Gut Hormones and Appetite Control

15 Pages·2007·0.45 MB·English

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