GASTROENTEROLOGY.132(2007)2116 Gut Hormones and Appetite Control

G

Mgufisrctatpagbsma

TonefiacTtoaedo

ocdac

GASTROENTEROLOGY 2007;132:2116 –2130

ut Hormones and Appetite Control

A. M. WREN and S. R. BLOOM

Department of Metabolic Medicine, Imperial College London, London, England

UtdwWod

itireTbbbghebembthsbet

r

cGtp

Stephen R. Bloom, MD

any peptides are synthesized and released from theastrointestinal tract. Although their roles in the reg-lation of gastrointestinal function have been knownor some time, it is now evident that they also phys-ologically influence eating behavior. Our under-tanding of how neurohormonal gut– brain signalingegulates energy homeostasis has advanced signifi-antly in recent years. Ghrelin is an orexigenic pep-ide produced by the stomach, which appears to act as

meal initiator. Satiety signals derived from the in-estine and pancreas include peptide YY, pancreaticolypeptide, glucagon-like peptide 1, oxyntomodulin,nd cholecystokinin. Recent research suggests thatut hormones can be manipulated to regulate energyalance in humans, and that obese subjects retainensitivity to the actions of gut hormones. Gut hor-

one-based therapies may thus provide an effectivend well-tolerated treatment for obesity.

he gut is the most exciting endocrine organ in thebody. This remark from an endocrinologist may

nce have been contentious in a gastroenterology jour-al. Currently, the neuroendocrine role of the gut innergy homeostasis is a dynamic and rapidly expandingeld of scientific investigation that has united researcherscross many fields, as testified to by this special issue. Theoncept of the gut as an endocrine organ is hardly new.he gut peptide secretin was the first substance to be

ermed a hormone, while the appetite inhibitory actionsf cholecystokinin (CCK) were first reported over 30 yearsgo. However, in recent years, intensification of scientificndeavor in this field has been motivated by the need toevelop new strategies to tackle the global pandemic ofbesity.

The prevalence of obesity in adults has increased byver 75% worldwide since 1980.1 Given that obesity isausally associated with cardiovascular disease, type 2iabetes, hypertension, stroke, obstructive sleep apnoea,nd certain cancers, this has translated into healthcare
osts of over half a billion pounds every year in the
nited Kingdom alone.2 Obesity is not only a problem inhe developed world, but is set to overtake infectiousiseases as the most significant contributor to ill healthorldwide, and has been classified as an epidemic by theorld Health Organization.3 The increasing prevalence

f obesity in younger generations suggests that this epi-emic will continue to worsen.Public health initiatives have failed to reverse the rising

ncidence of obesity. Medical and behavioral interven-ions, with the exception of bariatric surgery, have lim-ted success, in general promoting no more than 5%–10%eduction in body weight. Furthermore, weight regain,ven after this modest weight loss, is almost universal.4

here are good reasons for this, which can be understoody examining the homeostatic mechanisms that defendody weight. In attempting to lose weight by dieting, theody faces compensatory “starvation” signals from theut and adipose tissue, all with a single aim of promotingunger and storage of calories as fat. The notion thatnergy balance is tightly regulated to defend a “set-point”ody weight may seem contradictory to our commonxperience that food intake varies widely day to day. Sucharked diurnal variation may have led to the popular

elief, particularly among lean individuals, that regula-ion of body weight is largely a matter of willpower. It isard to imagine such a view of the regulation of anyimilarly important aspect of physiology, for examplelood pressure, persisting for so long. In fact, whenxamined over the longer term, energy balance is ex-remely finely regulated.

During the evolution of the homeostatic mechanismsegulating body weight, food shortage has been the

Abbreviations used in the paper: AgRP, agouti-related peptide; CCK,holecystokinin; CNS, central nervous system; GH, growth hormone;LP-1, glucagon-like peptide 1; NPY, neuropeptide Y; NTS, nucleus of

he solitary tract; POMC, pro-opiomelanocortin; PP, pancreaticolypeptide; PWS, Prader-Willi syndrome; PYY, peptide YY.

© 2007 by the AGA Institute0016-5085/07/$32.00

doi:10.1053/j.gastro.2007.03.048

nrccfhptbaddl

alsbrdaacaohpdmw

ckrwdtptptmia

taaihmathad

awh

wloteaamg“thhhleaepTntos

qmiaeeutcwenla(sibb

May 2007 GUT HORMONES AND APPETITE CONTROL 2117

orm. The mechanisms that have allowed the humanace to survive famine may not be so well suited to theurrent situation. The increasing incidence of obesityoincides with widespread availability of highly palatableood of high energy density that can be obtained withoutaving to expend energy. This review will focus on theeptide hormone signals from the gut that communicatehe status of body energy stores to the brain and therain centers on which they act. These regulatory systemsre not only of academic interest, but are likely to un-erpin any future strategy to tackle obesity, by providingrug targets for the holy grail of a safe sustainable weight

oss.Currently available drug therapies have limited efficacy

nd considerable side effects. Two agents are currentlyicensed for weight loss. Orlistat inhibits dietary fat ab-orption, resulting in an additional loss of 3% to 4% ofody weight over diet alone in a 2-year period.5 It alsoesults in deficiency of fat-soluble vitamins and fairlyramatic gastrointestinal side effects, which make it un-cceptable for many patients. Sibutramine is a serotoninnd norepinephrine reuptake inhibitor that acts in theentral nervous system (CNS) to reduce energy intakend increase energy expenditure. It has similar efficacy torlistat but also increases incidence of tachycardia andypertension. Both of these drugs only have data sup-orting treatment for up to 2 years. In the United King-om, national prescribing guidelines generally recom-end withdrawal after 1 year, after which significanteight regain is common.6

Several newer antiobesity therapies targeting CNS re-eptors are in development or have recently been mar-eted. Among these is rimonabant, a cannabinoid CB1eceptor antagonist. This appears to be an effectiveeight-loss agent but is associated with high levels ofrop-out due to anxiety and depression.7 The CB1 recep-or has a very wide distribution, both in the CNS and theeriphery, suggesting a wide range of physiologic func-ions.8 There is evidence that cannabinoids have neuro-rotective, anti-inflammatory and antiatherosclerotic ac-ions, and concerns have been raised that rimonabant

ay promote diseases including multiple sclerosis andschemic heart disease.9,10 Clearly, the search for the idealntiobesity agent is not at an end.

At the other end of the appetite regulation spectrum,here is a pressing need for more effective, better-toler-ted appetite-stimulatory treatments. Loss of appetitend weight are major causes of morbidity and mortalityn patients, including those with cancer, kidney failure,uman immunodificiency virus, cardiac failure, inflam-atory conditions, and postoperatively. Weight loss has

n important impact on health economics. Undernutri-ion is estimated to increase the duration of 10% ofospital admissions by an average of 5 days, costingpproximately £266 million annually in the United King-
om.11 Although a comprehensive overview of anorexia o
nd cachexia is beyond the scope of this review, whichill focus mainly on obesity, the potential role of gutormones in this area will be briefly discussed.

Long-Term and Short-Term EnergyBalance SignalsPeripheral signals involved in regulation of body

eight and ingestive behavior are often categorized asong-acting adiposity signals, such as insulin leptin andther adipokines and short-acting gastrointestinal fac-ors. Long-acting signals characteristically reflect the lev-ls of energy stores and regulate body weight and themount of energy stored as fat over the long term. Short-cting gastrointestinal signals are typified by gut hor-ones such as CCK and mechanical factors, such as

astric distension, which characteristically relay a sense offullness” resulting in postprandial satiation and mealermination. More recently identified appetite regulatingormones from the gut, including the appetite inhibitingormone peptide YY (PYY) and the appetite-stimulatingormone ghrelin, appear to blur the boundaries between

ong- and short-term appetite signals, with evidencemerging that they are involved in both regulation ofppetite on a meal-by-meal basis and also in longer termnergy balance. In addition, the incretin glucagon-likeeptide 1 (GLP-1), has been shown to inhibit appetite.his is reviewed in detail elsewhere in this issue and willot be covered here in depth. This review will focus onhe evidence for a role of the gut hormones ghrelin, PYY,xyntomodulin, and pancreatic polypeptide (PP) in thehort- and long-term regulation of energy balance.

Central Integration of Peripheral SignalsClearly, peripheral hunger and satiety signals re-

uire central integration to allow efficient energy ho-eostasis. Neurohormonal signals from the gut and ad-

pose tissue converge on the hypothalamus where theyre integrated, and in turn regulate energy intake andnergy expenditure. The reader is referred to a number ofxcellent reviews of the hypothalamic neurocircuits reg-lating energy balance.12–15 In brief, a vital component ofhe hypothalamic regulatory circuits is the arcuate nu-leus. Two key neuronal populations have been identifiedithin the arcuate nucleus with opposing effects on en-

rgy balance. A group of neurons in the medial arcuateucleus coexpress neuropeptide Y (NPY) and agouti-re-

ated peptide (AgRP) and act to stimulate food intakend weight gain. In contrast, pro-opiomelanocortinPOMC) and cocaine- and amphetamine-regulated tran-cript coexpressing neurons in the lateral arcuate nucleusnhibit feeding and promote weight loss. The balanceetween activity of these neuronal circuits is critical toody weight regulation.

Satiety is also regulated by the hindbrain. The nucleus
f the solitary tract (NTS) and the area postrema, com-

pvceiteswsc

acndpvTwvhtaptn

ceGgRsfpo

pelAotdattaapviiiaacltrsgoeicceosmmae

energ

2118 WREN AND BLOOM GASTROENTEROLOGY Vol. 132, No. 6

onents of the dorsal vagal complex, receive inputs fromagal afferents and circulating factors, and are recipro-ally connected with hypothalamic nuclei controlling en-rgy balance. These brainstem centers can also respondndependently to peripheral signals when communica-ion with higher brain centers are surgically interrupt-d.16 In addition, cortical inputs in terms of emotional,ocial, and learned behavior, as well as inputs from re-ard circuits, including the mesolimbic dopaminergic

ystem, all impact upon energy balance and communi-ate with the hypothalamus.

Peripheral feedback to the hypothalamus is complex,s illustrated in Figure 1. Many circulating signals, in-luding gut hormones, have direct access to the arcuateucleus. Leptin is the archetypal peripheral signal actingirectly on the arcuate nucleus.15,17 In contrast, othereripheral signals influence the hypothalamus indirectlyia afferent neuronal pathways and brainstem circuits.he most extensively characterized of these is CCK,hich binds to receptors on the vagus nerve, thus acti-

ating the NTS, which in turn, relays information to theypothalamus. Similarly, GLP-1R expressing neurons ofhe NTS project to hypothalamic regions involved inppetite control, including the arcuate, dorsomedial, andaraventricular nuclei. In the cases of ghrelin and PYY,here is evidence for both a direct action on the arcuateucleus and an action via the vagus nerve and brainstem.

Ghrelin, the Hunger HormoneGhrelin is the only known circulating orexigen. In

ontrast, all the other peripheral factors that regulatenergy balance act to restrain eating and weight gain.hrelin was discovered as an endogenous ligand for the

rowth hormone (GH) secretagogue receptor (GHS-1a).18 However, early work on this peptide demon-

trated a growth hormone-independent action to power-ully increase food intake and body weight. Theredominant focus of subsequent research has shifted

Figure 1. Overview of peripheral factors regulating

nto the role of ghrelin in energy balance.19 –22 g

Ghrelin is a 28-amino acid peptide, cleaved from arecursor, preproghrelin.18 It is principally synthesized inndocrine cells of the stomach, termed X/A-like or ghre-in cells, and particularly found in the gastric fundus.18,23

bout 2/3 to 3/4 of circulating ghrelin is of gastricrigin. Lesser concentrations of ghrelin are foundhroughout the small intestine, with the duodenum pro-ucing approximately 10 times less than the stomachnd progressively lower concentrations found more dis-ally.23,24 Ghrelin undergoes posttranslational modifica-ion with covalent attachment of a medium-chain fattycid, typically octanoic acid, to the serine-3 residue. Thiscylation is entirely unique among biologically activeeptides and is required for ghrelin to bind to and acti-ate its classical receptor, the GHS-R1a.18 The GHS-R1as widely expressed. In the CNS, it is found in areasnvolved in regulation of appetite and energy balancencluding hypothalamic nuclei, the dorsal vagal complex,nd the mesolimbic dopaminergic system.25–27 Peripher-lly, it is expressed in the pituitary, and pharmacologi-ally ghrelin acts at both pituitary and hypothalamicevels to powerfully stimulate growth hormone secre-ion.18,20,28 –30 The physiologic relevance of ghrelin in GHegulation is debated. Ghrelin is not essential for GHecretion, as ghrelin and GHS-R1a null mice are notrowth restricted, but it may play a role in augmentationf GHRH-stimulated GH pulses.31–33 GHS-R1a receptorxpression has also been described in diverse peripheral sitesncluding the myocardium, stomach, small intestine, pan-reas, colon, adipose tissue, liver, kidney, placenta, and Tells.25,26,34 An equally diverse series of biologic actions ofxogenous ghrelin have been documented, including effectsn glucose homeostasis, gut motility, pancreatic exocrineecretion, cardiovascular function, immunity, and inflam-

ation.33 The physiologic relevance of these actions re-ains unclear, and the major role of ghrelin is generally

ccepted to be in regulation of energy balance. There is alsovidence for a number of pharmacologic actions of des-acyl

y balance and their routes of signaling to the brain.

hrelin, which must be mediated via receptors other than

tteea

fpoaigctiNlwmntrhgiawAciVstpbnlt

rbunoiiiotibft

mRabfu

fhhiihippikgpaTgetrni

gaswdagtgprncdetsmdr

aa


he GHS-R1a.35 The physiologic significance of these ac-ions is contentious, as reviewed elsewhere.33,36 However,xperiments in GHS-R1a knockout mice have definitivelystablished that this receptor is required for the orexigenicnd GH stimulating effects of acylated ghrelin.32,37

When administered into the CNS, ghrelin stimulatesood intake as potently as NPY, previously the mostowerful known orexigen, and more powerfully than anyther substance examined.19 –21 Ghrelin also stimulatesppetite and food intake when administered systemicallyn rodents19,22 and humans.38 This property is unique tohrelin and not shared by any known neuropeptide orirculating hormone. The duration of feeding stimula-ion in response to central or peripheral ghrelin admin-stration is short, similar to that observed for central

PY. Indeed, several lines of evidence suggest that ghre-in acts via arcuate NPY/AgRP neurons, almost all ofhich express the GHS-R1a.39 Ghrelin stimulates feedingost potently when injected directly into the arcuate

ucleus and also stimulates release of NPY from hypo-halamic explants in vitro.22,30 Arcuate NPY/AgRP neu-ons are activated by ghrelin, as demonstrated by en-anced c-fos, NPY, and AgRP expression followinghrelin administration and by electrophysiologic stud-es.21,40 – 43 Further, the orexigenic actions of ghrelin arebolished in NPY/AgRP dual knockout mice and in miceith postembryonic ablation of NPY/AgRP neurons.37,44

lthough this neuronal population is the most well-haracterized ghrelin target, there is also evidence for anndirect action on these neurons via the vagus nerve.agotomy abolishes the feeding and arcuate c-fos re-ponse to peripheral, but not central ghrelin administra-ion.41,45 Other ghrelin targets include several other hy-othalamic nuclei, the dorsal vagal complex of therainstem and components of the mesolimbic dopami-ergic system. The GHS-R1a is also expressed in these

ocations and microinjection of ghrelin directly intohese areas stimulates food intake.22,25–27,46,47

Does Ghrelin Contribute to PreprandialHunger?Several lines of evidence suggest that ghrelin may

egulate preprandial hunger. Circumstantially, the distri-ution of ghrelin, predominantly in the stomach andpper small intestine, is ideal to monitor meal to mealutrient intake. The actions of exogenous ghrelin fulfill 1f the minimum requirements for a meal initiator, that

s, stimulation of food intake when administered system-cally, at doses that result in plasma concentrations sim-lar to those found in the fasted (hungry) state. The onsetf action is rapid, duration is short, and ghrelin appearso delay latency to feed and promote food-seeking behav-or in rodents. Ghrelin stimulates food intake across aroad range of species, including humans. The first 7, orewer, amino acids of ghrelin plus the octanoyl group on
he third serine residue constitute the minimum frag- t
ent required for binding to and activation of the GHS-1a.48,49 These residues are highly conserved, suggestingn important biologic role. Infusion of antighrelin anti-odies into the rat brain inhibits fasting-induced feeding,urther supporting ghrelin’s role as an endogenous reg-lator of food intake.21

Plasma ghrelin levels were first noted to increase onasting and fall on refeeding in rodents, as would befit aunger signal.19,22 Subsequently, more detailed studiesave demonstrated preprandial plasma ghrelin elevation

n humans and animals fed at scheduled times.50 –54 Moremportantly, plasma ghrelin also peaks preprandially inuman subjects, who have been deprived of time cues,

nitiating meals voluntarily.55 These plasma ghrelineaks correlated well with hunger scores. Postprandially,lasma ghrelin is suppressed in proportion to calories

ngested, when macronutrient content and volume areept constant.56 Interestingly, fat appears to suppresshrelin less potently per calorie than carbohydrate orrotein.57,58 This may, in part, explain the reduced satietynd enhanced weight gain associated with high-fat diets.aken together, these data strongly suggest a role forhrelin as a meal initiator. Whether ghrelin is the only, orven a physiologically vital, hunger signal is as yet unde-ermined. This would require demonstration that inter-uption of ghrelin signaling, for example using antago-ists or inducible knockouts, abolishes normal meal

nitiation.

Ghrelin and Long-Term EnergyHomeostasisIn addition to a candidate role as a meal initiator,

hrelin appears to participate in long-term energy bal-nce. Chronic administration of ghrelin in rodents re-ults in prolonged hyperphagia and weight gain.19,20 Theeight gain observed is greater than that expected for theegree of hyperphagia, and may reflect several reportedctions of ghrelin that could combine to promote weightain. These include stimulation of adipogenesis, inhibi-ion of apoptosis, transfer from fatty acid oxidation tolycolysis for energy expenditure, and inhibition of sym-athetic nervous system activity.19,35,59,60 There is 1 caseeport of an individual with a malignant gastric ghreli-oma, who had extremely high circulating ghrelin con-entrations and remained obese with preserved appetite,espite advanced and eventually fatal malignant dis-ase.61 Thus, prolonged elevation of plasma ghrelin cer-ainly promotes adiposity, in contrast to the classicalhort-term appetite regulator CCK, where prolonged ad-

inistration does not reduce body weight. However, thisoes not prove that endogenous ghrelin physiologicallyegulates body weight.

In humans, ghrelin levels are inversely correlated withdiposity, being low in the obese, higher in lean subjects,nd markedly elevated in subjects who are cachectic due
o a diverse range of conditions including anorexia ner-

vbtunliaoawsvmhcihtwfPh

dthtapwiwotNNNhnagdoofOwlpbspsio

dpHch

otppobgtlw

pttfcacrbaiikiIsreopugttaaviwdateocf


osa, cancer, and chronic cardiac failure.62– 67 This haseen interpreted as an adaptive response to restrain fur-her overeating in the obese or to stimulate it in thenderweight. This hypothesis is supported by longitudi-al studies. Ghrelin is increased in response to weight

oss achieved either by diet alone or diet and exercise, ands suppressed by overfeeding or successful treatment ofnorexia nervosa.64,68 –70 Thus, ghrelin levels alter, in thepposite direction to leptin, to reflect nutritional statusnd body fat stores, supporting a role in long-term bodyeight maintenance. An exception to this observation is

ubjects with Prader-Willi syndrome (PWS), who haveery high fasting and postprandial ghrelin levels, whichay contribute to their obesity.71,72 It is unclear whether

yperghrelinaemia drives the extreme hyperphagia asso-iated with this syndrome. It has been noted that ghrelins not elevated in young children with PWS, in whomyperphagia has not yet developed.73 However, soma-ostatin infusion in PWS subjects suppresses ghrelinithout suppressing appetite.74 This might suggest that

actors other than elevated ghrelin drive hyperphagia inWS, although concomitant suppression of anorectic gutormones by somatostatin is a likely confounding factor.If ghrelin is critical for body weight maintenance, re-

uction in ghrelin should promote weight loss and res-oration of ghrelin should promote weight regain. Thisas been demonstrated in mice undergoing total gastrec-omy that have an 80% reduction in circulating ghrelinssociated with weight loss. Replacement of ghrelin tohysiologic levels results in weight regain. However, miceith global deletions of ghrelin or the GHS-R1a were

nitially reported to have minimal disruption of bodyeight homeostasis. As always with such mouse models,ne must consider confounding by developmental adap-ation. A clear example of this can be found in thePY/AgRP system on which ghrelin is thought to act.PY/AgRP dual null mice or mice in which the arcuatePY/AgRP neurons are destroyed shortly after birth ex-ibit minimal phenotype, whereas destruction of theseeurons later in development causes marked anorexiand weight loss.44,75 Further studies on mice lackinghrelin or the GHS-R1a have demonstrated resistance toiet induced obesity in mature mice.27,76 The phenotypef ghrelin null mice might be further complicated by thebservation that the gene that codes for ghrelin has beenound to code for another peptide, named obestatin.bestatin was originally reported to reduce food intakehen administered peripherally or intracerebroventricu-

arly, and to reduce body weight gain when administerederipherally. These effects were proposed to be mediatedy the orphan G protein-coupled receptor, GPR39. Muchpeculation followed as to why the same gene wouldroduce an orexigenic and an anorectic signal. However,ubsequent reports have not supported the initial find-ngs and suggest that obestatin may not signal via GPR39
r play a role in the regulation of food intake.77,78 Mice H
evoid of ghrelin signaling certainly lack the extremehenotypes associated with mice lacking leptin signaling.owever, taken together, data from knockout models are

ompatible with a role for ghrelin in long-term energyomeostasis.

Ghrelin as a Drug TargetGiven that circulating ghrelin is already low in

bese subjects, one might question how much therapeu-ic benefit could be obtained from further ghrelin sup-ression. However, it has been reported that the rapidostprandial drop in circulating ghrelin is attenuated inbesity.79 It has also been shown that obese subjects maye more sensitive to appetite stimulation by exogenoushrelin.80 Thus, inhibition of ghrelin may have therapeu-ic potential, particularly in enhancing further weightoss and preventing weight regain following diet inducedeight loss, when ghrelin levels become elevated.Several major pharmaceutical companies have pursued

rograms investigating ghrelin inhibition. Interestingly,he GHS-R1a exhibits constitutive activity, suggestinghat an inverse agonist may be more therapeutically use-ul than an antagonist.81 Another strategy is to designompounds that bind to ghrelin itself and prevent inter-ction with its receptor. A novel group of moleculesalled RNA spiegelmers, oligonucleotides containing L-ibose, have been designed that are highly effective atlocking interaction of ghrelin with the GHS-R1a in vitrond in vivo. Antighrelin spiegelmers inhibit ghrelin-nduced GH secretion and reduce food intake and adiposityn mice fed a high-fat diet, but have no effect in ghrelinnockout mice.82– 84 However, to date, no ghrelin-block-

ng products have progressed as far as phase I trials.ndeed, there would be theoretical safety concerns aboutuch agents in view of the possible role of ghrelin inegulation of the growth axis,18 as well as reported ben-ficial cardiovascular85– 87 and anti-inflammatory88 effectsf ghrelin. Regulation of octanoylation of ghrelin mayrovide an alternative drug target that is, as yet, relativelynexplored. A more direct therapeutic application ofhrelin is in the treatment of anorexia and cachexia. Tohis end, proof of principle studies have demonstratedhat ghrelin stimulates appetite in patients with anorexiand weight loss due to cancer and chronic kidney disease,nd may also improve meal enjoyment, without any ad-erse effects.89,90 Ghrelin administration by intravenousnfusion over 3 weeks results in weight gain in patientsith cardiac cachexia and chronic obstructive pulmonaryisease.91,92 However, weight gain may have been in partttributable to improved general well-being, cardiac func-ion, and respiratory muscle strength, rather than a soleffect directly on energy balance. In addition these werepen-label studies and therefore did not control for pla-ebo effect. Intravenous infusion is not a practical routeor chronic administration in most therapeutic settings.
owever, ghrelin is effective when given by subcutaneous

iptietRbw

irttb

oittitnmdapcdmd

sanbptta

hAbttpCftis

ltacrip

rsrsosbCgowst

dtorsCmpadwcfi

pfPbhaTGbebefpa


njection in healthy lean individuals and in malnourishedatients on peritoneal dialysis.90,93 Further placebo-con-rolled trials of long-term subcutaneous ghrelin admin-stration in anorectic/cachectic patients are required tostablish whether this may be a useful therapy. In addi-ion, a wide variety of orally active agonists for the GHS-1a were developed throughout the 1980s and 1990s,efore the discovery of ghrelin as an endogenous ligand,hich may have therapeutic potential in this context.94,95

Satiety SignalsAfter a meal, nutrients pass into the stomach and

ntestine, and a number of gastrointestinal signals areeleased. These peptides and other signals act to optimizehe digestive process, and some also function as short-erm satiety signals and possibly long-term regulators ofody weight.

CCKCCK is the prototypical satiety hormone. It is now

ver 30 years since CCK was first shown to inhibit foodntake, and it remains 1 of the most intensively studied ofhe gut hormones.96 –99 CCK is widely distributed withinhe gastrointestinal tract, but the majority is synthesizedn the duodenum and jejunum. It is rapidly released intohe surrounding tissues and circulation in response toutrients in the gut, in particular, fat and protein-richeals, with levels rising approximately 5-fold postpran-

ially. In addition to inhibiting food intake, its mainctions include delaying gastric emptying, stimulatingancreatic enzyme secretion, and stimulating gall bladderontraction. Together these actions promote the effectiveigestion of fat and protein in the small intestine byatching the delivery of nutrient with the capacity to

igest it.97,98

There are 2 distinct G protein-coupled CCK receptorubtypes. In the rat, CCK-A (also called CCK-1) receptorsre found in the pancreas, on vagal afferent and entericeurons. CCK-A receptors are also found throughout therain, including the nucleus of the solitary tract, areaostrema, and dorsomedial hypothalamus. CCKB recep-ors are distributed throughout the brain, are present inhe afferent vagus nerve, and are found within the stom-ch.97,98

Administration of CCK, to humans and animals, in-ibits food intake by reducing meal size and duration.96

lthough at high dose nausea and taste aversion haveeen detected, at low dose, feeding is inhibited withouthese effects.100 The main receptor at which CCK exertshese effects is the CCK-A receptor.101 Only the sul-hated form of CCK binds with high affinity to theCK-A receptor, and it is only this form that inhibits

ood intake.96 Recent work suggests that CCK-A recep-ors expressed by vagal afferent neurons are a particularlymportant target for CCK in producing sensations of
atiety, as well as inhibiting gastric emptying and stimu- t
ating pancreatic digestive enzyme secretion.99 It ishought that the reduction in food intake may be medi-ted by a paracrine/neurocrine effect because high con-entrations of CCK, which occur only local to the site ofelease, are required.102 Thus, locally released CCK mayncrease vagal tone, without a significant increase inlasma CCK level.As would be expected if CCK is a satiety signal, CCK-A

eceptor antagonists increase calorie intake and reduceatiety, suggesting endogenous CCK plays a physiologicole in appetite regulation.103 CCK alone may be a veryhort-term modulator of appetite. It has a half-life ofnly 1–2 minutes, and it is not effective at reducing mealize if the peptide is administered more than 15 minutesefore a meal.96 Furthermore, chronic administration ofCK alone does not result in weight loss. However,reater body weight loss is reported with a combinationf peripheral CCK and central leptin administration thanith central leptin administration alone.104 Thus, the

hort-term meal terminator CCK may interact with lep-in, a long-term signal of adiposity.

Some, but not all, data from rodent models with re-uced CCK signaling support a role for CCK in regula-ion of long-term energy balance. Chronic administrationf either CCK antibodies or CCK-A receptor antagonistsesults in weight gain in rodent models but with noignificant increase in food intake.105,106 In addition, theCK-A receptor knockout rat (but not the knockoutouse) is hyperphagic and obese.107 The use of CCK as a

otential novel obesity therapy is in some doubt. Innimals, repeated preprandial administration of CCK re-uces food intake but it also increases meal frequency,ith no resulting effect on body weight.108 Furthermore,

ontinuous CCK administration is ineffective after therst 24 hours.109

PYY and PPPYY, PP, and NPY are members of the PP-fold

eptide family and are both putative circulating satietyactors. In addition to a shared tertiary structure, theP-fold structural motif, there is significant homologyetween peptide sequences within the family. They allave 36 amino acids, contain several tyrosine residues,nd require C-terminal amidation for biologic activity.he PP-fold family exert their effects via the Y family ofprotein-coupled receptors. Four receptor subtypes have

een identified—Y1, Y2, Y4, and Y5—all of which arexpressed in the hypothalamus.110 Y1 and Y5 have botheen put forward as the putative receptors via which NPYxerts its orexigenic action. The Y2 receptor is thought tounction as an autoinhibitory presynaptic receptor, ex-ressed on NPY neurons, and to mediate the anorecticctions of PYY, while the Y4 receptor appears to mediate
he anorectic actions of PP.

tarfPh

Ptpsirpff

tcisiaetrcl

rscaptcnppp

tireocTbee

a1irldnor

uswrutffbenelobsmio

efhajPccda

romatt


PYYPYY occurs in 2 forms: PYY1–36 and PYY3–36. PYY3–36,

he major circulating form (11), is a truncated 34-aminocid form created by cleavage of the N-terminal Tyr-Proesidues by dipeptidyl peptidase IV (DPPIV).111 Althoughull-length PYY binds with similar affinity to all Y receptors,YY3–36 shows selectivity for the Y2 receptor, for which it hasigh affinity, and some affinity for Y1 and Y5 receptors.110

PYY is secreted from entero-endocrine L-cells TheseYY immunoreactive cells are found throughout the en-ire gastrointestinal tract, but particularly in the distalortion. PYY immunoreactivity is almost absent in thetomach, sparse in the duodenum and jejunum, commonn the ileum and colon, and at very high levels in theectum (the converse pattern of that for ghrelin). Theattern of secretion is also a mirror image of that foundor ghrelin; that is, PYY is released into the circulationollowing meals and suppressed by fasting.112

PYY has long been known to exert numerous effects onhe gastrointestinal tract. Administration of PYY in-reases the absorption of fluids and electrolytes from theleum after a meal and inhibits pancreatic and gastricecretions, gallbladder contraction, and gastric empty-ng.113 Peripheral administration of PYY, like ghrelin,lso exerts effects on numerous other body systems. Forxample, it reduces cardiac output, causes vasoconstric-ion, and reduction in glomerular filtration rate, plasmaenin, and aldosterone activity. The physiologic signifi-ance of these numerous actions has not been estab-ished.

Does PYY Contribute to PostprandialSatiety?The pattern of PYY secretion in response to a meal

aises the possibility that it may be a physiologic satietyignal, acting to terminate the meal and stimulatingoordinated gastrointestinal responses to aid digestionnd absorption. PYY levels rise to a plateau at 1–2 hoursostprandially, with these peak levels influenced by bothhe number of calories and the composition of the foodonsumed.112,114 The onset of PYY release occurs beforeutrients have reached the predominant sites of PYYroduction in the distal gastrointestinal tract. This im-lies that peptide release may occur via a neural reflex,ossibly through the vagus nerve.Systemic administration of PYY3–36 inhibits food in-

ake in rodents and humans.115–119 Initially, these find-ngs were contentious, with several authors unable toeproduce feeding inhibition in rodents.120 A probablexplanation for this apparent conflict is that the effectsf anorectic agents in rodents are easily masked by stress,ausing a reduction of food intake in the control group.hus, significant inhibition of feeding by PYY3–36 cannote detected in rodents that are not fully acclimatized toxperimental procedures or following transfer to a novel
nvironment.121 a
In humans, intravenous infusion of PYY3–36 reducesppetite and food intake at a subsequent meal by about/3. Although initial reports detected inhibition of food

ntake at plasma PYY concentrations in the physiologicange, others have only detected an effect at pharmaco-ogic doses.115,116,119 Thus, although there remains someebate over whether PYY3–36 is a physiologic meal termi-ator in humans, appetite inhibition in response to ex-genous PYY, in both lean and obese individuals, is aobust and reproducible finding.

PYY and Long-Term EnergyHomeostasisIf circulating PYY3–36 is a long-term negative reg-

lator of body weight, analogous to leptin, then chronicystemic administration would be predicted to result ineight loss. This has been reported in some but not all

odent models, with more consistent effects observedsing intravenous administration and with dosage pat-ern also playing an important role.122 However, datarom knockout mice provide more convincing evidenceor a long-term role for PYY in regulation of energyalance. Three separate knockout models have been gen-rated, 2 of which develop obesity.123–125 One model didot become obese. This model also had disruption ofxpression of the PP gene.123 One would not predict thatoss of a second putative anorectic signal would attenuatebesity. However, subtle differences in technique andackground strain have frequently been reported to re-ult in differing phenotypes in other knockout mouse

odels. In 1 of the obese PYY null mouse models admin-stration of PYY corrected the phenotype, suggesting thatbesity was truly being driven by PYY deficiency.125

In contrast to leptin, circulating levels of PYY are notlevated in human obesity, and obese individuals retainull sensitivity to the anorectic actions of PYY3–36.116 Itas been reported that obese subjects have lower fastingnd postprandial circulating PYY than lean sub-ects.114,116,26,127 To produce an equivalent stimulation ofYY and equivalent satiety, obese individuals needed toonsume a much greater caloric load than their leanounterparts.114 However, not all studies have detected aifference in fasting PYY concentrations between leannd obese groups.128,129

Current data suggest that impaired postprandial PYYelease may, at least, impair satiety and help to maintainbesity, if not act as a primary driver of initial develop-ent of obesity. Whether or not reduced PYY signaling isprimary cause of obesity, it is certainly true that re-

ained PYY sensitivity in the obese makes it an attractiveherapeutic target.

Mechanism of Action of PYYThe exact mechanism whereby PYY3–36 inhibits

ppetite and food intake is contentious. Interestingly, in

ctTtrSaieitohtPbPapaittdasocprtmPtmfetfetpf

bPtgPPcgP

gmtwpitistdPipith

iTttaetmtwsecaawgp

itsomtarbattidaPi


ontrast to peripheral administration, intracerebroven-ricular administration of PYY stimulates food intake.his is thought to be via an action on Y1 and Y5 recep-

ors in the paraventricular nucleus, the second-order neu-ons targeted by orexigenic arcuate nucleus NPY neurons.everal lines of investigation suggest a direct anorecticction of circulating PYY3–36 on the arcuate nucleus. c-foss observed in the arcuate nucleus in response to periph-ral administration of PYY3–36 and direct microinjectionnto the arcuate nucleus inhibits feeding. This action ishought to be via autoinhibitory Y2 receptors on therexigenic NPY neurons. In support of this hypothesis, aighly specific Y2 agonist inhibits feeding following in-raarcuate injection, while the anorectic actions ofYY3–36 are absent in the Y2 knockout mouse andlocked by a Y2 receptor antagonist.115,130 Furthermore,YY3–36 reduces expression of NPY in the arcuate nucleusnd release of NPY from hypothalamic explants. Electro-hysiologic studies suggest that PYY3–36 directly inhibitsctivity of arcuate NPY neurons, thereby secondarily dis-nhibiting anorectic POMC neurons.115 However, the pic-ure appears to be more complex than a simple action onhe arcuate nucleus. First, POMC neuronal disinhibitionoes not appear to be necessary for the action of PYY3–36,s it retains efficacy in mice with deficient melanocortinignaling.131 Second, there is now evidence for an actionf PYY3–36 at the level of the vagus and of the dorsal vagalomplex.132 The relative contribution of these variousutative sites of action to physiologic appetite regulationemains unclear. The ascending vagal– brainstem– hypo-halamic pathways have, however, been implicated in

ediating sensations of nausea. In keeping with this,YY3–36 has, at high doses, been reported to cause condi-ioned taste avoidance in rodents and nausea in hu-

ans.114,119,133 However, lower doses inhibit appetite andood intake in rodents and humans without aversiveffects or nausea.114,115,119,133 Coupled with the observa-ion that PYY null mice become obese, this suggests a roleor PYY in appetite regulation independent of aversiveffects. Drug companies developing analogues of PYY forreatment of obesity will need to be mindful of thisotentially narrow therapeutic window to design success-ul agents.

PPPP is produced largely in the endocrine pancreas,

ut also in the exocrine pancreas, colon, and rectum. LikeYY, PP is released in response to a meal, in proportion tohe caloric load, and inhibits appetite.134 Pancreatic andastrointestinal hormones can also regulate circulatingP levels. Ghrelin, motilin, and secretin rapidly stimulateP release, whereas somatostatin and its analogs signifi-antly reduce plasma PP concentrations. PP binds withreatest affinity to Y4 receptors (with greater affinity than
YY) and Y5 receptors.110 e
The role of PP in appetite regulation has been investi-ated for over 30 years. It was initially noted that ob/obice lacked pancreatic PP cells, and peripheral adminis-

ration of PP could reduce their food intake and bodyeight.135 Peripheral administration of PP resulting inhysiologic plasma levels has been shown to reduce food

ntake in normal mice, with associated reduction in gas-ric emptying, and gastric expression of ghrelin, andncreased vagal tone.136 PP also increased oxygen con-umption and stimulated sympathetic activity, leading tohe suggestion that PP may also increase energy expen-iture. In normal-weight human volunteers infusion ofP reduces food intake without altering gastric empty-

ng.137 Subjects with PWS are reported to have sup-ressed basal and postprandial PP levels, while PP admin-

stration to PWS subjects reduced food intake.138,139 It is,herefore, possible that PP deficiency contributes to theyperphagia in this obesity syndrome.Apart from its acute effects on appetite and food

ntake, PP may also modulate long-term energy balance.ransgenic mice that overexpress PP have a lean pheno-

ype with reduced food intake.140 Repeated administra-ion of PP to ob/ob mice decreases body weight gain andmeliorates insulin resistance and dyslipidemia.136 How-ver, rodents with diet-induced obesity are less sensitiveo the anorectic actions of PP. Long-term energy stores

ay influence the circulating PP levels as well as short-erm food intake. Plasma PP is increased in individualsith anorexia nervosa, and there have been reports of

uppressed plasma PP in obese subjects. However, theffects of obesity on circulating concentrations of PP areonflicting; others have found no difference between leannd obese subjects or between obese subjects before andfter weight loss. The effects of PP on appetite and bodyeight in obese humans are unknown. Further investi-ation in obese subjects may indicate whether PP has theotential to be a novel treatment for obesity.PP, like PYY, has opposing effects on appetite, depend-

ng on the route of administration. Injection of PP intohe third ventricle stimulates daytime food intake inatiated rats.141 Similarly, central injection of PP has thepposite effect to peripheral administration on gastricotility, stimulating rather than inhibiting gastric emp-

ying. These contrasting effects of central and peripheraldministration of PP probably reflect differing sites ofeceptor activation. PP is unable to cross the blood– brainarrier. Circulating PP therefore acts on the CNS viareas that have a deficient blood– brain barrier, such ashe area postrema. The passage of PP into the area pos-rema has been demonstrated by autoradiographic stud-es and neuronal activation by expression of the imme-iate early gene, c-fos, in the area postrema.142 Thenorectic effect seen after peripheral administration ofP probably occurs via the Y4, which is highly expressed

n this region. The receptor mediating the orexigenic
ffect of PP after central injection is unclear. The stimu-

ln

ppbhsctrrmbstypcwtog

a

tswittipetractcaCaiGlcmoc

wdlplcitPpajli

pwhccvrcoom

FcgS


ation of food intake is blunted in Y5 knockout mice butot by Y5 receptor antisense oligonucleotides.

Oxyntomodulin and GLP-1Oxyntomodulin and GLP-1 are products of the

reproglucagon gene. Preproglucagon is expressed in theancreas, L-cells of the intestine, and in the NTS of therainstem and undergoes differential processing by pro-ormone convertase 1 and 2 depending on the site ofynthesis.143,144 as illustrated in Figure 2. In the pancreas,lassical preproglucagon processing yields glucagon andhe apparently inactive N-terminal fragment glicentin-elated pancreatic polypeptide while the GLP sequencesemain within a larger peptide, major proglucagon frag-

ent. The posttranslational processing in the gut andrain are very similar. In these tissues, the glucagonequence remains in a larger peptide, glicentin, which ishought to be inactive. Glicentin is further cleaved toield oxyntomodulin and glicentin-related pancreaticolypeptide. Oxyntomodulin is a 37-amino acid peptideomprising the 29 amino acids of pancreatic glucagonith an eight amino acid C-terminal extension, some-

imes called spacer peptide 1. The other major productsf preproglucagon processing in gut and brain are the 2lucagon-like peptides, GLP-1 and GLP-2.

GLP-1 and oxyntomodulin, along with PYY and CCK,

igure 2. Overview of differential preproglucagon processing in pan-reas vs brain and gut. MPGF, major proglucagon fragment; GRRP,licentin-related pancreatic polypeptide; GLP, glucagon-like peptide;P, spacer peptide.

re released from intestinal L-cells in response to inges- c

ion of nutrients and appear to act in part as satietyignals as well as possibly participating in long-term bodyeight regulation. GLP-1 is the most powerful known

ncretin in humans, and manipulation of the GLP-1 sys-em forms the basis of several major new treatments forype 2 diabetes. These include a subcutaneously admin-stered DPPIV-resistant GLP-1R agonist, exendin-4, aeptide component of gila monster saliva marketed asxenatide (Byetta), as well as orally active DPPIV inhibi-ors. The role of GLP-1 and other incretins in appetiteegulation is reviewed extensively elsewhere in this issuend will not be discussed here in detail. However, in brief,entral administration of GLP-1, both intracerebroven-ricularly and into the paraventricular nucleus, reducesalorie intake in animal models, while the GLP-1 receptorntagonist exendin 9-39 increases food intake.145

hronic administration of GLP-1 into the CNS attenu-tes weight gain146 and peripheral GLP-1 injection inhib-ts food intake in rodents and humans. Evidence suggests

LP-1 secretion is reduced in obese subjects, and weightoss normalizes the levels.147 Reduced GLP-1 secretionould, therefore, contribute to obesity, and replacementay restore satiety. Obese subjects receiving subcutane-

us GLP-1 for 5 days, just before each meal, reduced theiralorie intake by 15% and lost 0.5 kg in weight.148

OxyntomodulinOxyntomodulin inhibits calorie intake in rodents

hen given either centrally or peripherally, and results inecreased weight gain when administered peripheral-

y.149 –151 Oxyntomodulin is also an effective anorecticeptide in human subjects. An infusion of oxyntomodu-

in to normal-weight human subjects reduced immediatealorie intake by 19.3% and was effective at reducing foodntake up to 12 hours postinfusion.152 Part of its anorec-ic effect may be via suppression of plasma ghrelin levels.eripheral administration of oxyntomodulin, at post-randial concentrations, reduces circulating ghrelin byround 15%–20% in rodents and 44% in human sub-ects.151,152 It is possible that postprandial oxyntomodu-in release may contribute to the normal physiologicnhibition of plasma ghrelin after meals.

In contrast to GLP-1, oxyntomodulin is a much lessotent incretin but may have more potent effects oneight loss. Although acute oxyntomodulin infusion inumans reduces food intake, it only causes a small in-rease in plasma insulin without affecting plasma glu-ose.152 When administered 3 times daily in overweightolunteers for 4 weeks, subcutaneous oxyntomodulinesulted in 2.3 kg weight loss compared with 0.5 kg in theontrol group.153 Enhanced weight loss in response toxyntomodulin may be due to an additional effect ofxyntomodulin to increase energy expenditure. Acute ad-inistration of oxyntomodulin has been shown to in-

rease voluntary activity in human subjects and to in-

co

tntpmGtebGhonttNgftnttt

tclcDaa

obaltticphphanawwp

mw

bosdoatibGfehtealr“wtwaeuhadtscesswmtsGthtbiaf

wad


rease heart rate in rodents.151,154 The circulating levels ofxyntomodulin in obesity remain to be established.

Both GLP-1 and oxyntomodulin are thought to exertheir effects via the GLP-1 receptor (GLP-1R). Antago-ists of the GLP-1R, such as exendin (9 –39), antagonizehe effect of both GLP-1 and oxyntomodulin, and botheptides are ineffective in the GLP-1 receptor knockoutouse.155 However, the affinity of oxyntomodulin forLP-1R is approximately 2 orders of magnitude less than

hat of GLP-1, yet both peptides appear to be similarlyffective at reducing food intake. It is possible there maye a separate oxyntomodulin receptor not yet cloned. TheLP-1R is present in the NTS in the brainstem and theypothalamic arcuate nucleus. The mechanisms of actionf GLP-1 and oxyntomodulin appear to be similar butot identical. Peripheral and central GLP-1 administra-ion have been reported to activate neurons in the hypo-halamic arcuate nucleus and paraventricular nucleus,TS, and area postrema.144 In addition, ablation of va-

al– brainstem– hypothalamic projections attenuateseeding inhibition by GLP-1.132 Although systemic oxyn-omodulin administration results in a similar pattern ofeuronal activation to GLP-1, intraarcuate administra-ion of exendin 9-39 blocks the anorectic effects on oxyn-omodulin but not GLP-1, suggesting a direct action onhe arcuate nucleus.151

The duration of inhibition of food intake in responseo peripheral oxyntomodulin administration is short, ne-essitating 3 times daily subcutaneous injection in weightoss studies in humans.153 This may be due to rapidleavage of the 2 N-terminal amino acid residues byPPIV, as observed for GLP-1 and PYY. DDPIV resistant

nalogs of oxyntomodulin may, thus, have greater ther-peutic potential than the native peptide.

Dietary Manipulation of Gut HormonesIt has been suggested that a cause of the current

besity epidemic may be that modern processed foodsypass our natural satiety mechanisms. Low-fat dietsre the most well-established means of dietary weightoss. It has been reported that weight loss in responseo a low-fat diet does not produce the expected eleva-ion in plasma ghrelin.156,157 This may be due to anncrease in the proportion of calories consumed asarbohydrate that more potently suppresses ghreliner calorie consumed than does fat. High-protein dietsave also become popular in recent years as a means toromote satiety and weight loss. Diets high in proteinave recently been reported to elevate circulating PYYnd enhance satiety more effectively than other macro-utrients;125 however, previous data suggested that, atsingle meal, higher plasma concentrations of PYY

ere stimulated by high-fat isocaloric meals, comparedith protein or carbohydrate.112 It is an intriguing
ossibility that designer diets may help promote the w
ost favorable gut hormone profile to allow sustainedeight loss.

A Coordinated Response to ObesityIn designing an optimal treatment for obesity,

ased upon physiologic satiety mechanisms, perhapsur biggest clues come from the field of bariatricurgery. The only treatment to date associated withramatic and sustained weight loss in the morbidlybese is gastric bypass surgery. However, its cost andssociated morbidity and mortality make it an imprac-ical treatment for the majority of obese patients and its generally reserved for the morbidly obese. Gastricypass results in significant increases in plasma PYY,LP-1, and oxyntomodulin while ghrelin either falls or

ails to rise, despite significant weight loss.158,159 Inter-stingly, bypass patients report dramatically reducedunger long before substantial weight loss occurs. Fur-hermore, in rodent models, many of the beneficialffects of bypass can be mimicked by gut hormonedministration.158 Could the altered gut hormones fol-owing gastric bypass be sending “fullness” signalsesulting in sustained weight loss, in contrast to thestarvation” signals that accompany diet-inducedeight loss, promoting weight regain? It is notable

hat the changes in the 4 gut hormones above all favoreight loss following gastric bypass. This coordinatedction, mimicking natural satiety, may be a key toffective antiobesity therapy. As noted above, individ-al gut hormones administered at high concentrationsave been associated with aversive behaviors in rodentsnd nausea in humans. We have reported that lowoses of PYY3–36 and GLP-1 inhibit food intake addi-ively.160 Analogous to current treatment for hyperten-ion where several agents are commonly used, a smartocktail of gut hormone-based drugs may prove a moreffective antiobesity treatment than targeting a singleystem. This approach could potentially provide theustained weight loss offered by gastric bypass surgery,ithout the associated morbidity and mortality. Theajor therapeutic disadvantage of gut hormones is

heir short duration of action and the requirement forubcutaneous or intravenous administration. In theLP-1 system, degradation-resistant analogs and drugs

hat inhibit enzymes that degrade the endogenousormone have already been brought to market for thereatment of type 2 diabetes. Similar approaches maye successful for oxyntomodulin, PYY, and PP, while

ntranasal delivery systems or development of orallyctive small molecule mimetics could avoid the needor administration by injection.

Obesity is the most significant growing health concernorldwide. Current treatments, barring bariatric surgery,re insufficiently effective. Many drugs in developmento not target physiologic satiety mechanisms and have
orrisome side effects attributable to the ubiquitous

dsmtis


istribution of the receptor systems targeted. Recent datauggests that gut hormones regulate when and how

uch we eat for every meal and offer a safe, logical drugarget. Mimicking natural satiety mechanisms by deliver-ng combinations of gut hormones may replace bariatricurgery as the only truly effective antiobesity treatment.

References

1. Flegal KM. Epidemiologic aspects of overweight and obesity inthe United States. Physiol Behav 2005;86:599–602.

2. Bourn J. Tackling obesity in England. Report by the comptrollerand auditor general. England: The Stationery Office, House ofCommons, 2001.

3. WHO. Obesity: preventing and managing the global epidemic.Report of a WHO consultation on obesity. Geneva, Switzerland:Author, 2004.

4. Yanovski SZ, Yanovski JA. Obesity. N Engl J Med 2002;346:591–602.

5. Curran MP, Scott LJ. Spotlight on orlistat in the management ofpatients with obesity. Treat Endocrinol 2005;4:127–129.

6. Finer N. Pharmacotherapy of obesity. Best Pract Res Clin Endo-crinol Metab 2002;16:717–742.

7. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S.Effects of the cannabinoid-1 receptor blocker rimonabant onweight reduction and cardiovascular risk factors in overweightpatients: 1-year experience from the RIO-Europe study. Lancet2005;365:1389–1397.

8. Howlett AC. The cannabinoid receptors. Prostaglandins OtherLipid Mediat 2002;68-69:619–631.

9. van OB, Killestein J, Polman C. Effect of rimonabant on weightreduction and cardiovascular risk. Lancet 2005;366:368–369.

10. Hirschel B. Effect of rimonabant on weight reduction and car-diovascular risk. Lancet 2005;366:369–370.

11. Kings Fund. A positive approach to nutrition as a treatment.Report of a working party charied by JE Lennard-Jones. 2003.

12. Cone RD, Cowley MA, Butler AA, Fan W, Marks DL, Low MJ. Thearcuate nucleus as a conduit for diverse signals relevant toenergy homeostasis. Int J Obes Relat Metab Disord 2001;25(Suppl 5):S63–S67.

13. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG.Central nervous system control of food intake. Nature 2000;404:661–671.

14. Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS. Interactingappetite-regulating pathways in the hypothalamic regulation ofbody weight. Endocr Rev 1999;20:68–100.

15. Flier JS. Obesity wars: molecular progress confronts an expand-ing epidemic. Cell 2004;116:337–350.

16. Grill HJ, Smith GP. Cholecystokinin decreases sucrose intake inchronic decerebrate rats. Am J Physiol 1988;254:R853–R856.

17. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, FriedmanJM. Positional cloning of the mouse obese gene and its humanhomologue. Nature 1994;372:425–432.

18. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, KangawaK. Ghrelin is a growth-hormone-releasing acylated peptide fromstomach. Nature 1999;402:656–660.

19. Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity inrodents. Nature 2000;407:908–913.

20. Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S,Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom SR.The novel hypothalamic peptide ghrelin stimulates food intakeand growth hormone secretion. Endocrinology 2000;141:4325–4328.

21. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kan-gawa K, Matsukura S. A role for ghrelin in the central regulation
of feeding. Nature 2001;409:194–198.
22. Wren AM, Small CJ, Abbott CR, Dhillo WS, Seal l, Cohen MA,Batterham RL, Taheri S, Stanley SA, Ghatei MA, Bloom SR.Ghrelin causes hyperphagia and obesity in rats. Diabetes 2001;50:2540–2547.

23. Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Sug-anuma T, Matsukura S, Kangawa K, Nakazato M. Ghrelin, anovel growth hormone-releasing acylated peptide, is synthe-sized in a distinct endocrine cell type in the gastrointestinaltracts of rats and humans. Endocrinology 2000;141:4255–4261.

24. Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T,Suda M, Koh T, Natsui K, Toyooka S, Shirakami G, Usui T,Shimatsu A, Doi K, Hosoda H, Kojima M, Kangawa K, Nakao K.Stomach is a major source of circulating ghrelin, and feedingstate determines plasma ghrelin-like immunoreactivity levels inhumans. J Clin Endocrinol Metab 2001;86:4753–4758.

25. Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinaths-inghji DJ, Smith RG, van der Ploeg LH, Howard AD. Distributionof mRNA encoding the growth hormone secretagogue receptorin brain and peripheral tissues. Brain Res Mol Brain Res 1997;48:23–29.

26. Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fair-clough P, Bhattacharya S, Carpenter R, Grossman AB, KorbonitsM. The tissue distribution of the mRNA of ghrelin and subtypesof its receptor, GHS-R, in humans. J Clin Endocrinol Metab2002;87:2988.

27. Zigman JM, Jones JE, Lee CE, Saper CB, Elmquist JK. Expres-sion of ghrelin receptor mRNA in the rat and the mouse brain.J Comp Neurol 2006;494:528–548.

28. Date Y, Murakami N, Kojima M, Kuroiwa T, Matsukura S, Kan-gawa K, Nakazato M. Central effects of a novel acylated pep-tide, ghrelin, on growth hormone release in rats. Biochem Bio-phys Res Commun 2000;275:477–480.

29. Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A,Harada M, Mori K, Komatsu Y, Usui T, Shimatsu A, Ogawa Y,Hosoda K, Akamizu T, Kojima M, Kangawa K, Nakao K. Ghrelinstrongly stimulates growth hormone release in humans. J ClinEndocrinol Metab 2000;85:4908–4911.

30. Wren AM, Small CJ, Fribbens CV, Neary NM, Ward HL, Seal LJ,Ghatei MA, Bloom SR. The hypothalamic mechanisms of thehypophysiotropic action of ghrelin. Neuroendocrinology 2002;76:316–324.

31. Sun Y, Ahmed S, Smith RG. Deletion of ghrelin impairs neithergrowth nor appetite. Mol Cell Biol 2003;23:7973–7981.

32. Sun Y, Wang P, Zheng H, Smith RG. Ghrelin stimulation ofgrowth hormone release and appetite is mediated through thegrowth hormone secretagogue receptor. Proc Natl Acad Sci U SA 2004;101:4679–4684.

33. Van Der Lely AJ, Tschop M, Heiman ML, Ghigo E. Biological,physiological, pathophysiological, and pharmacological aspectsof ghrelin. Endocr Rev 2004;25:426–457.

34. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA,Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J,Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS,Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M,Sirinathsinghji DJS, Dean DC, Melillo DG, van der Ploeg LH. Areceptor in pituitary and hypothalamus that functions in growthhormone release. Science 1996;273:974–977.

35. Thompson NM, Gill DA, Davies R, Loveridge N, Houston PA,Robinson IC, Wells T. Ghrelin and des-octanoyl ghrelin promoteadipogenesis directly in vivo by a mechanism independent ofthe type 1a growth hormone secretagogue receptor. Endocrinol-ogy 2004;145:234–242.

36. Cummings DE, Foster-Schubert KE, Overduin J. Ghrelin andenergy balance: focus on current controversies. Curr Drug Tar-
gets 2005;6:153–169.


37. Chen HY, Trumbauer ME, Chen AS, Weingarth DT, Adams JR,Frazier EG, Shen Z, Marsh DJ, Feighner SD, Guan XM, Ye Z,Nargund RP, Smith RG, van der Ploeg LH, Howard AD, MacNeilDJ, Qian S. Orexigenic action of peripheral ghrelin is mediatedby neuropeptide Y (NPY) and agouti-related protein (AgRP). En-docrinology 2004;145:2007–2012.

38. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG,Dhillo WS, Ghatei MA, Bloom SR. Ghrelin enhances appetiteand increases food intake in humans. J Clin Endocrinol Metab2001;86:5992–5995.

39. Willesen MG, Kristensen P, Romer J. Co-localization of growthhormone secretagogue receptor and NPY mRNA in the arcuatenucleus of the rat. Neuroendocrinology 1999;70:306–316.

40. Dickson SL, Luckman SM. Induction of c-fos messenger ribonu-cleic acid in neuropeptide Y and growth hormone (GH)-releasingfactor neurons in the rat arcuate nucleus following systemicinjection of the GH secretagogue, GH-releasing peptide-6. Endo-crinology 1997;138:771–777.

41. Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Fujimiya M,Katsuura G, Makino S, Fujino MA, Kasuga M. A role of ghrelin inneuroendocrine and behavioral responses to stress in mice.Neuroendocrinology 2001;74:143–147.

42. Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Wakaba-yashi I. Central effect of ghrelin, an endogenous growth hor-mone secretagogue, on hypothalamic peptide gene expression.Endocrinology 2000;141:4797–4800.

43. Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, GroveKL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML,Garcia-Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P,Friedman JM, Liu H, Pinto S, Colmers WF, Cone RD, Horvath TL.The distribution and mechanism of action of ghrelin in the CNSdemonstrates a novel hypothalamic circuit regulating energyhomeostasis. Neuron 2003;37:649–661.

44. Bewick GA, Gardiner JV, Dhillo WS, Kent AS, White NE, WebsterZ, Ghatei MA, Bloom SR. Post-embryonic ablation of AgRP neu-rons in mice leads to a lean, hypophagic phenotype. FASEB J2005;19:1680–1682.

45. Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Mat-suo H, Kangawa K, Nakazato M. The role of the gastric afferentvagal nerve in ghrelin-induced feeding and growth hormone se-cretion in rats. Gastroenterology 2002;123:1120–1128.

46. Carlini VP, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN,de Barioglio SR. Differential role of the hippocampus, amygdala,and dorsal raphe nucleus in regulating feeding, memory, andanxiety-like behavioral responses to ghrelin. Biochem BiophysRes Commun 2004;313:635–641.

47. Naleid AM, Grace MK, Cummings DE, Levine AS. Ghrelin in-duces feeding in the mesolimbic reward pathway between theventral tegmental area and the nucleus accumbens. Peptides2005;26:2274–2279.

48. Bednarek MA, Feighner SD, Pong SS, McKee KK, Hreniuk DL,Silva MV, Warren VA, Howard AD, van der Ploeg LH, Heck JV.Structure–function studies on the new growth hormone-releas-ing peptide, ghrelin: minimal sequence of ghrelin necessary foractivation of growth hormone secretagogue receptor 1a. J MedChem 2000;43:4370–4376.

49. Matsumoto M, Kitajima Y, Iwanami T, Hayashi Y, Tanaka S,Minamitake Y, Hosoda H, Kojima M, Matsuo H, Kangawa K.Structural similarity of ghrelin derivatives to peptidyl growthhormone secretagogues. Biochem Biophys Res Commun 2001;284:655–659.

50. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE,Weigle DS. A preprandial rise in plasma ghrelin levels suggestsa role in meal initiation in humans. Diabetes 2001;50:1714–1719.

51. Tschop M, Wawarta R, Riepl RL, Friedrich S, Bidlingmaier M,
Landgraf R, Folwaczny C. Post-prandial decrease of circulating
human ghrelin levels. J Endocrinol Invest 2001;24:RC19–RC21.

52. Drazen DL, Vahl TP, D’Alessio DA, Seeley RJ, Woods SC. Effectsof a fixed meal pattern on ghrelin secretion: evidence for alearned response independent of nutrient status. Endocrinology2006;147:23–30.

53. Sugino T, Yamaura J, Yamagishi M, Ogura A, Hayashi R, KuroseY, Kojima M, Kangawa K, Hasegawa Y, Terashima Y. A transientsurge of ghrelin secretion before feeding is modified by differentfeeding regimens in sheep. Biochem Biophys Res Commun2002;298:785–788.

54. Miura H, Tsuchiya N, Sasaki I, Kikuchi M, Kojima M, Kangawa K,Hasegawa Y, Ohnami Y. Changes in plasma ghrelin and growthhormone concentrations in mature Holstein cows and three-month-old calves. J Anim Sci 2004;82:1329–1333.

55. Cummings DE, Frayo RS, Marmonier C, Aubert R, Chapelot D.Plasma ghrelin levels and hunger scores in humans initiatingmeals voluntarily without time- and food-related cues. Am JPhysiol Endocrinol Metab 2004;287:E297–E304.

56. Callahan HS, Cummings DE, Pepe MS, Breen PA, Matthys CC,Weigle DS. Postprandial suppression of plasma ghrelin level isproportional to ingested caloric load but does not predict inter-meal interval in humans. J Clin Endocrinol Metab 2004;89:1319–1324.

57. Monteleone P, Bencivenga R, Longobardi N, Serritella C, Maj M.Differential responses of circulating ghrelin to high-fat or high-carbohydrate meal in healthy women. J Clin Endocrinol Metab2003;88:5510–5514.

58. Overduin J, Frayo RS, Grill HJ, Kaplan JM, Cummings DE. Role ofthe duodenum and macronutrient type in ghrelin regulation.Endocrinology 2005;146:845–850.

59. Choi K, Roh SG, Hong YH, Shrestha YB, Hishikawa D, Chen C,Kojima M, Kangawa K, Sasaki S. The role of ghrelin and growthhormone secretagogues receptor on rat adipogenesis. Endocri-nology 2003;144:754–759.

60. Matsumura K, Tsuchihashi T, Fujii K, Abe I, Iida M. Centralghrelin modulates sympathetic activity in conscious rabbits.Hypertension 2002;40:694–699.

61. Tsolakis AV, Portela-Gomes GM, Stridsberg M, Grimelius L,Sundin A, Eriksson BK, Oberg KE, Janson ET. Malignant gastricghrelinoma with hyperghrelinemia. J Clin Endocrinol Metab2004;89:3739–3744.

62. Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E,Heiman ML. Circulating ghrelin levels are decreased in humanobesity. Diabetes 2001;50:707–709.

63. Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M,Nozoe S, Hosoda H, Kangawa K, Matsukura S. Plasma ghrelinlevels in lean and obese humans and the effect of glucose onghrelin secretion. J Clin Endocrinol Metab 2002;87:240–244.

64. Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL,Heiman ML, Lehnert P, Fichter M, Tschop M. Weight gain de-creases elevated plasma ghrelin concentrations of patients withanorexia nervosa. Eur J Endocrinol 2001;145:669–673.

65. Tolle V, Kadem M, Bluet-Pajot MT, Frere D, Foulon C, Bossu C,Dardennes R, Mounier C, Zizzari P, Lang F, Epelbaum J, EstourB. Balance in ghrelin and leptin plasma levels in anorexia ner-vosa patients and constitutionally thin women. J Clin EndocrinolMetab 2003;88:109–116.

66. Nagaya N, Uematsu M, Kojima M, Date Y, Nakazato M, Oku-mura H, Hosoda H, Shimizu W, Yamagishi M, Oya H, Koh H,Yutani C, Kangawa K. Elevated circulating level of ghrelin incachexia associated with chronic heart failure: relationshipsbetween ghrelin and anabolic/catabolic factors. Circulation2001;104:2034–2038.

67. Shimizu Y, Nagaya N, Isobe T, Imazu M, Okumura H, Hosoda H,Kojima M, Kangawa K, Kohno N. Increased plasma ghrelin level
in lung cancer cachexia. Clin Cancer Res 2003;9:774–778.

1

1

1

1


68. Hansen TK, Dall R, Hosoda H, Kojima M, Kangawa K, Chris-tiansen JS, Jorgensen JO. Weight loss increases circulatinglevels of ghrelin in human obesity. Clin Endocrinol (Oxf) 2002;56:203–206.

69. Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Del-linger EP, Purnell JQ. Plasma ghrelin levels after diet-inducedweight loss or gastric bypass surgery. N Engl J Med 2002;346:1623–1630.

70. Ravussin E, Tschop M, Morales S, Bouchard C, Heiman ML.Plasma ghrelin concentration and energy balance: overfeedingand negative energy balance studies in twins. J Clin EndocrinolMetab 2001;86:4547–4551.

71. Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE,Frayo RS, Schwartz MW, Basdevant A, Weigle DS. Elevatedplasma ghrelin levels in Prader Willi syndrome. Nat Med 2002;8:643–644.

72. DelParigi A, Tschop M, Heiman ML, Salbe AD, Vozarova B, SellSM, Bunt JC, Tataranni PA. High circulating ghrelin: a potentialcause for hyperphagia and obesity in prader-willi syndrome.J Clin Endocrinol Metab 2002;87:5461–5464.

73. Erdie-Lalena CR, Holm VA, Kelly PC, Frayo RS, Cummings DE.Ghrelin levels in young children with Prader-Willi syndrome. J Pe-diatr 2006;149:199–204.

74. Tan TM, Vanderpump M, Khoo B, Patterson M, Ghatei MA,Goldstone AP. Somatostatin infusion lowers plasma ghrelinwithout reducing appetite in adults with Prader-Willi syndrome.J Clin Endocrinol Metab 2004;89:4162–4165.

75. Luquet S, Perez FA, Hnasko TS, Palmiter RD. NPY/AgRP neu-rons are essential for feeding in adult mice but can be ablatedin neonates. Science 2005;310:683–685.

76. Wortley KE, Del Rincon JP, Murray JD, Garcia K, Iida K, ThornerMO, Sleeman MW. Absence of ghrelin protects against early-onset obesity. J Clin Invest 2005;115:3573–3578.

77. Holst B, Egerod KL, Schild E, Vickers SP, Cheetham S, GerlachLO, Storjohann L, Stidsen CE, Jones R, Beck-Sickinger AG,Schwartz TW. GPR39 signaling is stimulated by zinc ions but notby obestatin. Endocrinology 2007;148:13–20.

78. Nogueiras R, Pfluger P, Tovar S, Myrtha A, Mitchell S, Morris A,Perez-Tilve D, Vazquez MJ, Wiedmer P, Castaneda TR, DimarchiR, Tschop M, Schurmann A, Joost HG, Williams LM, LanghansW, Dieguez C. Effects of obestatin on energy balance and growthhormone secretion in rodents. Endocrinology 2007;148:21–26.

79. English PJ, Ghatei MA, Malik IA, Bloom SR, Wilding JP. Food failsto suppress ghrelin levels in obese humans. J Clin EndocrinolMetab 2002;87:2984.

80. Druce MR, Wren AM, Park AJ, Milton JE, Patterson M, Frost G,Ghatei MA, Small C, Bloom SR. Ghrelin increases food intake inobese as well as lean subjects. Int J Obes (Lond) 2005;29:1130–1136.

81. Holst B, Cygankiewicz A, Jensen TH, Ankersen M, Schwartz TW.High constitutive signaling of the ghrelin receptor—identificationof a potent inverse agonist. Mol Endocrinol 2003;17:2201–2210.

82. Helmling S, Maasch C, Eulberg D, Buchner K, Schroder W, LangeC, Vonhoff S, Wlotzka B, Tschop MH, Rosewicz S, Klussmann S.Inhibition of ghrelin action in vitro and in vivo by an RNA-Spiegelmer. Proc Natl Acad Sci U S A 2004;101:13174–13179.

83. Kobelt P, Helmling S, Stengel A, Wlotzka B, Andresen V, KlappBF, Wiedenmann B, Klussmann S, Monnikes H. Anti-ghrelinSpiegelmer NOX-B11 inhibits neurostimulatory and orexigeniceffects of peripheral ghrelin in rats. Gut 2006;55:788–792.

84. Shearman LP, Wang SP, Helmling S, Stribling DS, Mazur P, GeL, Wang L, Klussmann S, MacIntyre DE, Howard AD, Strack AM.Ghrelin neutralization by a ribonucleic acid-SPM amelioratesobesity in diet-induced obese mice. Endocrinology 2006;147:
1517–1526.
85. Baldanzi G, Filigheddu N, Cutrupi S, Catapano F, Bonissoni S,Fubini A, Malan D, Baj G, Granata R, Broglio F, Papotti M, SuricoN, Bussolino F, Isgaard J, Deghenghi R, Sinigaglia F, Prat M,Muccioli G, Ghigo E, Graziani A. Ghrelin and des-acyl ghrelininhibit cell death in cardiomyocytes and endothelial cellsthrough ERK1/2 and PI 3-kinase/AKT. J Cell Biol 2002;159:1029–1037.

86. Nagaya N, Kojima M, Uematsu M, Yamagishi M, Hosoda H, OyaH, Hayashi Y, Kangawa K. Hemodynamic and hormonal effectsof human ghrelin in healthy volunteers. Am J Physiol Regul IntegrComp Physiol 2001;280:R1483–R1487.

87. Nagaya N, Uematsu M, Kojima M, Ikeda Y, Yoshihara F, ShimizuW, Hosoda H, Hirota Y, Ishida H, Mori H, Kangawa K. Chronicadministration of ghrelin improves left ventricular dysfunctionand attenuates development of cardiac cachexia in rats withheart failure. Circulation 2001;104:1430–1435.

88. Dixit VD, Taub DD. Ghrelin and immunity: a young player in anold field. Exp Gerontol 2005;40:900–910.

89. Neary NM, Small CJ, Wren AM, Lee JL, Druce MR, Palmieri C,Frost GS, Ghatei MA, Coombes RC, Bloom SR. Ghrelin in-creases energy intake in cancer patients with impaired appetite:acute, randomized, placebo-controlled trial. J Clin EndocrinolMetab 2004;89:2832–2836.

90. Wynne K, Giannitsopoulou K, Small CJ, Patterson M, Frost G,Ghatei MA, Brown EA, Bloom SR, Choi P. Subcutaneous ghrelinenhances acute food intake in malnourished patients who re-ceive maintenance peritoneal dialysis: a randomized, placebo-controlled trial. J Am Soc Nephrol 2005;16:2111–2118.

91. Nagaya N, Moriya J, Yasumura Y, Uematsu M, Ono F, Shimizu W,Ueno K, Kitakaze M, Miyatake K, Kangawa K. Effects of ghrelinadministration on left ventricular function, exercise capacity,and muscle wasting in patients with chronic heart failure. Cir-culation 2004;110:3674–3679.

92. Nagaya N, Itoh T, Murakami S, Oya H, Uematsu M, Miyatake K,Kangawa K. Treatment of cachexia with ghrelin in patients withCOPD. Chest 2005;128:1187–1193.

93. Druce MR, Neary NM, Small CJ, Milton J, Monteiro M, PattersonM, Ghatei MA, Bloom SR. Subcutaneous administration of gh-relin stimulates energy intake in healthy lean human volunteers.Int J Obes (Lond) 2006;30:293–296.

94. Bowers CY. Unnatural growth hormone-releasing peptide begetsnatural ghrelin. J Clin Endocrinol Metab 2001;86:1464–1469.

95. Smith RG, Palyha OC, Feighner SD, Tan CP, McKee KK, HreniukDL, Yang L, Morriello G, Nargund R, Patchett AA, Howard AD.Growth hormone releasing substances: types and their recep-tors. Horm Res 1999;51(Suppl 3):1–8.

96. Gibbs J, Young RC, Smith GP. Cholecystokinin decreases foodintake in rats. J Comp Physiol Psychol 1973;84:488–495.

97. Dockray GJ. Peptides of the gut and brain: the cholecystokinins.Proc Nutr Soc 1987;46:119–124.

98. Moran TH. Cholecystokinin and satiety: current perspectives.Nutrition 2000;16:858–865.

99. Dockray G. Gut endocrine secretions and their relevance tosatiety. Curr Opin Pharmacol 2004;4:557–560.

00. West DB, Greenwood MR, Marshall KA, Woods SC. Lithiumchloride, cholecystokinin and meal patterns: evidence that cho-lecystokinin suppresses meal size in rats without causing mal-aise. Appetite 1987;8:221–227.

01. Asin KE, Gore PA Jr, Bednarz L, Holladay M, Nadzan AM. Effectsof selective CCK receptor agonists on food intake after centralor peripheral administration in rats. Brain Res 1992;571:169–174.

02. Reidelberger RD, Solomon TE. Comparative effects of CCK-8 onfeeding, sham feeding, and exocrine pancreatic secretion inrats. Am J Physiol 1986;251:R97–105.

03. Beglinger C, Degen L, Matzinger D, D’Amato M, Drewe J. Loxi-
glumide, a CCK-A receptor antagonist, stimulates calorie intake

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1


and hunger feelings in humans. Am J Physiol Regul Integr CompPhysiol 2001;280:R1149–R1154.

04. Matson CA, Reid DF, Cannon TA, Ritter RC. Cholecystokinin andleptin act synergistically to reduce body weight. Am J PhysiolRegul Integr Comp Physiol 2000;278:R882–R890.

05. McLaughlin CL, Baile CA, Buonomo FC. Effect of CCK antibodieson food intake and weight gain in Zucker rats. Physiol Behav1985;34:277–282.

06. Meereis-Schwanke K, Klonowski-Stumpe H, Herberg L, Nied-erau C. Long-term effects of CCK-agonist and -antagonist onfood intake and body weight in Zucker lean and obese rats.Peptides 1998;19:291–299.

07. Moran TH, Katz LF, Plata-Salaman CR, Schwartz GJ. Disorderedfood intake and obesity in rats lacking cholecystokinin A recep-tors. Am J Physiol 1998;274:R618–R625.

08. West DB, Fey D, Woods SC. Cholecystokinin persistently sup-presses meal size but not food intake in free-feeding rats. Am JPhysiol 1984;246:R776–R787.

09. Crawley JN, Beinfeld MC. Rapid development of tolerance to thebehavioural actions of cholecystokinin. Nature 1983;302:703–706.

10. Larhammar D. Structural diversity of receptors for neuropeptideY, peptide YY and pancreatic polypeptide. Regul Pept 1996;65:165–174.

11. Eberlein GA, Eysselein VE, Schaeffer M, Layer P, Grandt D,Goebell H, Niebel W, Davis M, Lee TD, Shively JE. A newmolecular form of PYY: structural characterization of humanPYY(3–36) and PYY(1–36). Peptides 1989;10:797–803.

12. Adrian TE, Ferri GL, Bacarese-Hamilton AJ, Fuessl HS, Polak JM,Bloom SR. Human distribution and release of a putative new guthormone, peptide YY. Gastroenterology 1985;89:1070–1077.

13. Adrian TE, Savage AP, Sagor GR, Allen JM, Bacarese-HamiltonAJ, Tatemoto K, Polak JM, Bloom SR. Effect of peptide YY ongastric, pancreatic, and biliary function in humans. Gastroen-terology 1985;89:494–499.

14. Le Roux CW, Batterham RL, Aylwin SJ, Patterson M, Borg CM,Wynne KJ, Kent A, Vincent RP, Gardiner J, Ghatei MA, Bloom SR.Attenuated peptide YY release in obese subjects is associatedwith reduced satiety. Endocrinology 2006;147:3–8.

15. Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA,Dakin CL, Wren AM, Brynes AE, Low MJ, Ghatei MA, Cone RD,Bloom SR. Gut hormone PYY(3-36) physiologically inhibits foodintake. Nature 2002;418:650–654.

16. Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ,Frost GS, Ghatei MA, Bloom SR. Inhibition of food intake inobese subjects by peptide YY3-36. N Engl J Med 2003;349:941–948.

17. Chelikani PK, Haver AC, Reidelberger RD. Intravenous infusionof peptide YY(3–36) potently inhibits food intake in rats. Endo-crinology 2005;146:879–888.

18. Adams SH, Won WB, Schonhoff SE, Leiter AB, Paterniti JR Jr.Effects of peptide YY[3-36] on short-term food intake in miceare not affected by prevailing plasma ghrelin levels. Endocrinol-ogy 2004;145:4967–4975.

19. Degen L, Oesch S, Casanova M, Graf S, Ketterer S, Drewe J,Beglinger C. Effect of peptide YY3-36 on food intake in humans.Gastroenterology 2005;129:1430–1436.

20. Tschop M, Castaneda TR, Joost HJ, Thone-Reinke C, Klaus S,Hagan MM, Chandler PC, Oswald KD, Benoit SC, Seeley RJ,Kinzig KP, Moran TH, Beck-Sickinger AG, Koglin N, Rodgers RJ,et al. Does gut hormone PYY 3-36 decrease food intake inrodents? Nature 2004;430:1–4.

21. Abbott CR, Small CJ, Sajedi A, Smith KL, Parkinson JR, Broad-head LL, Ghatei MA, Bloom SR. The importance of acclimatisa-tion and habituation to experimental conditions when investi-gating the anorectic effects of gastrointestinal hormones in the
rat. Int J Obes (Lond) 2006;30:288–292.
22. Chelikani PK, Haver AC, Reeve JR, Jr., Keire DA, ReidelbergerRD. Daily, intermittent intravenous infusion of peptide YY(3–36)reduces daily food intake and adiposity in rats. Am J PhysiolRegul Integr Comp Physiol 2006;290:R298–R305.

23. Schonhoff S, Baggio L, Ratineau C, Ray SK, Lindner J, Magnu-son MA, Drucker DJ, Leiter AB. Energy homeostasis and gas-trointestinal endocrine differentiation do not require the anorec-tic hormone peptide YY. Mol Cell Biol 2005;25:4189–4199.

24. Boey D, Lin S, Karl T, Baldock P, Lee N, Enriquez R, Couzens M,Slack K, Dallmann R, Sainsbury A, Herzog H. Peptide YY abla-tion in mice leads to the development of hyperinsulinaemia andobesity. Diabetologia 2006;49:1360–1370.

25. Batterham RL, Heffron H, Kapoor S, Chivers JE, Chandarana K,Herzog H, Le Roux CW, Thomas EL, Bell JD, Withers DJ. Criticalrole for peptide YY in protein-mediated satiation and body-weight regulation. Cell Metab 2006;4:223–233.

26. Roth CL, Enriori PJ, Harz K, Woelfle J, Cowley MA, Reinehr T.Peptide YY is a regulator of energy homeostasis in obesechildren before and after weight loss. J Clin Endocrinol Metab2005;90:6386–6391.

27. Alvarez BM, Borque M, Martinez-Sarmiento J, Aparicio E, Her-nandez C, Cabrerizo L, Fernandez-Represa JA. Peptide YY se-cretion in morbidly obese patients before and after verticalbanded gastroplasty. Obes Surg 2002;12:324–327.

28. Stock S, Leichner P, Wong AC, Ghatei MA, Kieffer TJ, Bloom SR,Chanoine JP. Ghrelin, peptide YY, glucose-dependent insulino-tropic polypeptide, and hunger responses to a mixed meal inanorexic, obese, and control female adolescents. J Clin Endo-crinol Metab 2005;90:2161–2168.

29. Korner J, Bessler M, Cirilo LJ, Conwell IM, Daud A, RestucciaNL, Wardlaw SL. Effects of Roux-en-Y gastric bypass surgery onfasting and postprandial concentrations of plasma ghrelin, pep-tide YY, and insulin. J Clin Endocrinol Metab 2005;90:359–365.

30. Abbott CR, Small CJ, Kennedy AR, Neary NM, Sajedi A, GhateiMA, Bloom SR. Blockade of the neuropeptide Y Y2 receptor withthe specific antagonist BIIE0246 attenuates the effect of en-dogenous and exogenous peptide YY(3–36) on food intake.Brain Res 2005;1043:139–144.

31. Halatchev IG, Ellacott KL, Fan W, Cone RD. Peptide YY3–36 inhib-its food intake in mice through a melanocortin-4 receptor-indepen-dent mechanism. Endocrinology 2004;145:2585–2590.

32. Abbott CR, Monteiro M, Small CJ, Sajedi A, Smith KL, ParkinsonJR, Ghatei MA, Bloom SR. The inhibitory effects of peripheraladministration of peptide YY(3–36) and glucagon-like peptide-1on food intake are attenuated by ablation of the vagal-brain-stem-hypothalamic pathway. Brain Res 2005;1044:127–131.

33. Halatchev IG, Cone RD. Peripheral administration of PYY(3–36)produces conditioned taste aversion in mice. Cell Metab 2005;1:159–168.

34. Track NS, McLeod RS, Mee AV. Human pancreatic polypeptide:studies of fasting and postprandial plasma concentrations. CanJ Physiol Pharmacol 1980;58:1484–1489.

35. Malaisse-Lagae F, Carpentier JL, Patel YC, Malaisse WJ, Orci L.Pancreatic polypeptide: a possible role in the regulation of foodintake in the mouse. Hypothesis. Experientia 1977;33:915–917.

36. Asakawa A, Inui A, Yuzuriha H, Ueno N, Katsuura G, Fujimiya M,Fujino MA, Niijima A, Meguid MM, Kasuga M. Characterizationof the effects of pancreatic polypeptide in the regulation ofenergy balance. Gastroenterology 2003;124:1325–1336.

37. Batterham RL, Le Roux CW, Cohen MA, Park AJ, Ellis SM,Patterson M, Frost GS, Ghatei MA, Bloom SR. Pancreaticpolypeptide reduces appetite and food intake in humans. J Clin
Endocrinol Metab 2003;88:3989–3992.

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

mCW


38. Zipf WB, O’Dorisio TM, Cataland S, Sotos J. Blunted pancreaticpolypeptide responses in children with obesity of Prader-Willisyndrome. J Clin Endocrinol Metab 1981;52:1264–1266.

39. Berntson GG, Zipf WB, O’Dorisio TM, Hoffman JA, Chance RE.Pancreatic polypeptide infusions reduce food intake in Prader-Willi syndrome. Peptides 1993;14:497–503.

40. Ueno N, Inui A, Iwamoto M, Kaga T, Asakawa A, Okita M,Fujimiya M, Nakajima Y, Ohmoto Y, Ohnaka M, Nakaya Y,Miyazaki JI, Kasuga M. Decreased food intake and body weightin pancreatic polypeptide-overexpressing mice. Gastroenterol-ogy 1999;117:1427–1432.

41. Clark JT, Kalra PS, Crowley WR, Kalra SP. Neuropeptide Y andhuman pancreatic polypeptide stimulate feeding behavior inrats. Endocrinology 1984;115:427–429.

42. Whitcomb DC, Taylor IL, Vigna SR. Characterization of saturablebinding sites for circulating pancreatic polypeptide in rat brain.Am J Physiol 1990;259:G687–G691.

43. Holst JJ. On the physiology of GIP and GLP-1. Horm Metab Res2004;36:747–754.

44. Drucker DJ. The biology of incretin hormones. Cell Metab 2006;3:153–165.

45. Turton MD, O’Shea D, Gunn I, Beak SA, Edwards CM, Meeran K,Choi SJ, Taylor GM, Heath MM, Lambert PD, Wilding JP, SmithDM, Ghatei MA, Herbert J, Bloom SR. A role for glucagon-likepeptide-1 in the central regulation of feeding. Nature 1996;379:69–72.

46. Meeran K, O’Shea D, Edwards CM, Turton MD, Heath MM, GunnI, Abusnana S, Rossi M, Small CJ, Goldstone AP, Taylor GM,Sunter D, Steere J, Choi SJ, Ghatei MA, Bloom SR. Repeatedintracerebroventricular administration of glucagon-like peptide-1-(7–36) amide or exendin-(9–39) alters body weight in the rat.Endocrinology 1999;140:244–250.

47. Verdich C, Toubro S, Buemann B, Lysgard MJ, Juul HJ, Astrup A.The role of postprandial releases of insulin and incretin hor-mones in meal-induced satiety—effect of obesity and weightreduction. Int J Obes Relat Metab Disord 2001;25:1206–1214.

48. Naslund E, King N, Mansten S, Adner N, Holst JJ, Gutniak M,Hellstrom PM. Prandial subcutaneous injections of glucagon-like peptide-1 cause weight loss in obese human subjects. Br JNutr 2004;91:439–446.

49. Dakin CL, Gunn I, Small CJ, Edwards CM, Hay DL, Smith DM,Ghatei MA, Bloom SR. Oxyntomodulin inhibits food intake in therat. Endocrinology 2001;142:4244–4250.

50. Dakin CL, Small CJ, Park AJ, Seth A, Ghatei MA, Bloom SR.Repeated ICV administration of oxyntomodulin causes a greaterreduction in body weight gain than in pair-fed rats. Am J PhysiolEndocrinol Metab 2002;283:E1173–E1177.

51. Dakin CL, Small CJ, Batterham RL, Neary NM, Cohen MA,
Patterson M, Ghatei MA, Bloom SR. Peripheral oxyntomodulin 3
reduces food intake and body weight gain in rats. Endocrinology2004;145:2687–2695.

52. Cohen MA, Ellis SM, Le Roux CW, Batterham RL, Park A, Patter-son M, Frost GS, Ghatei MA, Bloom SR. Oxyntomodulin sup-presses appetite and reduces food intake in humans. J ClinEndocrinol Metab 2003;88:4696–4701.

53. Wynne K, Park AJ, Small CJ, Patterson M, Ellis SM, Murphy KG,Wren AM, Frost GS, Meeran K, Ghatei MA, Bloom SR. Subcu-taneous oxyntomodulin reduces body weight in overweight andobese subjects: a double-blind, randomized, controlled trial.Diabetes 2005;54:2390–2395.

54. Wynne K, Park A, Small C J, Meeran K, Ghatei M A, Frost G,Bloom S R. Oxyntomodulin increases energy expenditure inaddition to decreasing energy intake in overweight and obesehumans: a randomised controlled trial. Int J Obes (Lond) 2006;30:1729–1736.

55. Baggio LL, Huang Q, Brown TJ, Drucker DJ. Oxyntomodulin andglucagon-like peptide-1 differentially regulate murine food in-take and energy expenditure. Gastroenterology 2004;127:546–558.

56. Weigle DS, Duell PB, Connor WE, Steiner RA, Soules MR, Kui-jper JL. Effect of fasting, refeeding, and dietary fat restriction onplasma leptin levels. J Clin Endocrinol Metab 1997;82:561–565.

57. Reinehr T, Roth CL, Alexy U, Kersting M, Kiess W, Andler W.Ghrelin levels before and after reduction of overweight due to alow-fat high-carbohydrate diet in obese children and adoles-cents. Int J Obes (Lond) 2005;29:362–368.

58. Le Roux CW, Aylwin SJ, Batterham RL, Borg CM, Coyle F, PrasadV, Shurey S, Ghatei MA, Patel AG, Bloom SR. Gut hormoneprofiles following bariatric surgery favor an anorectic state,facilitate weight loss, and improve metabolic parameters. AnnSurg 2006;243:108–114.

59. Cummings DE, Shannon MH. Ghrelin and gastric bypass: isthere a hormonal contribution to surgical weight loss? J ClinEndocrinol Metab 2003;88:2999–3002.

60. Neary NM, Small CJ, Druce MR, Park AJ, Ellis SM, SemjonousNM, Dakin CL, Filipsson K, Wang F, Kent AS, Frost GS, GhateiMA, Bloom SR. Peptide YY3-36 and glucagon-like peptide-17-36 inhibit food intake additively. Endocrinology 2005;146:5120–5127.

Received November 16, 2006. Accepted January 2, 2007.Address requests for reprints to: Stephen R. Bloom, MD, Depart-ent of Metabolic Medicine, Imperial College London, Hammersmith

ampus, 6th Floor, Commonwealth Building, Du Cane Road, London,12 0NN, England. e-mail: [email protected]; fax: (44) 20 8383

142.

Documents

GASTROENTEROLOGY.132(2007)2116 Gut Hormones and Appetite Control