CanCan thethe gutgut fightfight obesity?obesity? TheThe rolerole ofof thethe gastrointestinalgastrointestinal tracttract inin controllingcontrolling whatwhat wewe eateat

PhysiologyPhysiology conferenceconference By:By: AmyAmy TiuTiu,, MDMD TheThe problemproblem ofof obesityobesity

ResponsibleResponsible forfor aboutabout 300,000300,000 preventablepreventable deathsdeaths perper yearyear inin thethe UnitedUnited StatesStates (second(second onlyonly toto cigarettecigarette asas thethe leadingleading causecause ofof preventablepreventable death)death) Obesity Trends* Among U.S. Adults BRFSS, 1991, 1996, 2003 (*BMI ≥30, or about 30 lbs overweight for 5’4” person)

1991 1996

2003

No Data <10% 10%–14% 15%–19% 20%–24% ? 25%

Source: Behavioral Risk Factor Surveillance System, CDC. ObjectivesObjectives

UnderstandUnderstand thethe role,role, interactions,interactions, andand clinicalclinical implicationsimplications ofof thethe followingfollowing gutgut peptidespeptides – Ghrelin – PP-fold peptides (PYY,PP, and NPY) – Proglucagon products (OXM and GLP 1) – CCK BrieflyBriefly commentcomment onon thethe effecteffect ofof gastricgastric bypassbypass andand thethe peptidespeptides AppetiteAppetite control:control: BasicBasic StructureStructure

CentralCentral andand PeripheralPeripheral NeedsNeeds signalssignals forfor longlong--termterm nutritionalnutritional statusstatus andand acuteacute changeschanges inin nutritionnutrition InvolvesInvolves brainstembrainstem andand rewardreward pathwayspathways BrainBrain receivesreceives signalssignals fromfrom thethe gutgut andand adiposeadipose tissuetissue Figure 1. Interactions among Hormonal and Neural Pathways That Regulate Food Intake and Body-Fat Mass. In this schematic diagram of the brain, the dashed lines indicate hormonal inhibitory effects, and the solid lines stimulatory effects. The paraventricular and arcuate nuclei each contain neurons that are capable of stimulating or inhibiting food intake. Y1R and Y2R denote the Y1 and Y2 subtypes of the neuropeptide Y (NPY) receptor, MC4R melanocortin 4 receptor, PYY peptide YY(3-36)), GHsR growth hormone secretagogue receptor, AgRP agouti-related protein, POMC proopiomelanocortin, (alpha)-MSH (alpha)-melanocyte-stimulating protein, LEPR leptin receptor, and INSR insulin receptor. From: Korner: N Engl J Med, Volume 349(10).September 4, 2003.926-928 CentralCentral Control:Control: TheThe arcuatearcuate nucleusnucleus (ARC)(ARC) WhatWhat isis inin thethe ARC?ARC?

NeuropeptideNeuropeptide YY (( ProPro--opiomelanocortinopiomelanocortin NPY)NPY) andand thethe agoutiagouti-- (POMC)(POMC) andand alphaalpha relatedrelated peptidepeptide melanocytemelanocyte-- ((AgRPAgRP)) stimulatingstimulating hormonehormone NPYNPY andand AgRPAgRP areare andand cocainecocaine andand populationspopulations ofof amphetamineamphetamine neuronsneurons thatthat stimulatestimulate regulatedregulated transcripttranscript foodfood intakeintake (CART)(CART) decreasedecrease (orexigenic)(orexigenic) foodfood intakeintake (anorexigenic)(anorexigenic) Wynne et al, Appetite control. J of Endocrinology, 2005. 184, 291-318 PraderPrader--WilliWilli SyndromeSyndrome

ChromosomalChromosomal deletiondeletion ofof 15q1115q11--1313 HighHigh ghrelinghrelin levelslevels NoNo cure;cure; treatmenttreatment mainlymainly byby exerciseexercise andand dietdiet controlcontrol GhrelinGhrelin

DiscoveredDiscovered inin 19991999 ReleasedReleased inin aa pulsatilepulsatile mannermanner fromfrom thethe oxynticoxyntic cellscells ofof thethe stomach,stomach, alsoalso fromfrom thethe duodenum,duodenum, ileum,ileum, cecum,cecum, andand coloncolon EndogenousEndogenous ligandligand forfor growthgrowth hormonehormone secretagoguesecretagogue receptorreceptor (GHS(GHS--R)R) StimulatesStimulates foodfood intakeintake GhrelinGhrelin

UpUp--regulatedregulated byby fastingfasting DecreasedDecreased byby eatingeating ProkineticProkinetic InverseInverse relationshiprelationship withwith BMIBMI Overlaid average plasma ghrelin (•) and leptin ([white circle]) concentrations during a 24-h period in 10 human subjects consuming breakfast (B), lunch (L), and dinner (D) at the times indicated. From: Cummings: Diabetes, Volume 50(8).August 2001.1714-1719 GhrelinGhrelin inin obeseobese subjectssubjects

GhrelinGhrelin levelslevels areare lowlow inin obesityobesity DoDo obeseobese subjectssubjects havehave aa normalnormal postpost-- prandialprandial ghrelinghrelin level?level? NO,NO, unlikeunlike leanlean subjects,subjects, obeseobese subjectssubjects dodo notnot havehave thethe samesame rapidrapid postpost--prandialprandial dropdrop inin ghrelinghrelin levelslevels FoodFood failsfails toto decreasedecrease levelslevels inin obeseobese patientspatients GhrelinGhrelin inin obeseobese subjectssubjects afterafter aa mealmeal ObeseObese subjectssubjects dodo notnot exhibitexhibit thethe declinedecline inin ghrelinghrelin afterafter aa mealmeal English et al. Food Fails To SuppressSuppress Ghrelin Levels in Obese Humans. JCEM. 200287(6):2984-2987

Lean subjects

Obese subjects GhrelinGhrelin inin anorexiaanorexia andand bulimiabulimia

PatientsPatients withwith anorexiaanorexia havehave aa veryvery highhigh level,level, whichwhich returnreturn toto referencereference rangerange afterafter treatmenttreatment andand weightweight gaingain PatientsPatients withwith bulimiabulimia showshow higherhigher circulatingcirculating levelslevels ofof ghrelinghrelin whenwhen comparedcompared withwith controls.controls. FrequentFrequent vomitingvomiting maymay bebe thethe causecause ofof increasedincreased ghrelinghrelin levels.levels. WhatWhat HappensHappens toto GhrelinGhrelin withwith changechange inin bodybody weightweight Ghrelin increased over time in the weight loss group (p<0.05) Ghrelin responds in a compensatory manner to changes in energy homeostasis in healthy young women Leidy et al. Circulating GhreGhrelinlin Is Sensitive to Changes in Body Weight during a Diet and Exercise Program in Normal Weight Young Women. 2004 J Clin Endocrinol Metab 89(6):2659-2664 WhatWhat happenshappens withwith exogenousexogenous infusioninfusion ofof ghrelinghrelin inin humans?humans? IncreasedIncreased appetiteappetite IncreasedIncreased foodfood intakeintake WrenWren etet al.al. showedshowed subjectssubjects consumedconsumed aa meanmean 28%28% additionaladditional caloriescalories fromfrom anan unlimitedunlimited buffetbuffet afterafter administrationadministration LeptinLeptin andand GhrelinGhrelin

LeptinLeptin isis anan adipoctyeadipoctye AnalogousAnalogous butbut reciprocalreciprocal toto ghrelinghrelin BothBoth releasedreleased inin pulsatilepulsatile mannermanner CounterCounter regulatoryregulatory rolesroles inin energyenergy homeostasishomeostasis A simplified model of the feeding-regulatory signaling of ghrelin and leptin. Leptin stimulates the POMC anorexigenic pathway and inhibits the NPY–AGRP orexigenic pathway, resulting in reduced food intake. The effect of ghrelin in the hypothalamus is opposite to that of leptin. The orexigenic effect of ghrelin is mediated by activating on the output of the NPY–AGRP neurons. Fasting increases ghrelin and decreases leptin production, leading to the activation of the orexigenic pathway. This response might be important for the adaptation to fasting.Molecular Interventions 2002;2: 495-503 GhrelinGhrelin andand Leptin:Leptin: IsIs therethere anan associationassociation withwith obesity?obesity? ExampleExample

Spiegel et al. Sleep Curtailment in Healthy Young Men is Associated with Decreased Leptin levels, Elevated Ghrelin Levels, and Increased Hunger and Appetite. Annals of Internal Medicine 2004;141(11):846-850 Figure 1. Effect of sleep duration on daytime leptin levels, ghrelin levels, hunger, and appetite. A. Mean (±SE) daytime (9:00 a.m. to 9:00 p.m.) profiles of leptin after 2 days with 4 hours in bed or 2 days with 10 hours in bed. Mean leptin levels were 18% lower when sleep was restricted. B. Mean (±SE) daytime (9:00 a.m. to 9:00 p.m.) profiles of ghrelin from 9 of the 12 participants after 2 days with 4 hours in bed or 2 days with 10 hours in bed. Mean ghrelin levels were 28% higher in the afternoon and early evening (12:00 noon to 9:00 p.m.) when sleep was restricted. C and D. Ratings of hunger (C) (0- to 10-cm visual analogue scale) and overall appetite (D) (0- to 70-cm visual analogue scale) after 2 days with 4 hours in bed or 2 days with 10 hours in bed. When sleep was restricted, ratings of hunger and overall appetite increased by 24% and 23%, respectively. ConclusionsConclusions fromfrom StudyStudy

LessLess sleep:sleep: decreaseddecreased LeptinLeptin andand increasedincreased GhrelinGhrelin LessLess sleep:sleep: IncreasedIncreased hungerhunger (24%)(24%) andand increaseincrease appetiteappetite (23%)(23%) especiallyespecially forfor caloriecalorie densedense foodsfoods NoNo changechange inin weightweight lossloss oror energyenergy supplysupply FurtherFurther studiesstudies areare neededneeded toto clarifyclarify ifif sleepsleep deprivation,deprivation, leptin,leptin, andand ghrelinghrelin areare associatedassociated withwith obesityobesity GhrelinGhrelin hashas otherother associationsassociations

LeptinLeptin maymay notnot bebe thethe onlyonly peptidepeptide associatedassociated withwith GhrelinGhrelin OrexinOrexin fromfrom thethe laterallateral hypothalamushypothalamus maymay alsoalso bebe involvedinvolved inin aa balancebalance withwith ghrelinghrelin.. OfOf note,note, disruptiondisruption ofof thisthis systemsystem isis aa majormajor causecause ofof narcolepsynarcolepsy AlsoAlso associatedassociated withwith PYY,PYY, OXMOXM StateState GhrelinGhrelin levellevel

ObeseObese LowLow

GastricGastric bypassbypass LowLow

PraderPrader--WilliWilli ExtremelyExtremely highhigh

LeanLean HighHigh

DietDiet inducedinduced HighHigh weightweight lossloss

It may not the level that contributes to the obesity, but the antagonism on ghrelin That will contribute to application to weight loss. TheThe PPPP--foldfold peptidespeptides

PeptidePeptide YYYY (PYY):(PYY): GutGut peptidepeptide PancreaticPancreatic polypeptidepolypeptide (PP):(PP): GutGut peptidepeptide NeuropeptideNeuropeptide YY (NPY)(NPY) (in(in neurons)neurons) CharacteristicCharacteristic UU shapedshaped foldfold knownknown asas aa PPPP foldfold PYYPYY andand PPPP areare peripheralperipheral gutgut peptidespeptides thatthat helphelp toto reducereduce foodfood intakeintake PYYPYY

SecretedSecreted fromfrom thethe entireentire gastrointestinalgastrointestinal tracttract CommonCommon inin thethe ileum,ileum, colon,colon, andand veryvery highhigh levelslevels inin thethe rectumrectum LowerLower basalbasal fastingfasting levellevel inin obeseobese patientspatients ReducesReduces foodfood intakeintake FastingFasting PYYPYY levelslevels werewere significantlysignificantly lowerlower inin obeseobese thanthan leanlean subjectssubjects

Batterham R et al. Inhibition of Foo dIntake in Obese Subjects by Peptide YY. 2003 NEJM 349(10): 941-948 Batterham R et al. Inhibition of Foo dIntake in Obese Subjects by Peptide YY. 2003 NEJM 349(10): 941-948 EffectsEffects ofof exogenousexogenous infusioninfusion ofof PYYPYY ReductionReduction inin foodfood intakeintake inin humanshumans byby 30%30% inin obeseobese subjectssubjects andand byby 31%31% inin leanlean groupgroup ReductionReduction inin plasmaplasma levelslevels ofof ghrelinghrelin ObeseObese subjectssubjects werewere notnot resistantresistant toto anorecticanorectic effectseffects ofof PYYPYY Figure 1. Caloric Intake by Obese and Lean Subjects after Infusion of Peptide YY(3-36)) (PYY) or Saline. Panel A shows the caloric intake by individual obese subjects, and Panel B shows the intake by individual lean subjects, during a buffet lunch two hours after the infusion of PYY or saline. Panel C shows the mean (+/-SE) caloric intake by obese subjects, and Panel D shows the intake by lean subjects, during a buffet lunch two hours after infusion of saline or PYY. Panel E shows the mean (+/-SE) cumulative 24- hour caloric intake by obese subjects, and Panel F shows the intake by lean subjects, after infusion of saline or PYY. In all panels, the lean and obese groups each consisted of 12 subjects: 6 women and 6 men. Batterham R et al. Inhibition of Foo dIntake in Obese Subjects by Peptide YY. 2003 NEJM 349(10): 941-948 Batterham R et al. Inhibition of Foo dIntake in Obese Subjects by Peptide YY. 2003 NEJM 349(10): 941-948 PYYPYY

InfluencedInfluenced byby bothboth thethe numbernumber ofof caloriescalories andand thethe compositioncomposition ofof foodfood (higher(higher ifif moremore fat)fat) ReleaseRelease occursoccurs BEFOREBEFORE nutrientsnutrients reachreach distaldistal GIGI tracttract GastricGastric acid,acid, CCK,CCK, andand luminalluminal bilebile saltssalts stimulatestimulate GastricGastric distentiondistention hashas notnot beenbeen foundfound toto stimulatestimulate PYYPYY CanCan crosscross thethe bloodblood brainbrain barrierbarrier PancreaticPancreatic PolypeptidePolypeptide (PP)(PP)

LargelyLargely producedproduced byby pancreas,pancreas, butbut alsoalso foundfound inin thethe coloncolon andand rectumrectum MainMain stimulusstimulus isis foodfood intakeintake ProportionalProportional toto caloriccaloric loadload BiphasicBiphasic releaserelease CanCan bebe influencedinfluenced byby gastricgastric distention,distention, vagalvagal tone,tone, adrenergicadrenergic stimulationstimulation EffectsEffects ofof exogenousexogenous infusioninfusion PP:PP: EnergyEnergy intakeintake salinesaline vsvs PPPP

Buffet meal 12-24 hr P<0.01 Post-buffet P<0.05

12 hour period Total cumulative Post-buffet P<0.05 24 hour P<0.01

Batterham et al. Pancreatic Polypeptide reduces appetite and food intake in humans. 2003 JCEM 88(8):3989-3992 EffectsEffects ofof exogenousexogenous infusioninfusion PPPP

NormalNormal--weightweight humanhuman volunteersvolunteers givengiven anan infusioninfusion ofof PPPP demonstratedemonstrate decreaseddecreased appetiteappetite andand aa 25%25% reductionreduction inin foodfood intakeintake overover thethe followingfollowing 2424 hourshours NoNo studiesstudies onon obeseobese humanshumans AppearsAppears toto bebe efficaciousefficacious treatmenttreatment forfor PraderPrader WilliWilli AbleAble toto reducereduce ghrelinghrelin

ProductsProducts ofof PreproglucagonPreproglucagon genegene

OXMOXM (oxyntomodulin)(oxyntomodulin)

GlucagonGlucagon--likelike peptidepeptide 11 (GLP(GLP 1)1)

ReleasedReleased inin proportionproportion toto caloriecalorie intakeintake

SatietySatiety signalssignals fromfrom thethe LL cellscells ofof thethe smallsmall intestineintestine WhatWhat happenshappens whenwhen OXMOXM isis givengiven IVIV toto normalnormal subjects?subjects?

Cohen et al. Oxyntomodulin Suppresses Appetite and Reduces Food Intake in Humans 2003. J of Clinical Endocrinol & Metab 88(10): 4696-4701 OxyntomodulinOxyntomodulin (OXM)(OXM)

FromFrom posttranslationalposttranslational processingprocessing ofof proglucagonproglucagon inin intestinalintestinal cellscells AnAn infusioninfusion inin humanshumans waswas shownshown toto immediatelyimmediately reducereduce caloriecalorie intakeintake byby 19.3%19.3% andand waswas effectiveeffective inin reducingreducing foodfood intakeintake forfor upup toto 1212 hourshours postpost infusioninfusion PartPart ofof itsits effecteffect maymay bebe viavia suppressionsuppression ofof plasmaplasma ghrelinghrelin EffectsEffects ofof OXMOXM infusioninfusion onon plasmaplasma GhrelinGhrelin

Cohen et al. Oxyntomodulin Suppresses Appetite and Reduces Food Intake in Humans. 2003. J of Clinical Endocrinol & Metab 88(10): 4696-4701 OXMOXM

NoNo effectseffects onon PYYPYY oror leptinleptin InhibitInhibit gastricgastric emptyingemptying inin humanshumans MayMay augmentaugment postprandialpostprandial insulininsulin ReducesReduces gastricgastric motilitymotility ExactExact receptorreceptor forfor whichwhich OXMOXM usesuses andand longlong termterm effectseffects areare unknownunknown TheThe secondsecond proglucagonproglucagon product:product: GLPGLP--11 GlucagonGlucagon--LikeLike PeptidePeptide 11 ReleasedReleased inin proportionproportion toto caloriecalorie intakeintake RegulatorRegulator ofof satietysatiety AlsoAlso ableable toto actact onon thethe pancreaspancreas toto causecause insulininsulin releaserelease (incretin)(incretin) WhatWhat happenshappens withwith IVIV GLPGLP--11 inin bothboth leanlean andand obeseobese individuals?individuals? DecreasedDecreased foodfood intakeintake inin bothboth groupsgroups inin aa dosedose dependentdependent mannermanner HOWEVER,HOWEVER, whenwhen infusionsinfusions achieveachieve levelslevels comparablecomparable toto thosethose seenseen inin thethe physiologicalphysiological statestate afterafter meals,meals, thethe effecteffect smallsmall GLPGLP--11 inin obeseobese subjectssubjects

UnclearUnclear asas toto whetherwhether levelslevels areare reducedreduced inin obeseobese subjectssubjects ObeseObese subjectssubjects givengiven subcutaneoussubcutaneous GLPGLP-- 11 priorprior toto mealsmeals reducedreduced theirtheir caloriecalorie intakeintake byby 15%15% andand lostlost 0.5kg0.5kg inin weightweight overover 55 daysdays CanCan GLPGLP--11 makemake aa differencedifference inin diabetes?diabetes? YESYES GLPGLP--11 hashas beenbeen foundfound toto normalizenormalize bloodblood glucoseglucose levelslevels inin poorlypoorly controlledcontrolled typetype 22 diabetesdiabetes duringduring bothboth aa shortshort--termterm IVIV infusioninfusion andand afterafter aa 66 weekweek subcutaneoussubcutaneous infusioninfusion GLPGLP--11

MayMay bebe implicatedimplicated inin thethe pathogenesispathogenesis ofof obesityobesity withwith replacementreplacement restoringrestoring satietysatiety MayMay playplay anan importantimportant rolerole diabetesdiabetes treatmenttreatment CholecytokininCholecytokinin (CCK)(CCK) CCKCCK

FoundFound predominantlypredominantly inin duodenumduodenum andand jejunumjejunum ReleasedReleased immediatelyimmediately andand remainsremains elevatedelevated forfor 55 hourshours InvolvedInvolved inin rewardreward behavior,behavior, memorymemory andand anxiety,anxiety, asas wellwell asas satietysatiety CCKCCK

StimulatesStimulates thethe releaserelease ofof enzymesenzymes fromfrom thethe pancreaspancreas andand gallbladdergallbladder IncreaseIncrease motilitymotility andand inhibitinginhibiting gastricgastric emptyingemptying WhatWhat happenshappens whenwhen CCKCCK given?given?

InhibitInhibit foodfood intakeintake byby reducingreducing mealmeal sizesize andand durationduration AtAt highhigh dose,dose, nauseanausea andand tastetaste aversionaversion VeryVery shortshort termterm modulatormodulator ofof appetiteappetite NOTE:NOTE: whilewhile repeatedrepeated preprandialpreprandial administrationadministration ofof CCKCCK reducesreduces foodfood intake,intake, itit increasesincreases mealmeal frequencyfrequency GutGut peptidespeptides andand GastricGastric bypassbypass RouxRoux--enen YY GastricGastric BypassBypass

PatientsPatients typicallytypically loselose 3535--40%40% ofof totaltotal bodybody weightweight andand mostmost ofof thisthis effecteffect isis maintainedmaintained forfor 1515 yearsyears VerticalVertical bandedbanded gastroplastygastroplasty

CausesCauses 3030--50%50% reductionreduction inin excessexcess bodybody weightweight withinwithin thethe firstfirst 11--22 yearsyears LongLong termterm resultsresults disappointingdisappointing PatientPatient startstart toto accommodateaccommodate byby eatingeating frequent,frequent, smallsmall meals,meals, andand caloriecalorie densedense foodsfoods WhyWhy mightmight RYGBRYGB bebe betterbetter thanthan VBG?VBG? PatientsPatients whowho underwentunderwent RYGBRYGB typicallytypically eateat fewerfewer mealsmeals andand snackssnacks Perhaps,Perhaps, eveneven ifif thethe degreedegree ofof gastricgastric restrictionrestriction isis thethe same,same, thethe physiologicallyphysiologically changeschanges thatthat occuroccur withwith RYGBRYGB maymay bebe thethe keykey toto itsits successsuccess AfterAfter RYGB,RYGB, ghrelinghrelin valuesvalues werewere 77%77% lowerlower GhrelinGhrelin inin RYGBRYGB

MostMost studiesstudies havehave demonstrateddemonstrated thatthat levelslevels decreasedecrease Why?Why? ““overrideoverride inhibitioninhibition”” becausebecause thethe stomachstomach (fundus)(fundus) nono longerlonger exposedexposed toto enteralenteral nutrientsnutrients thethe ghrelinghrelin producingproducing cellscells areare inhibitedinhibited NoteNote ifif thethe partitionpartition slightlyslightly includesincludes thethe fundus,fundus, thisthis mightmight undermineundermine thisthis inhibitioninhibition AntidiabeticAntidiabetic effectseffects ofof gastricgastric bypassbypass InIn fivefive publishedpublished studies,studies, aa totaltotal ofof 35683568 peoplepeople undergoingundergoing RYGB,RYGB, diabeticdiabetic patientspatients hadhad completecomplete remissionremission ofof theirtheir diseasedisease atat ratesrates rangingranging fromfrom 8282--98%98% AntidiabeticAntidiabetic effectseffects ofof gastricgastric bypassbypass StarvationStarvation inducedinduced alleviationalleviation DecreaseDecrease inin ghrelinghrelin ((ghrelinghrelin hashas diabetogenicdiabetogenic effects)effects) LargerLarger postprandialpostprandial bolusbolus ofof nutrientsnutrients intointo thethe hindguthindgut afterafter RYGBRYGB maymay leadlead toto increaseincrease inin GLPGLP--11 PYYPYY levelslevels increaseincrease afterafter otherother surgeriessurgeries thatthat expediteexpedite nutrientnutrient deliverydelivery toto thethe hindguthindgut FutureFuture inin ObesityObesity treatmenttreatment TargetTarget DeliveryDelivery TrialTrial

NPYNPY IntranasalIntranasal ClinicalClinical trialtrial antagonistantagonist (Pfizer) Hypothalamus PO Acomplia PhasePhase IIIIII (Rimonanbant) (Sanofi-Aventis) PYYPYY IntranasalIntranasal PhasePhase II (Merck) GLPGLP--11 IVIV PhasePhase IIIIII (Amylin) CCKCCK OralOral PhasePhase IIII

Korner et al. Pharmacological Approaches to Weight Reduction 2004;JCEM 89(6):2616-2621 SummarySummary TheThe brainbrain integratesintegrates peripheralperipheral signalssignals fromfrom thethe gutgut viavia peptidespeptides toto regulateregulate energyenergy homeostasishomeostasis GhrelinGhrelin isis anan importantimportant gutgut peptidepeptide signallingsignalling hungerhunger PYY,PP,PYY,PP, OXM,OXM, CCK,CCK, andand GLPGLP--11 areare thoughtthought toto contributecontribute moremore toto satietysatiety UnderstandingUnderstanding thethe contributionscontributions ofof thethe gutgut peptidespeptides maymay leadlead toto betterbetter understandingunderstanding ofof weightweight lossloss andand weightweight maintenancemaintenance TheseThese peptidespeptides maymay leadlead toto furtherfurther therapeutictherapeutic optionsoptions forfor obesityobesity andand aa betterbetter understandingunderstanding forfor thethe mechanismsmechanisms ofof weightweight lossloss inin gastricgastric bypassbypass