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Appetite Control: the Role of the Gastrointestinal Tract

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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
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  • Glucagon-Like Peptide 1 Secretion by the L-Cell the View from Within Gareth E

    Glucagon-Like Peptide 1 Secretion by the L-Cell the View from Within Gareth E

    Glucagon-Like Peptide 1 Secretion by the L-Cell The View From Within Gareth E. Lim1 and Patricia L. Brubaker1,2 Glucagon-like peptide 1 (GLP-1) is a gut-derived peptide GLP-1 receptor antagonists as well as GLP-1 receptor null secreted from intestinal L-cells after a meal. GLP-1 has mice have demonstrated that GLP-1 makes an essential numerous physiological actions, including potentiation of contribution to the “incretin” effect after a meal (3,4). glucose-stimulated insulin secretion, enhancement of However, GLP-1 secretion is reduced in patients with type ␤-cell growth and survival, and inhibition of glucagon 2 diabetes (5–7), and this may contribute in part to the release, gastric emptying, and food intake. These antidia- reduced incretin effect and the hyperglycemia that is betic effects of GLP-1 have led to intense interest in the use observed in these individuals (8). Thus, interest has now of this peptide for the treatment of patients with type 2 focused on the factors that regulate the release of this diabetes. Oral nutrients such as glucose and fat are potent physiological regulators of GLP-1 secretion, but non-nutri- peptide after nutrient ingestion. Many different GLP-1 ent stimulators of GLP-1 release have also been identified, secretagogues have been described in the literature over including the neuromodulators acetylcholine and gastrin- the past few decades, including nutrients, neurotransmit- releasing peptide. Peripheral hormones that participate in ters, neuropeptides, and peripheral hormones (rev. in energy homeostasis, such as leptin, have also been impli- 9,10). However, the specific receptors, ion channels, and cated in the regulation of GLP-1 release.