%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 Kcells5 #esponses to GIP have +een sho8n to +e defective in type 2 dia+etic patients5 Interestingly in gene (noc(-out mice it has +een sho8n that loss of the GIP# is correlated to resistance to o+esity even if the animals are fed a high fat diet5 +ac( to the top

$%yntomodulin
Oxyntomodulin )O<$* is so called given that is 8as originally discovered from 8or( examining the inhi+ition of the activity of oxyntic glands )gastric acid secreting* of the stomach5 O<$ is a 4G amino acid peptide derived from the pre-pro-glucagon gene and contains the entire 2/ amino acids of the pancreas-derived glucose regulating hormone glucagon5 'he O<$ protein contains an additional H amino acids at its C-terminus relative to glucagon5 9ynthesis and release of O<$ occurs in the enteroendocrine % cells of the distal gut5 'hese are the same cell populations that secrete G%P-- and P!!5 'he secretion of O<$ occurs 8ithin C--3 minutes follo8ing ingestion of food and pea(s 8ithin

43 minutes5 'he amount of O<$ that is released is directly proportional to caloric inta(e5 In addition to stimulated release in response to food inta(e O<$ exhi+its diurnal variation in its concentration in the +lood 8ith highest levels detected in the evening and lo8est levels in the morning5 'hus far there has +een no specific O<$ receptor identified5 ,vidence suggests that the anorexigenic effects of O<$ are in fact exerted via the G%P-- receptor )G%P--#*5 In mice in 8hich the G%P--# gene has +een (noc(ed out the anorectic responses to in:ected O<$ are a+olished5 %i(e G%P-- O<$ has demonstrated incretin activity )incretins stimulate insulin release in response to food inta(e* and this activity is a+olished in the G%P--# (noc(-out mouse5 In addition O<$ exerts a protective effect on pancreatic K-cells similar to that exerted +y G%P--5 "lthough the affinity of O<$ for the G%P--# is at least C3 fold less than that of G%P-- itself the a+ility of O<$ to exert inhi+ition of food inta(e is e>ual to that of G%P--5 Dith respect to effects on food inta(e exerted via the hypothalamus 8hen either O<$ or G%P-- are administered peripherally they exert differential neuronal activation 8ithin the hypothalamus5 'his suggests that these t8o hormones act via different hypothalamic path8ays involved in appetite control5 Dhen O<$ is administered into the +rain the response is suppression of the effects of circulating ghrelin5 'hese results suggest that part of the appetite suppressing effects of O<$ are mediated +y reduced ghrelin as 8ell as increased hypothalamic release of anorexigenic peptides5 Of potential significance to the treatment of o+esity 8hen O<$ is administered intravenously to human su+:ects there is an o+served reduction )-/54I* in food inta(e at mealtime5 "dditionally significant is the fact that this reduction in desire for food inta(e persisted over the course of -2 hours5 Dhen O<$ is administered su+cutaneously to over8eight and o+ese su+:ects over a period of A 8ee(s there is a significant reduction in +ody 8eight5 'he average 8eight loss in the volunteers 8as 254(g )l+* compared to only 35C(g in untreated control su+:ects5 'he 8eight loss o+served in these studies 8as li(ely due to a com+ination of reduced desire for food inta(e as 8ell as an increased meta+olic expenditure5 Dhen O<$ 8as administered over a A day period to human su+:ects there 8as an o+served -3I increase in total energy expenditure5 "lthough these results prove promising for the potential for O<$ in the treatment of o+esity it is important to note that O<$ is a target for inactivation +y &PP-A :ust as is G%P--5 'herefore any O<$ agonist must +e resistant to inactivation +y &PP-A5 +ac( to the top

Cholecysto(inin" CC/
Cholecysto(inin )CC;* is derived via post-translational modification of the pro-cholecysto(inin gene product5 CC; 8as the first gut hormone to +e identified as having an effect on appetite5 'here are several +ioactive forms of CC; that are designated +ased upon the num+er of amino acids in the peptide5 'he four ma:or forms are CC;-H CC;-22 CC;-44 and CC;-CH5 'he predominant form that is found in human plasma is the CC;-44 form5 'he CC; isoforms are also found as sulfated and nonsulfated variants5 CC; is secreted from intestinal enteroendocrine I cells predominantly in the duodenum and :e:unum5 'he level of CC; in the +lood rises 8ithin -C minutes of food ingestion and reaches a pea( +y 2C minutes5 'he elevation in plasma CC; levels remains for approximately 4 hours follo8ing a meal5 'he most potent su+stances initiating a release of CC; from the I cells are fats and proteins5 Conversely duodenal +ile acids are potent suppressors of the secretion of CC;5 CC; exerts its +iological actions +y +inding to specific G-protein coupled receptors )GPC#s*5 'here are t8o CC; receptor types identified as CC;-- and CC;-25 'he CC; receptors are also identified as CC;" and CC; 8hose designations referred to their location of prominent expression 8ith CC;"

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 HF there+y generating gastric acid5 Lpon +inding its receptors in the gut CC; induces contractions of the gall+ladder and release of pancreatic enBymes and also inhi+its gastric emptying5 Dithin the +rain )specifically the median eminence and ventromedial nucleus of the hypothalamus =$H* CC; actions elicit +ehavioral responses and satiation5 'he CC;-- receptor is +elieved to +e the receptor primarily responsi+le for alterations in feeding +ehavior5 ,vidence for this comes from the Otsu(a %ong ,vans 'o(ushima Fatty rat 8hich has a null mutation in the CC;-- receptor5 'hese rats are hyperphagic and develop o+esity even on a fat restricted diet5 'he situation is not entirely conclusive since (noc(-out of the CC;-receptor in mice does not result in a similar phenotype5 Ho8ever the a+ility of CC; to regulate food inta(e has +een clearly demonstrated in numerous studies5 For example central administration of CC; results in reduced food inta(e5 Of significance to appetite control this effect is enhanced 8ith coadministration of leptin5 'he synergistic effects of CC; and leptin may +e due to the fact that their receptors are co-localiBed to the same sensory vagal afferent neurons5 In humans the correlations +et8een CC; and o+esity are gro8ing5 9tudies have sho8n that the fasting levels of CC; are lo8er in mor+idly o+ese individuals than in lean individuals5 In addition the postfeeding responses to CC; in mor+idly o+ese individuals in attenuated compared to lean individuals5 'he primary appetite suppressing effects of CC; are exerted via its inhi+itory actions on NP! neurons )orexigenic neurons* in the &$H and the N'95 Lsing genome 8ide screens for polymorphisms in genes associated 8ith o+esity and@or increased feeding +ehaviors have sho8n a correlation to the CC;PH4 haplotype5 Polymorphisms in the CC;-receptor gene may also predispose an individual to o+esity5 "lthough CC; is (no8n to +e involved in satiation 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 in reduced meal siBe +ut the animals increased their fre>uency of food inta(e such that the overall outcome 8as no net change in +ody 8eight5 Ho8ever given the synergistic actions of CC; and leptin com+ination therapies of these t8o hormones may prove useful5 +ac( to the top

Ghrelin and $+estatin


Gro8th hormone secretagogues )GH9s* 8ere originally characteriBed +y small synthetic molecules that acted 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 ligand for the GH9#5 'he name ghrelin is derived from gro8th-hormone release5 'he specific receptor to 8hich ghrelin +inds and activates is identified as GH9# type -a )GH9#-a*5 'he ghrelin gene )sym+ol M GH#%* is located on chromosome 4p201p2C and is composed of C exons and 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 name o+estatin is derived from a contraction of o+ese and statin )to suppress*5 Dhereas treatment of animals 8ith ghrelin results in increased appetite and food inta(e o+estatin treatment suppresses food inta(e5

Ghrelin is produced and secreted +y the <@"-li(e enteroendocrine cells of the stomach oxyntic )acid secreting* glands5 Because the <@"-li(e cells express ghrelin they are also sometimes referred to as ghrelin cells or Gr cells5 <@"-li(e cells express the receptor for gastrin )gut hormone that stimulates gastric acid secretion +y the stomach* and therefore it is +elieved that gastrin may directly stimulate ghrelin release5 9maller amounts of ghrelin are released from the small intestine and even less from the colon5 'he ghrelin gene primary transcription product can undergo alternative splicing5 "s a result of alternative splicing and post-translational cleavage the --G amino acid preproghrelin protein can +e processed into ghrelin )2H amino acids corresponding to amino acids 2A1C- of the preproprotein* o+estatin )24 amino acids corresponding to amino acids G01/H of the preproprotein* and des-acyl ghrelin )2G amino acids*5 Bioactive ghrelin is acylated on the serine at position 4 8ith n-octanic acid5 'he processing of ghrelin from preproghrelin involves cleavage +y prohormone convertase -@4 )PC-@4*5 'he attachment of ocatnoic acid to 9er4 of ghrelin is accomplished +y the acyltransferase identified as ghrelin O-acyltransferase )GO"'J also referred to as mem+rane-+ound O-acyltransferase domain-containing A $BO"'A*5 #ecent data implicates the non-acylated form of ghrelin may act as an antagonist of the acylated hormone5 'he des-acyl ghrelin protein is also acylated on 9er4 and that acylation is re>uired for its activity as for full-length ghrelin5 'he formation of des-ghrelin is the conse>uence of alternative splicing due to an intron that reside +et8een the glutamines at positions -4 and -A )Q-4 and Q-A* of the preproghrelin se>uence5 'he ma:or effect of ghrelin is exerted 8ithin the central nervous system at the level of the arcuate nucleus 8here it stimulates the release of neuropeptide ! )NP!* and agouti-related protein )"g#P*5 'he actions of NP! and "g#P enhance appetite and thus food inta(e5 Dithin the hypothalamus ghrelin action results in activation of "$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 +inding to GH9#-a are complex5 'here is activation of a G-protein coupled to P%C-E activation 8ith resultant activation 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 leptin5 Conversely inhi+ition of ghrelin production is exerted +y food inta(e hyperglycemia and o+esity5 'he action of ghrelin at the level of increasing 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(ines influences exocrine and endocrine functions of the pancreas controls gastric acid secretion and gastric motility 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 food inta(e and gastric emptying activity5 %i(e ghrelin 8hich is post-translationally modified o+estatin is also modified +ut its modification is an amidation5 O+estatin 8as found to +ind to an orphan G-protein coupled receptor )GPC#* identified as GP#4/5 ,vidence indicates that GP#4/ is also the Binc-sensing receptor )Rn#* that responds to Rn2F in the processes of tissue repair5 GP#4/ is expressed in liver gastrointestinal tract adipose tissue and pancreas5 "ctivation of the receptor results in increased c"$P and conse>uent activation of P;" medicated signaling path8ays5 Dithin the pancreas GP#4/ has +een sho8n to regulate the expression of insulin receptor su+strate-2 )I#9-2* and pancreatic and duodenal homeo+ox-- )P&<--* and that activation of the receptor is re>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+le that activation of GP#4/ +y preparations of o+estatin 8ere due to Binc present in the assays5 +ac( to the top

Pancreatic Polypeptide" PP
Pancreatic polypeptide 8as the first mem+er of the PP-fold family to +e isolated and characteriBed5 It 8as originally found as an impurity in preparations of insulin from chic(en pancreas5 9u+se>uently it 8as sho8n to +e produced and secreted +y type F cells 8ithin the periphery of pancreatic islets5 'he stimulus 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 hours follo8ing ingestion of food5 Humoral signals that are involved in food inta(e-mediated secretion of PP include ghrelin cholecysto(inin )CC;* motilin and secretin5 "dditionally adrenergic stimulation secondary to either hypoglycemia or exercise results in increased release of PP5 'he actions of PP include delaying gastric emptying inhi+ition of gall+ladder contraction and attenuation of pancreatic exocrine secretions5 'hese gut actions of PP are associated 8ith the mechanism referred to as the Nileal +ra(eN 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 'hese responses are mediated via activation of the !A receptor 8hich +inds PP 8ith highest affinity5 In addition to its expression in the "P the !A receptor is also expressed in regions of the hypothalamus including the "#C5 'herefore additional anorexigenic responses to PP can +e induced 8ithin the hypothalamus5 'hus PP plays an important role in the regulation of satiety )the sensation of +eing full*5 In o+ese individuals there is a reduced level of PP secretion in response to food inta(e 8hereas in anorexia nervosa there is increased PP release follo8ing consumption of food5 PP may also play a role in the pathogenesis of Prader-Dilli syndrome )PD9*5 'his disorder is characteriBed +y short stature reduced intellect and hyperphagia )excessive hunger and a+normally large food inta(e*5 In patients 8ith PD9 there is a reduced secretion of PP in response to food inta(e as 8ell as a reduced +asal level of circulating PP5 +ac( to the top

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<$*5 Both of these latter gut hormones are discussed a+ove5 9ecreted forms of P!! include P!!--40 and P!!4-405 P!!--40 is full-length protein and is more commonly referred to as :ust P!!5 P!!4-40 is generated via the actions of dipetidylpeptidase A )&PPA or &PP-I=* on P!!5 &PPA is the same enByme that inactivates G%P--5 Dithin the gastrointestinal tract the highest detecta+le levels P!! are found in the rectum 8ith lo8 levels found in the duodenum and :e:unum5 Dithin the central nervous system )CN9* P!! is detecta+le in the hypothalamus medulla pons and spinal cord5 "s indicated a+ove in the discussion of NP! P!! +inds to mem+ers of the ! receptor family5 P!! is a potent agonist of +oth !- and !2 receptors 8hereas P!!4-40 is a !2-specific agonist5 'he affinity of P!!4-40 for the !2 receptor is approximately - 333-fold higher than for the !- receptor5 'he release of P!! results in reduced gut motility a delay in gastric emptying and an inhi+ition of gall+ladder contraction5 "ll of these actions are li(e that of PP associated 8ith the ileal +ra(e5 Given that P!! is secreted from cells of the distal gut there must +e signals associated 8ith the response of the proximal gut to food inta(e that lead to P!! release5 Indeed humoral factors such as CC; and gastrin are thought to mediate the rapid release of P!! in response to eating5 'he amount of P!!

released in response to the ingestion of food is proportional to the caloric inta(e5 "nimal and human studies 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 the hypothalamus thus allo8ing this region to respond rapidly to the release of a gut hormone into the circulation5 ,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 food inta(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 appetite suppression it is thought that distur+ances in P!! release in response to food inta(e may play a role in the development of o+esity5 Indeed in o+ese humans there is a +lunted P!! response follo8ing food inta(e compared to lean humans5 Current therapeutic interventions designed to com+at o+esity involve studies of the efficacy of P!! at suppressing appetite5 +ac( to the top #eturn to 'he $edical Biochemistry Page
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