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GASTROENTEROLOGY2007;132:2116–2130 Gut Hormones and Appetite Control A. M. WREN and S. R. BLOOM DepartmentofMetabolicMedicine,ImperialCollegeLondon,London,England StephenR.Bloom,MD Manypeptidesaresynthesizedandreleasedfromthe UnitedKingdomalone.2Obesityisnotonlyaproblemin gastrointestinaltract.Althoughtheirrolesinthereg- the developed world, but is set to overtake infectious ulationofgastrointestinalfunctionhavebeenknown diseases as the most significant contributor to ill health for some time, it is now evident that they also phys- worldwide,andhasbeenclassifiedasanepidemicbythe iologically influence eating behavior. Our under- World Health Organization.3 The increasing prevalence standingofhowneurohormonalgut–brainsignaling of obesity in younger generations suggests that this epi- regulates energy homeostasis has advanced signifi- demic will continue to worsen. cantly in recent years. Ghrelin is an orexigenic pep- Publichealthinitiativeshavefailedtoreversetherising tideproducedbythestomach,whichappearstoactas incidence of obesity. Medical and behavioral interven- a meal initiator. Satiety signals derived from the in- tions, with the exception of bariatric surgery, have lim- testine and pancreas include peptide YY, pancreatic itedsuccess,ingeneralpromotingnomorethan5%–10% polypeptide,glucagon-likepeptide1,oxyntomodulin, reduction in body weight. Furthermore, weight regain, and cholecystokinin. Recent research suggests that even after this modest weight loss, is almost universal.4 gut hormones can be manipulated to regulate energy Therearegoodreasonsforthis,whichcanbeunderstood balance in humans, and that obese subjects retain by examining the homeostatic mechanisms that defend sensitivity to the actions of gut hormones. Gut hor- bodyweight.Inattemptingtoloseweightbydieting,the mone-based therapies may thus provide an effective body faces compensatory “starvation” signals from the and well-tolerated treatment for obesity. gutandadiposetissue,allwithasingleaimofpromoting hunger and storage of calories as fat. The notion that The gut is the most exciting endocrine organ in the energybalanceistightlyregulatedtodefenda“set-point” body. This remark from an endocrinologist may body weight may seem contradictory to our common once have been contentious in a gastroenterology jour- experiencethatfoodintakevarieswidelydaytoday.Such nal. Currently, the neuroendocrine role of the gut in marked diurnal variation may have led to the popular energy homeostasis is a dynamic and rapidly expanding belief, particularly among lean individuals, that regula- fieldofscientificinvestigationthathasunitedresearchers tionofbodyweightislargelyamatterofwillpower.Itis acrossmanyfields,astestifiedtobythisspecialissue.The hard to imagine such a view of the regulation of any concept of the gut as an endocrine organ is hardly new. similarly important aspect of physiology, for example The gut peptide secretin was the first substance to be blood pressure, persisting for so long. In fact, when termed a hormone, while the appetite inhibitory actions examined over the longer term, energy balance is ex- ofcholecystokinin(CCK)werefirstreportedover30years tremely finely regulated. ago.However,inrecentyears,intensificationofscientific During the evolution of the homeostatic mechanisms endeavor in this field has been motivated by the need to regulating body weight, food shortage has been the develop new strategies to tackle the global pandemic of obesity. Abbreviationsusedinthepaper:AgRP,agouti-relatedpeptide;CCK, The prevalence of obesity in adults has increased by cholecystokinin; CNS, central nervous system; GH, growth hormone; over 75% worldwide since 1980.1 Given that obesity is GLP-1,glucagon-likepeptide1;NPY,neuropeptideY;NTS,nucleusof causally associated with cardiovascular disease, type 2 the solitary tract; POMC, pro-opiomelanocortin; PP, pancreatic polypeptide;PWS,Prader-Willisyndrome;PYY,peptideYY. diabetes, hypertension, stroke, obstructive sleep apnoea, ©2007bytheAGAInstitute and certain cancers, this has translated into healthcare 0016-5085/07/$32.00 costs of over half a billion pounds every year in the doi:10.1053/j.gastro.2007.03.048 May2007 GUTHORMONESANDAPPETITECONTROL 2117 norm. The mechanisms that have allowed the human and cachexia is beyond the scope of this review, which race to survive famine may not be so well suited to the will focus mainly on obesity, the potential role of gut current situation. The increasing incidence of obesity hormones in this area will be briefly discussed. coincideswithwidespreadavailabilityofhighlypalatable foodofhighenergydensitythatcanbeobtainedwithout Long-Term and Short-Term Energy having to expend energy. This review will focus on the Balance Signals peptidehormonesignalsfromthegutthatcommunicate Peripheral signals involved in regulation of body the status of body energy stores to the brain and the weight and ingestive behavior are often categorized as braincentersonwhichtheyact.Theseregulatorysystems long-acting adiposity signals, such as insulin leptin and are not only of academic interest, but are likely to un- other adipokines and short-acting gastrointestinal fac- derpinanyfuturestrategytotackleobesity,byproviding tors.Long-actingsignalscharacteristicallyreflectthelev- drugtargetsfortheholygrailofasafesustainableweight els of energy stores and regulate body weight and the loss. amountofenergystoredasfatoverthelongterm.Short- Currentlyavailabledrugtherapieshavelimitedefficacy acting gastrointestinal signals are typified by gut hor- and considerable side effects. Two agents are currently mones such as CCK and mechanical factors, such as licensed for weight loss. Orlistat inhibits dietary fat ab- gastricdistension,whichcharacteristicallyrelayasenseof sorption, resulting in an additional loss of 3% to 4% of “fullness” resulting in postprandial satiation and meal body weight over diet alone in a 2-year period.5 It also termination.Morerecentlyidentifiedappetiteregulating results in deficiency of fat-soluble vitamins and fairly hormonesfromthegut,includingtheappetiteinhibiting dramatic gastrointestinal side effects, which make it un- hormone peptide YY (PYY) and the appetite-stimulating acceptableformanypatients.Sibutramineisaserotonin hormoneghrelin,appeartoblurtheboundariesbetween and norepinephrine reuptake inhibitor that acts in the long- and short-term appetite signals, with evidence central nervous system (CNS) to reduce energy intake emerging that they are involved in both regulation of andincreaseenergyexpenditure.Ithassimilarefficacyto appetiteonameal-by-mealbasisandalsoinlongerterm orlistat but also increases incidence of tachycardia and energy balance. In addition, the incretin glucagon-like hypertension. Both of these drugs only have data sup- peptide 1 (GLP-1), has been shown to inhibit appetite. porting treatment for up to 2 years. In the United King- This is reviewed in detail elsewhere in this issue and will dom, national prescribing guidelines generally recom- not be covered here in depth. This review will focus on mend withdrawal after 1 year, after which significant theevidenceforaroleoftheguthormonesghrelin,PYY, weight regain is common.6 oxyntomodulin, and pancreatic polypeptide (PP) in the Several newer antiobesity therapies targeting CNS re- short- and long-term regulation of energy balance. ceptors are in development or have recently been mar- keted. Among these is rimonabant, a cannabinoid CB1 Central Integration of Peripheral Signals receptor antagonist. This appears to be an effective weight-loss agent but is associated with high levels of Clearly, peripheral hunger and satiety signals re- drop-outduetoanxietyanddepression.7TheCB1recep- quire central integration to allow efficient energy ho- torhasaverywidedistribution,bothintheCNSandthe meostasis. Neurohormonal signals from the gut and ad- periphery, suggesting a wide range of physiologic func- ipose tissue converge on the hypothalamus where they tions.8 There is evidence that cannabinoids have neuro- are integrated, and in turn regulate energy intake and protective, anti-inflammatory and antiatherosclerotic ac- energyexpenditure.Thereaderisreferredtoanumberof tions, and concerns have been raised that rimonabant excellent reviews of the hypothalamic neurocircuits reg- may promote diseases including multiple sclerosis and ulatingenergybalance.12–15Inbrief,avitalcomponentof ischemicheartdisease.9,10Clearly,thesearchfortheideal the hypothalamic regulatory circuits is the arcuate nu- antiobesity agent is not at an end. cleus.Twokeyneuronalpopulationshavebeenidentified At the other end of the appetite regulation spectrum, within the arcuate nucleus with opposing effects on en- there is a pressing need for more effective, better-toler- ergy balance. A group of neurons in the medial arcuate ated appetite-stimulatory treatments. Loss of appetite nucleus coexpress neuropeptide Y (NPY) and agouti-re- and weight are major causes of morbidity and mortality lated peptide (AgRP) and act to stimulate food intake in patients, including those with cancer, kidney failure, and weight gain. In contrast, pro-opiomelanocortin human immunodificiency virus, cardiac failure, inflam- (POMC) and cocaine- and amphetamine-regulated tran- matory conditions, and postoperatively. Weight loss has scriptcoexpressingneuronsinthelateralarcuatenucleus an important impact on health economics. Undernutri- inhibit feeding and promote weight loss. The balance tion is estimated to increase the duration of 10% of between activity of these neuronal circuits is critical to hospital admissions by an average of 5 days, costing body weight regulation. approximately£266millionannuallyintheUnitedKing- Satietyisalsoregulatedbythehindbrain.Thenucleus dom.11 Although a comprehensive overview of anorexia of the solitary tract (NTS) and the area postrema, com- 2118 WRENANDBLOOM GASTROENTEROLOGYVol.132,No.6 Figure1. Overviewofperipheralfactorsregulatingenergybalanceandtheirroutesofsignalingtothebrain. ponentsofthedorsalvagalcomplex,receiveinputsfrom Ghrelin is a 28-amino acid peptide, cleaved from a vagal afferents and circulating factors, and are recipro- precursor,preproghrelin.18Itisprincipallysynthesizedin callyconnectedwithhypothalamicnucleicontrollingen- endocrine cells of the stomach, termed X/A-like or ghre- ergy balance. These brainstem centers can also respond lincells,andparticularlyfoundinthegastricfundus.18,23 independently to peripheral signals when communica- About 2/3 to 3/4 of circulating ghrelin is of gastric tion with higher brain centers are surgically interrupt- origin. Lesser concentrations of ghrelin are found ed.16 In addition, cortical inputs in terms of emotional, throughoutthesmallintestine,withtheduodenumpro- social, and learned behavior, as well as inputs from re- ducing approximately 10 times less than the stomach ward circuits, including the mesolimbic dopaminergic and progressively lower concentrations found more dis- system, all impact upon energy balance and communi- tally.23,24 Ghrelin undergoes posttranslational modifica- cate with the hypothalamus. tion with covalent attachment of a medium-chain fatty Peripheral feedback to the hypothalamus is complex, acid,typicallyoctanoicacid,totheserine-3residue.This as illustrated in Figure 1. Many circulating signals, in- acylation is entirely unique among biologically active cluding gut hormones, have direct access to the arcuate peptides and is required for ghrelin to bind to and acti- nucleus.Leptinisthearchetypalperipheralsignalacting vate its classical receptor, the GHS-R1a.18 The GHS-R1a directly on the arcuate nucleus.15,17 In contrast, other is widely expressed. In the CNS, it is found in areas peripheral signals influence the hypothalamus indirectly involved in regulation of appetite and energy balance via afferent neuronal pathways and brainstem circuits. includinghypothalamicnuclei,thedorsalvagalcomplex, The most extensively characterized of these is CCK, and the mesolimbic dopaminergic system.25–27 Peripher- which binds to receptors on the vagus nerve, thus acti- ally, it is expressed in the pituitary, and pharmacologi- vatingtheNTS,whichinturn,relaysinformationtothe cally ghrelin acts at both pituitary and hypothalamic hypothalamus. Similarly, GLP-1R expressing neurons of levels to powerfully stimulate growth hormone secre- the NTS project to hypothalamic regions involved in tion.18,20,28–30ThephysiologicrelevanceofghrelininGH appetitecontrol,includingthearcuate,dorsomedial,and regulation is debated. Ghrelin is not essential for GH paraventricular nuclei. In the cases of ghrelin and PYY, secretion, as ghrelin and GHS-R1a null mice are not there is evidence for both a direct action on the arcuate growthrestricted,butitmayplayaroleinaugmentation nucleusandanactionviathevagusnerveandbrainstem. of GHRH-stimulated GH pulses.31–33 GHS-R1a receptor expressionhasalsobeendescribedindiverseperipheralsites Ghrelin, the Hunger Hormone including the myocardium, stomach, small intestine, pan- Ghrelinistheonlyknowncirculatingorexigen.In creas, colon, adipose tissue, liver, kidney, placenta, and T contrast, all the other peripheral factors that regulate cells.25,26,34 An equally diverse series of biologic actions of energy balance act to restrain eating and weight gain. exogenousghrelinhavebeendocumented,includingeffects Ghrelin was discovered as an endogenous ligand for the on glucose homeostasis, gut motility, pancreatic exocrine growth hormone (GH) secretagogue receptor (GHS- secretion, cardiovascular function, immunity, and inflam- R1a).18 However, early work on this peptide demon- mation.33 The physiologic relevance of these actions re- stratedagrowthhormone-independentactiontopower- mains unclear, and the major role of ghrelin is generally fully increase food intake and body weight. The acceptedtobeinregulationofenergybalance.Thereisalso predominant focus of subsequent research has shifted evidenceforanumberofpharmacologicactionsofdes-acyl onto the role of ghrelin in energy balance.19–22 ghrelin, which must be mediated via receptors other than May2007 GUTHORMONESANDAPPETITECONTROL 2119 the GHS-R1a.35 The physiologic significance of these ac- mentrequiredforbindingtoandactivationoftheGHS- tions is contentious, as reviewed elsewhere.33,36 However, R1a.48,49 These residues are highly conserved, suggesting experiments in GHS-R1a knockout mice have definitively an important biologic role. Infusion of antighrelin anti- establishedthatthisreceptorisrequiredfortheorexigenic bodiesintotheratbraininhibitsfasting-inducedfeeding, andGHstimulatingeffectsofacylatedghrelin.32,37 further supporting ghrelin’s role as an endogenous reg- When administered into the CNS, ghrelin stimulates ulator of food intake.21 food intake as potently as NPY, previously the most Plasma ghrelin levels were first noted to increase on powerfulknownorexigen,andmorepowerfullythanany fasting and fall on refeeding in rodents, as would befit a other substance examined.19–21 Ghrelin also stimulates hunger signal.19,22 Subsequently, more detailed studies appetiteandfoodintakewhenadministeredsystemically have demonstrated preprandial plasma ghrelin elevation inrodents19,22andhumans.38Thispropertyisuniqueto inhumansandanimalsfedatscheduledtimes.50–54More ghrelin and not shared by any known neuropeptide or importantly, plasma ghrelin also peaks preprandially in circulating hormone. The duration of feeding stimula- human subjects, who have been deprived of time cues, tion in response to central or peripheral ghrelin admin- initiating meals voluntarily.55 These plasma ghrelin istration is short, similar to that observed for central peakscorrelatedwellwithhungerscores.Postprandially, NPY. Indeed, several lines of evidence suggest that ghre- plasma ghrelin is suppressed in proportion to calories lin acts via arcuate NPY/AgRP neurons, almost all of ingested, when macronutrient content and volume are whichexpresstheGHS-R1a.39Ghrelinstimulatesfeeding kept constant.56 Interestingly, fat appears to suppress most potently when injected directly into the arcuate ghrelin less potently per calorie than carbohydrate or nucleus and also stimulates release of NPY from hypo- protein.57,58Thismay,inpart,explainthereducedsatiety thalamic explants in vitro.22,30 Arcuate NPY/AgRP neu- andenhancedweightgainassociatedwithhigh-fatdiets. rons are activated by ghrelin, as demonstrated by en- Taken together, these data strongly suggest a role for hanced c-fos, NPY, and AgRP expression following ghrelinasamealinitiator.Whetherghrelinistheonly,or ghrelin administration and by electrophysiologic stud- even a physiologically vital, hunger signal is as yet unde- ies.21,40–43 Further, the orexigenic actions of ghrelin are termined. This would require demonstration that inter- abolishedinNPY/AgRPdualknockoutmiceandinmice ruption of ghrelin signaling, for example using antago- with postembryonic ablation of NPY/AgRP neurons.37,44 nists or inducible knockouts, abolishes normal meal Although this neuronal population is the most well- initiation. characterized ghrelin target, there is also evidence for an indirect action on these neurons via the vagus nerve. Ghrelin and Long-Term Energy Vagotomy abolishes the feeding and arcuate c-fos re- Homeostasis sponsetoperipheral,butnotcentralghrelinadministra- Inadditiontoacandidateroleasamealinitiator, tion.41,45 Other ghrelin targets include several other hy- ghrelin appears to participate in long-term energy bal- pothalamic nuclei, the dorsal vagal complex of the ance. Chronic administration of ghrelin in rodents re- brainstem and components of the mesolimbic dopami- sultsinprolongedhyperphagiaandweightgain.19,20The nergic system. The GHS-R1a is also expressed in these weightgainobservedisgreaterthanthatexpectedforthe locations and microinjection of ghrelin directly into degree of hyperphagia, and may reflect several reported these areas stimulates food intake.22,25–27,46,47 actionsofghrelinthatcouldcombinetopromoteweight gain. These include stimulation of adipogenesis, inhibi- Does Ghrelin Contribute to Preprandial tion of apoptosis, transfer from fatty acid oxidation to Hunger? glycolysis for energy expenditure, and inhibition of sym- Severallinesofevidencesuggestthatghrelinmay pathetic nervous system activity.19,35,59,60 There is 1 case regulatepreprandialhunger.Circumstantially,thedistri- report of an individual with a malignant gastric ghreli- bution of ghrelin, predominantly in the stomach and noma, who had extremely high circulating ghrelin con- upper small intestine, is ideal to monitor meal to meal centrations and remained obese with preserved appetite, nutrientintake.Theactionsofexogenousghrelinfulfill1 despite advanced and eventually fatal malignant dis- of the minimum requirements for a meal initiator, that ease.61 Thus, prolonged elevation of plasma ghrelin cer- is,stimulationoffoodintakewhenadministeredsystem- tainly promotes adiposity, in contrast to the classical ically, at doses that result in plasma concentrations sim- short-term appetite regulator CCK, where prolonged ad- ilartothosefoundinthefasted(hungry)state.Theonset ministrationdoesnotreducebodyweight.However,this of action is rapid, duration is short, and ghrelin appears does not prove that endogenous ghrelin physiologically todelaylatencytofeedandpromotefood-seekingbehav- regulates body weight. ior in rodents. Ghrelin stimulates food intake across a In humans, ghrelin levels are inversely correlated with broadrangeofspecies,includinghumans.Thefirst7,or adiposity,beinglowintheobese,higherinleansubjects, fewer,aminoacidsofghrelinplustheoctanoylgroupon and markedly elevated in subjects who are cachectic due the third serine residue constitute the minimum frag- to a diverse range of conditions including anorexia ner- 2120 WRENANDBLOOM GASTROENTEROLOGYVol.132,No.6 vosa, cancer, and chronic cardiac failure.62–67 This has devoid of ghrelin signaling certainly lack the extreme been interpreted as an adaptive response to restrain fur- phenotypesassociatedwithmicelackingleptinsignaling. ther overeating in the obese or to stimulate it in the However,takentogether,datafromknockoutmodelsare underweight. This hypothesis is supported by longitudi- compatible with a role for ghrelin in long-term energy nal studies. Ghrelin is increased in response to weight homeostasis. lossachievedeitherbydietaloneordietandexercise,and is suppressed by overfeeding or successful treatment of Ghrelin as a Drug Target anorexia nervosa.64,68–70 Thus, ghrelin levels alter, in the Given that circulating ghrelin is already low in opposite direction to leptin, to reflect nutritional status obesesubjects,onemightquestionhowmuchtherapeu- andbodyfatstores,supportingaroleinlong-termbody tic benefit could be obtained from further ghrelin sup- weight maintenance. An exception to this observation is pression. However, it has been reported that the rapid subjects with Prader-Willi syndrome (PWS), who have postprandial drop in circulating ghrelin is attenuated in very high fasting and postprandial ghrelin levels, which obesity.79Ithasalsobeenshownthatobesesubjectsmay maycontributetotheirobesity.71,72Itisunclearwhether be more sensitive to appetite stimulation by exogenous hyperghrelinaemia drives the extreme hyperphagia asso- ghrelin.80Thus,inhibitionofghrelinmayhavetherapeu- ciatedwiththissyndrome.Ithasbeennotedthatghrelin tic potential, particularly in enhancing further weight is not elevated in young children with PWS, in whom lossandpreventingweightregainfollowingdietinduced hyperphagia has not yet developed.73 However, soma- weight loss, when ghrelin levels become elevated. tostatin infusion in PWS subjects suppresses ghrelin Severalmajorpharmaceuticalcompanieshavepursued without suppressing appetite.74 This might suggest that programs investigating ghrelin inhibition. Interestingly, factors other than elevated ghrelin drive hyperphagia in the GHS-R1a exhibits constitutive activity, suggesting PWS,althoughconcomitantsuppressionofanorecticgut thataninverseagonistmaybemoretherapeuticallyuse- hormonesbysomatostatinisalikelyconfoundingfactor. ful than an antagonist.81 Another strategy is to design If ghrelin is critical for body weight maintenance, re- compoundsthatbindtoghrelinitselfandpreventinter- duction in ghrelin should promote weight loss and res- action with its receptor. A novel group of molecules toration of ghrelin should promote weight regain. This called RNA spiegelmers, oligonucleotides containing L- hasbeendemonstratedinmiceundergoingtotalgastrec- ribose, have been designed that are highly effective at tomy that have an 80% reduction in circulating ghrelin blockinginteractionofghrelinwiththeGHS-R1ainvitro associated with weight loss. Replacement of ghrelin to and in vivo. Antighrelin spiegelmers inhibit ghrelin- physiologiclevelsresultsinweightregain.However,mice inducedGHsecretionandreducefoodintakeandadiposity with global deletions of ghrelin or the GHS-R1a were in mice fed a high-fat diet, but have no effect in ghrelin initially reported to have minimal disruption of body knockout mice.82–84 However, to date, no ghrelin-block- weight homeostasis. As always with such mouse models, ing products have progressed as far as phase I trials. onemustconsider confoundingby developmentaladap- Indeed,therewouldbetheoreticalsafetyconcernsabout tation. A clear example of this can be found in the such agents in view of the possible role of ghrelin in NPY/AgRP system on which ghrelin is thought to act. regulation of the growth axis,18 as well as reported ben- NPY/AgRP dual null mice or mice in which the arcuate eficialcardiovascular85–87andanti-inflammatory88effects NPY/AgRP neurons are destroyed shortly after birth ex- of ghrelin. Regulation of octanoylation of ghrelin may hibit minimal phenotype, whereas destruction of these provideanalternativedrugtargetthatis,asyet,relatively neurons later in development causes marked anorexia unexplored. A more direct therapeutic application of and weight loss.44,75 Further studies on mice lacking ghrelin is in the treatment of anorexia and cachexia. To ghrelinortheGHS-R1ahavedemonstratedresistanceto this end, proof of principle studies have demonstrated diet induced obesity in mature mice.27,76 The phenotype thatghrelinstimulatesappetiteinpatientswithanorexia ofghrelinnullmicemightbefurthercomplicatedbythe andweightlossduetocancerandchronickidneydisease, observationthatthegenethatcodesforghrelinhasbeen and may also improve meal enjoyment, without any ad- found to code for another peptide, named obestatin. verse effects.89,90 Ghrelin administration by intravenous Obestatin was originally reported to reduce food intake infusion over 3 weeks results in weight gain in patients when administered peripherally or intracerebroventricu- withcardiaccachexiaandchronicobstructivepulmonary larly,andtoreducebodyweightgainwhenadministered disease.91,92 However, weight gain may have been in part peripherally.Theseeffectswereproposedtobemediated attributabletoimprovedgeneralwell-being,cardiacfunc- bytheorphanGprotein-coupledreceptor,GPR39.Much tion, and respiratory muscle strength, rather than a sole speculation followed as to why the same gene would effect directly on energy balance. In addition these were produce an orexigenic and an anorectic signal. However, open-label studies and therefore did not control for pla- subsequent reports have not supported the initial find- cebo effect. Intravenous infusion is not a practical route ingsandsuggestthatobestatinmaynotsignalviaGPR39 for chronic administration in most therapeutic settings. or play a role in the regulation of food intake.77,78 Mice However,ghreliniseffectivewhengivenbysubcutaneous May2007 GUTHORMONESANDAPPETITECONTROL 2121 injectioninhealthyleanindividualsandinmalnourished lating pancreatic digestive enzyme secretion.99 It is patients on peritoneal dialysis.90,93 Further placebo-con- thought that the reduction in food intake may be medi- trolled trials of long-term subcutaneous ghrelin admin- ated by a paracrine/neurocrine effect because high con- istration in anorectic/cachectic patients are required to centrationsofCCK,whichoccuronlylocaltothesiteof establish whether this may be a useful therapy. In addi- release, are required.102 Thus, locally released CCK may tion,awidevarietyoforallyactiveagonistsfortheGHS- increase vagal tone, without a significant increase in R1a were developed throughout the 1980s and 1990s, plasma CCK level. before the discovery of ghrelin as an endogenous ligand, AswouldbeexpectedifCCKisasatietysignal,CCK-A whichmayhavetherapeuticpotentialinthiscontext.94,95 receptor antagonists increase calorie intake and reduce satiety, suggesting endogenous CCK plays a physiologic Satiety Signals role in appetite regulation.103 CCK alone may be a very Afterameal,nutrientspassintothestomachand short-term modulator of appetite. It has a half-life of intestine, and a number of gastrointestinal signals are only1–2minutes,anditisnoteffectiveatreducingmeal released.Thesepeptidesandothersignalsacttooptimize sizeifthepeptideisadministeredmorethan15minutes the digestive process, and some also function as short- before a meal.96 Furthermore, chronic administration of term satiety signals and possibly long-term regulators of CCK alone does not result in weight loss. However, body weight. greater body weight loss is reported with a combination ofperipheralCCKandcentralleptinadministrationthan CCK with central leptin administration alone.104 Thus, the CCKistheprototypicalsatietyhormone.Itisnow short-term meal terminator CCK may interact with lep- over 30 years since CCK was first shown to inhibit food tin, a long-term signal of adiposity. intake,anditremains1ofthemostintensivelystudiedof Some, but not all, data from rodent models with re- the gut hormones.96–99 CCK is widely distributed within duced CCK signaling support a role for CCK in regula- thegastrointestinaltract,butthemajorityissynthesized tionoflong-termenergybalance.Chronicadministration intheduodenumandjejunum.Itisrapidlyreleasedinto of either CCK antibodies or CCK-A receptor antagonists the surrounding tissues and circulation in response to results in weight gain in rodent models but with no nutrients in the gut, in particular, fat and protein-rich significant increase in food intake.105,106 In addition, the meals, with levels rising approximately 5-fold postpran- CCK-A receptor knockout rat (but not the knockout dially. In addition to inhibiting food intake, its main mouse)ishyperphagicandobese.107TheuseofCCKasa actions include delaying gastric emptying, stimulating potential novel obesity therapy is in some doubt. In pancreaticenzymesecretion,andstimulatinggallbladder animals,repeatedpreprandialadministrationofCCKre- contraction.Togethertheseactionspromotetheeffective duces food intake but it also increases meal frequency, digestion of fat and protein in the small intestine by withnoresultingeffectonbodyweight.108Furthermore, matching the delivery of nutrient with the capacity to continuous CCK administration is ineffective after the digest it.97,98 first 24 hours.109 There are 2 distinct G protein-coupled CCK receptor subtypes.Intherat,CCK-A(alsocalledCCK-1)receptors are found in the pancreas, on vagal afferent and enteric PYY and PP neurons.CCK-Areceptorsarealsofoundthroughoutthe PYY, PP, and NPY are members of the PP-fold brain, including the nucleus of the solitary tract, area peptide family and are both putative circulating satiety postrema, and dorsomedial hypothalamus. CCKB recep- factors. In addition to a shared tertiary structure, the tors are distributed throughout the brain, are present in PP-fold structural motif, there is significant homology theafferentvagusnerve,andarefoundwithinthestom- between peptide sequences within the family. They all ach.97,98 have 36 amino acids, contain several tyrosine residues, Administration of CCK, to humans and animals, in- and require C-terminal amidation for biologic activity. hibits food intake by reducing meal size and duration.96 Although at high dose nausea and taste aversion have The PP-fold family exert their effects via the Y family of been detected, at low dose, feeding is inhibited without Gprotein-coupledreceptors.Fourreceptorsubtypeshave these effects.100 The main receptor at which CCK exerts been identified—Y1, Y2, Y4, and Y5—all of which are these effects is the CCK-A receptor.101 Only the sul- expressed in the hypothalamus.110 Y1 and Y5 have both phated form of CCK binds with high affinity to the beenputforwardastheputativereceptorsviawhichNPY CCK-A receptor, and it is only this form that inhibits exertsitsorexigenicaction.TheY2receptoristhoughtto food intake.96 Recent work suggests that CCK-A recep- function as an autoinhibitory presynaptic receptor, ex- torsexpressedbyvagalafferentneuronsareaparticularly pressed on NPY neurons, and to mediate the anorectic important target for CCK in producing sensations of actionsofPYY,whiletheY4receptorappearstomediate satiety,aswellasinhibitinggastricemptyingandstimu- the anorectic actions of PP. 2122 WRENANDBLOOM GASTROENTEROLOGYVol.132,No.6 PYY In humans, intravenous infusion of PYY reduces 3–36 appetite and food intake at a subsequent meal by about PYYoccursin2forms:PYY andPYY .PYY , 1–36 3–36 3–36 1/3. Although initial reports detected inhibition of food the major circulating form (11), is a truncated 34-amino intake at plasma PYY concentrations in the physiologic acid form created by cleavage of the N-terminal Tyr-Pro range, others have only detected an effect at pharmaco- residues by dipeptidyl peptidase IV (DPPIV).111 Although logic doses.115,116,119 Thus, although there remains some full-lengthPYYbindswithsimilaraffinitytoallYreceptors, debate over whether PYY is a physiologic meal termi- PYY showsselectivityfortheY2receptor,forwhichithas 3–36 3–36 nator in humans, appetite inhibition in response to ex- highaffinity,andsomeaffinityforY1andY5receptors.110 ogenous PYY, in both lean and obese individuals, is a PYY is secreted from entero-endocrine L-cells These robust and reproducible finding. PYY immunoreactive cells are found throughout the en- tire gastrointestinal tract, but particularly in the distal portion. PYY immunoreactivity is almost absent in the PYY and Long-Term Energy stomach,sparseintheduodenumandjejunum,common Homeostasis in the ileum and colon, and at very high levels in the If circulating PYY is a long-term negative reg- 3–36 rectum (the converse pattern of that for ghrelin). The ulator of body weight, analogous to leptin, then chronic patternofsecretionisalsoamirrorimageofthatfound systemic administration would be predicted to result in for ghrelin; that is, PYY is released into the circulation weight loss. This has been reported in some but not all following meals and suppressed by fasting.112 rodent models, with more consistent effects observed PYYhaslongbeenknowntoexertnumerouseffectson using intravenous administration and with dosage pat- the gastrointestinal tract. Administration of PYY in- tern also playing an important role.122 However, data creasestheabsorptionoffluidsandelectrolytesfromthe from knockout mice provide more convincing evidence ileum after a meal and inhibits pancreatic and gastric for a long-term role for PYY in regulation of energy secretions, gallbladder contraction, and gastric empty- balance.Threeseparateknockoutmodelshavebeengen- ing.113 Peripheral administration of PYY, like ghrelin, erated, 2 of which develop obesity.123–125 One model did also exerts effects on numerous other body systems. For not become obese. This model also had disruption of example, it reduces cardiac output, causes vasoconstric- expressionofthePPgene.123Onewouldnotpredictthat tion, and reduction in glomerular filtration rate, plasma lossofasecondputativeanorecticsignalwouldattenuate renin, and aldosterone activity. The physiologic signifi- obesity. However, subtle differences in technique and cance of these numerous actions has not been estab- background strain have frequently been reported to re- lished. sult in differing phenotypes in other knockout mouse models.In1oftheobesePYYnullmousemodelsadmin- Does PYY Contribute to Postprandial istrationofPYYcorrectedthephenotype,suggestingthat Satiety? obesity was truly being driven by PYY deficiency.125 ThepatternofPYYsecretioninresponsetoameal In contrast to leptin, circulating levels of PYY are not raises the possibility that it may be a physiologic satiety elevated in human obesity, and obese individuals retain signal, acting to terminate the meal and stimulating full sensitivity to the anorectic actions of PYY .116 It 3–36 coordinated gastrointestinal responses to aid digestion has been reported that obese subjects have lower fasting andabsorption.PYYlevelsrisetoaplateauat1–2hours and postprandial circulating PYY than lean sub- postprandially,withthesepeaklevelsinfluencedbyboth jects.114,116,26,127Toproduceanequivalentstimulationof the number of calories and the composition of the food PYY and equivalent satiety, obese individuals needed to consumed.112,114 The onset of PYY release occurs before consume a much greater caloric load than their lean nutrients have reached the predominant sites of PYY counterparts.114However,notallstudieshavedetecteda production in the distal gastrointestinal tract. This im- difference in fasting PYY concentrations between lean plies that peptide release may occur via a neural reflex, and obese groups.128,129 possibly through the vagus nerve. Current data suggest that impaired postprandial PYY Systemic administration of PYY inhibits food in- 3–36 releasemay,atleast,impairsatietyandhelptomaintain take in rodents and humans.115–119 Initially, these find- obesity, if not act as a primary driver of initial develop- ings were contentious, with several authors unable to mentofobesity.WhetherornotreducedPYYsignalingis reproduce feeding inhibition in rodents.120 A probable a primary cause of obesity, it is certainly true that re- explanation for this apparent conflict is that the effects tainedPYYsensitivityintheobesemakesitanattractive ofanorecticagentsinrodentsareeasilymaskedbystress, therapeutic target. causing a reduction of food intake in the control group. Thus,significantinhibitionoffeedingbyPYY cannot 3–36 Mechanism of Action of PYY be detected in rodents that are not fully acclimatized to experimental procedures or following transfer to a novel The exact mechanism whereby PYY inhibits 3–36 environment.121 appetite and food intake is contentious. Interestingly, in May2007 GUTHORMONESANDAPPETITECONTROL 2123 contrast to peripheral administration, intracerebroven- The role of PP in appetite regulation has been investi- tricular administration of PYY stimulates food intake. gated for over 30 years. It was initially noted that ob/ob This is thought to be via an action on Y1 and Y5 recep- mice lacked pancreatic PP cells, and peripheral adminis- torsintheparaventricularnucleus,thesecond-orderneu- tration of PP could reduce their food intake and body ronstargetedbyorexigenicarcuatenucleusNPYneurons. weight.135 Peripheral administration of PP resulting in Several lines of investigation suggest a direct anorectic physiologicplasmalevelshasbeenshowntoreducefood actionofcirculatingPYY onthearcuatenucleus.c-fos intake in normal mice, with associated reduction in gas- 3–36 isobservedinthearcuatenucleusinresponsetoperiph- tric emptying, and gastric expression of ghrelin, and eral administration of PYY and direct microinjection increased vagal tone.136 PP also increased oxygen con- 3–36 into the arcuate nucleus inhibits feeding. This action is sumptionandstimulatedsympatheticactivity,leadingto thought to be via autoinhibitory Y2 receptors on the the suggestion that PP may also increase energy expen- orexigenicNPYneurons.Insupportofthishypothesis,a diture. In normal-weight human volunteers infusion of highly specific Y2 agonist inhibits feeding following in- PP reduces food intake without altering gastric empty- traarcuate injection, while the anorectic actions of ing.137 Subjects with PWS are reported to have sup- PYY are absent in the Y2 knockout mouse and pressedbasalandpostprandialPPlevels,whilePPadmin- 3–36 blocked by a Y2 receptor antagonist.115,130 Furthermore, istrationtoPWSsubjectsreducedfoodintake.138,139Itis, PYY reducesexpressionofNPYinthearcuatenucleus therefore, possible that PP deficiency contributes to the 3–36 andreleaseofNPYfromhypothalamicexplants.Electro- hyperphagia in this obesity syndrome. physiologic studies suggest that PYY directly inhibits Apart from its acute effects on appetite and food 3–36 activityofarcuateNPYneurons,therebysecondarilydis- intake, PP may also modulate long-term energy balance. inhibitinganorecticPOMCneurons.115However,thepic- Transgenic mice that overexpress PP have a lean pheno- tureappearstobemorecomplexthanasimpleactionon type with reduced food intake.140 Repeated administra- thearcuatenucleus.First,POMCneuronaldisinhibition tion of PP to ob/ob mice decreases body weight gain and doesnotappeartobenecessaryfortheactionofPYY , ameliorates insulin resistance and dyslipidemia.136 How- 3–36 as it retains efficacy in mice with deficient melanocortin ever, rodents with diet-induced obesity are less sensitive signaling.131 Second, there is now evidence for an action to the anorectic actions of PP. Long-term energy stores ofPYY atthelevelofthevagusandofthedorsalvagal may influence the circulating PP levels as well as short- 3–36 complex.132 The relative contribution of these various term food intake. Plasma PP is increased in individuals putativesitesofactiontophysiologicappetiteregulation with anorexia nervosa, and there have been reports of remains unclear. The ascending vagal–brainstem–hypo- suppressed plasma PP in obese subjects. However, the thalamic pathways have, however, been implicated in effectsofobesityoncirculatingconcentrationsofPPare mediating sensations of nausea. In keeping with this, conflicting;othershavefoundnodifferencebetweenlean PYY has,athighdoses,beenreportedtocausecondi- and obese subjects or between obese subjects before and 3–36 tioned taste avoidance in rodents and nausea in hu- afterweightloss.TheeffectsofPPonappetiteandbody mans.114,119,133However,lowerdosesinhibitappetiteand weight in obese humans are unknown. Further investi- food intake in rodents and humans without aversive gationinobesesubjectsmayindicatewhetherPPhasthe effects or nausea.114,115,119,133 Coupled with the observa- potential to be a novel treatment for obesity. tionthatPYYnullmicebecomeobese,thissuggestsarole PP,likePYY,hasopposingeffectsonappetite,depend- for PYY in appetite regulation independent of aversive ing on the route of administration. Injection of PP into effects.DrugcompaniesdevelopinganaloguesofPYYfor the third ventricle stimulates daytime food intake in treatment of obesity will need to be mindful of this satiated rats.141 Similarly, central injection of PP has the potentiallynarrowtherapeuticwindowtodesignsuccess- opposite effect to peripheral administration on gastric ful agents. motility, stimulating rather than inhibiting gastric emp- tying.Thesecontrastingeffectsofcentralandperipheral administration of PP probably reflect differing sites of PP receptoractivation.PPisunabletocrosstheblood–brain PP is produced largely in the endocrine pancreas, barrier. Circulating PP therefore acts on the CNS via butalsointheexocrinepancreas,colon,andrectum.Like areas that have a deficient blood–brain barrier, such as PYY,PPisreleasedinresponsetoameal,inproportionto the area postrema. The passage of PP into the area pos- the caloric load, and inhibits appetite.134 Pancreatic and trema has been demonstrated by autoradiographic stud- gastrointestinal hormones can also regulate circulating ies and neuronal activation by expression of the imme- PPlevels.Ghrelin,motilin,andsecretinrapidlystimulate diate early gene, c-fos, in the area postrema.142 The PP release, whereas somatostatin and its analogs signifi- anorectic effect seen after peripheral administration of cantly reduce plasma PP concentrations. PP binds with PP probably occurs via the Y4, which is highly expressed greatestaffinitytoY4receptors(withgreateraffinitythan in this region. The receptor mediating the orexigenic PYY) and Y5 receptors.110 effect of PP after central injection is unclear. The stimu- 2124 WRENANDBLOOM GASTROENTEROLOGYVol.132,No.6 tion of nutrients and appear to act in part as satiety signalsaswellaspossiblyparticipatinginlong-termbody weight regulation. GLP-1 is the most powerful known incretin in humans, and manipulation of the GLP-1 sys- tem forms the basis of several major new treatments for type 2 diabetes. These include a subcutaneously admin- istered DPPIV-resistant GLP-1R agonist, exendin-4, a peptide component of gila monster saliva marketed as exenatide (Byetta), as well as orally active DPPIV inhibi- tors. The role of GLP-1 and other incretins in appetite regulation is reviewed extensively elsewhere in this issue andwillnotbediscussedhereindetail.However,inbrief, central administration of GLP-1, both intracerebroven- tricularly and into the paraventricular nucleus, reduces calorieintakeinanimalmodels,whiletheGLP-1receptor antagonist exendin 9-39 increases food intake.145 Chronic administration of GLP-1 into the CNS attenu- atesweightgain146andperipheralGLP-1injectioninhib- itsfoodintakeinrodentsandhumans.Evidencesuggests GLP-1 secretion is reduced in obese subjects, and weight loss normalizes the levels.147 Reduced GLP-1 secretion could, therefore, contribute to obesity, and replacement may restore satiety. Obese subjects receiving subcutane- ousGLP-1for5days,justbeforeeachmeal,reducedtheir Figure2. Overviewofdifferentialpreproglucagonprocessinginpan- calorie intake by 15% and lost 0.5 kg in weight.148 creasvsbrainandgut.MPGF,majorproglucagonfragment;GRRP, glicentin-related pancreatic polypeptide; GLP, glucagon-like peptide; SP,spacerpeptide. Oxyntomodulin Oxyntomodulininhibitscalorieintakeinrodents lationoffoodintakeisbluntedinY5knockoutmicebut whengiveneithercentrallyorperipherally,andresultsin not by Y5 receptor antisense oligonucleotides. decreased weight gain when administered peripheral- ly.149–151 Oxyntomodulin is also an effective anorectic Oxyntomodulin and GLP-1 peptideinhumansubjects.Aninfusionofoxyntomodu- Oxyntomodulin and GLP-1 are products of the lintonormal-weighthumansubjectsreducedimmediate preproglucagongene.Preproglucagonisexpressedinthe calorieintakeby19.3%andwaseffectiveatreducingfood pancreas, L-cells of the intestine, and in the NTS of the intakeupto12hourspostinfusion.152Partofitsanorec- brainstem and undergoes differential processing by pro- ticeffectmaybeviasuppressionofplasmaghrelinlevels. hormone convertase 1 and 2 depending on the site of Peripheral administration of oxyntomodulin, at post- synthesis.143,144asillustratedinFigure2.Inthepancreas, prandial concentrations, reduces circulating ghrelin by classical preproglucagon processing yields glucagon and around 15%–20% in rodents and 44% in human sub- the apparently inactive N-terminal fragment glicentin- jects.151,152 It is possible that postprandial oxyntomodu- related pancreatic polypeptide while the GLP sequences lin release may contribute to the normal physiologic remain within a larger peptide, major proglucagon frag- inhibition of plasma ghrelin after meals. ment. The posttranslational processing in the gut and In contrast to GLP-1, oxyntomodulin is a much less brain are very similar. In these tissues, the glucagon potent incretin but may have more potent effects on sequence remains in a larger peptide, glicentin, which is weight loss. Although acute oxyntomodulin infusion in thought to be inactive. Glicentin is further cleaved to humans reduces food intake, it only causes a small in- yield oxyntomodulin and glicentin-related pancreatic crease in plasma insulin without affecting plasma glu- polypeptide. Oxyntomodulin is a 37-amino acid peptide cose.152 When administered 3 times daily in overweight comprising the 29 amino acids of pancreatic glucagon volunteers for 4 weeks, subcutaneous oxyntomodulin with an eight amino acid C-terminal extension, some- resultedin2.3kgweightlosscomparedwith0.5kginthe times called spacer peptide 1. The other major products control group.153 Enhanced weight loss in response to of preproglucagon processing in gut and brain are the 2 oxyntomodulin may be due to an additional effect of glucagon-like peptides, GLP-1 and GLP-2. oxyntomodulintoincreaseenergyexpenditure.Acutead- GLP-1 and oxyntomodulin, along with PYY and CCK, ministration of oxyntomodulin has been shown to in- are released from intestinal L-cells in response to inges- crease voluntary activity in human subjects and to in- May2007 GUTHORMONESANDAPPETITECONTROL 2125 creaseheartrateinrodents.151,154Thecirculatinglevelsof most favorable gut hormone profile to allow sustained oxyntomodulin in obesity remain to be established. weight loss. Both GLP-1 and oxyntomodulin are thought to exert their effects via the GLP-1 receptor (GLP-1R). Antago- A Coordinated Response to Obesity nists of the GLP-1R, such as exendin (9–39), antagonize In designing an optimal treatment for obesity, the effect of both GLP-1 and oxyntomodulin, and both based upon physiologic satiety mechanisms, perhaps peptides are ineffective in the GLP-1 receptor knockout our biggest clues come from the field of bariatric mouse.155 However, the affinity of oxyntomodulin for surgery. The only treatment to date associated with GLP-1Risapproximately2ordersofmagnitudelessthan dramatic and sustained weight loss in the morbidly that of GLP-1, yet both peptides appear to be similarly obese is gastric bypass surgery. However, its cost and effectiveatreducingfoodintake.Itispossibletheremay associatedmorbidityandmortalitymakeitanimprac- beaseparateoxyntomodulinreceptornotyetcloned.The ticaltreatmentforthemajorityofobesepatientsandit GLP-1R is present in the NTS in the brainstem and the is generally reserved for the morbidly obese. Gastric hypothalamicarcuatenucleus.Themechanismsofaction bypass results in significant increases in plasma PYY, of GLP-1 and oxyntomodulin appear to be similar but GLP-1,andoxyntomodulinwhileghrelineitherfallsor not identical. Peripheral and central GLP-1 administra- fails to rise, despite significant weight loss.158,159Inter- tionhavebeenreportedtoactivateneuronsinthehypo- estingly, bypass patients report dramatically reduced thalamic arcuate nucleus and paraventricular nucleus, hungerlongbeforesubstantialweightlossoccurs.Fur- NTS, and area postrema.144 In addition, ablation of va- thermore, in rodent models, many of the beneficial gal–brainstem–hypothalamic projections attenuates effects of bypass can be mimicked by gut hormone feeding inhibition by GLP-1.132 Although systemic oxyn- administration.158Couldthealteredguthormonesfol- tomodulin administration results in a similar pattern of lowing gastric bypass be sending “fullness” signals neuronal activation to GLP-1, intraarcuate administra- resulting in sustained weight loss, in contrast to the tionofexendin9-39blockstheanorecticeffectsonoxyn- “starvation” signals that accompany diet-induced tomodulin but not GLP-1, suggesting a direct action on weight loss, promoting weight regain? It is notable the arcuate nucleus.151 thatthechangesinthe4guthormonesaboveallfavor The duration of inhibition of food intake in response weight loss following gastric bypass. This coordinated toperipheraloxyntomodulinadministrationisshort,ne- action, mimicking natural satiety, may be a key to cessitating3timesdailysubcutaneousinjectioninweight effective antiobesity therapy. As noted above, individ- loss studies in humans.153 This may be due to rapid ualguthormonesadministeredathighconcentrations cleavage of the 2 N-terminal amino acid residues by havebeenassociatedwithaversivebehaviorsinrodents DPPIV,asobservedforGLP-1andPYY.DDPIVresistant and nausea in humans. We have reported that low analogs of oxyntomodulin may, thus, have greater ther- doses of PYY and GLP-1 inhibit food intake addi- 3–36 apeutic potential than the native peptide. tively.160Analogoustocurrenttreatmentforhyperten- sion where several agents are commonly used, a smart cocktailofguthormone-baseddrugsmayproveamore Dietary Manipulation of Gut Hormones effective antiobesity treatment than targeting a single Ithasbeensuggestedthatacauseofthecurrent system. This approach could potentially provide the obesity epidemic may be that modern processed foods sustainedweightlossofferedbygastricbypasssurgery, bypass our natural satiety mechanisms. Low-fat diets without the associated morbidity and mortality. The are the most well-established means of dietary weight major therapeutic disadvantage of gut hormones is loss. It has been reported that weight loss in response their short duration of action and the requirement for to a low-fat diet does not produce the expected eleva- subcutaneous or intravenous administration. In the tion in plasma ghrelin.156,157 This may be due to an GLP-1system,degradation-resistantanalogsanddrugs increase in the proportion of calories consumed as that inhibit enzymes that degrade the endogenous carbohydrate that more potently suppresses ghrelin hormone have already been brought to market for the percalorieconsumedthandoesfat.High-proteindiets treatment of type 2 diabetes. Similar approaches may havealsobecomepopularinrecentyearsasameansto be successful for oxyntomodulin, PYY, and PP, while promote satiety and weight loss. Diets high in protein intranasal delivery systems or development of orally have recently been reported to elevate circulating PYY active small molecule mimetics could avoid the need andenhancesatietymoreeffectivelythanothermacro- for administration by injection. nutrients;125 however, previous data suggested that, at Obesityisthemostsignificantgrowinghealthconcern a single meal, higher plasma concentrations of PYY worldwide.Currenttreatments,barringbariatricsurgery, werestimulatedbyhigh-fatisocaloricmeals,compared are insufficiently effective. Many drugs in development with protein or carbohydrate.112 It is an intriguing do not target physiologic satiety mechanisms and have possibility that designer diets may help promote the worrisome side effects attributable to the ubiquitous

Description:
tions, with the exception of bariatric surgery, have lim- ited success, in . appetite control, including the arcuate, dorsomedial, and . been interpreted as an adaptive response to restrain fur- .. robust and reproducible finding.
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