Effects of glucagon-like peptide 1 on appetite and body weight: focus on the CNS

16 Pages·2014·0.55 MB·English

Thematic Review LVANBLOEMENDAAL,JSTENKULVE EffectsofGLP-1onappetiteand 221:1 T1–T16
andothers bodyweight
Effects of glucagon-like peptide 1 on
appetite and body weight: focus on
the CNS
LvanBloemendaal*,JStenKulve*,SElaFleur1,RGIjzermanandMDiamant
Correspondence
DiabetesCentre,VUUniversityMedicalCentre,POBox7057,1007MBAmsterdam,TheNetherlands shouldbeaddressed
1DepartmentofEndocrinologyandMetabolism,AcademicMedicalCentre,UniversityofAmsterdam,Amsterdam, toLvanBloemendaal
TheNetherlands Email
*(LvanBloemendaalandJStenKulvecontributedequallytothiswork) [email protected]
Abstract
Thedeliveryofnutrientstothegastrointestinaltractafterfoodingestionactivatesthe KeyWords
secretionofseveralgut-derivedmediators,includingtheincretinhormoneglucagon-like " glucagon-likepeptide1
y peptide1(GLP-1).GLP-1receptoragonists(GLP-1RA),suchasexenatideandliraglutide,are " CNS
g
o currentlyemployedsuccessfullyinthetreatmentofpatientswithtype2diabetesmellitus. " feedingbehaviour
ol
rin GLP-1RAimproveglycaemiccontrolandstimulatesatiety,leadingtoreductionsinfood " obesity
c
o intakeandbodyweight.Besidesgastricdistensionandperipheralvagalnerveactivation, " type2diabetes
d
n
E GLP-1RAinducesatietybyinfluencingbrainregionsinvolvedintheregulationoffeeding,
f
o andseveralroutesofactionhavebeenproposed.Thisreviewsummarisestheevidencefora
al
n physiologicalroleofGLP-1inthecentralregulationoffeedingbehaviourandthedifferent
r
u
o routesofactioninvolved.Also,weprovideanoverviewofpresentlyavailabledataon
J
pharmacologicalstimulationofGLP-1pathwaysleadingtoalterationsinCNSactivity,
reductionsinfoodintakeandweightloss.
JournalofEndocrinology
(2014)221,T1–T16
Introduction
Obesityandtype2diabetesmellitus(T2DM),alsotermed orexigenic hormone ghrelin and the prandially secreted
‘diabesity’,aremajorpublichealthproblemsduetotheir anorexigenic hormones cholecystokinin (CCK), peptide
pandemic occurrence (Whiting et al. 2011, Flegal et al. YY (PYY), oxyntomodulin (OXM) and glucagon-like
2012) and their association with adverse consequences, peptide 1 (GLP-1), have been identified as players in the
such as cardiovascular disease and cancer (Stratton et al. regulationoffeedingbyrelayingmeal-relatedinformation
2000,Fieldetal.2001).Obesityistheresultofalong-term onnutritionalstatustothebrain.
positive energy balance whereby energy intake surpasses Based on more than three decades of experimental
expenditure.TheCNSplaysamajorroleinthemainten- evidence from rodent models and humans, GLP-1 was
anceofbodyweightandenergybalancewithinanarrow shown to lower blood glucose by stimulating insulin
rangebyregulatingenergyintakeandenergyexpenditure. secretion and production and suppressing glucagon
To regulate energy intake, signals, both neuronal and secretion in a glucose-dependent manner. Also GLP-1
humoral,arisingfromperipheralorgansinvolvedinfood decelerates gastric emptying, reduces body weight and
intake,–digestionand–storage,suchasthegut,pancreas, induces satiety (Holst 2007). As native GLP-1 is quickly
andadiposetissue,conveyinformationonhungerand/or inactivated by the ubiquitous enzyme dipeptidyl pepti-
satiety to the brain. Gut-derived hormones, such as the dase 4 (DPP-4), requiring continuous parenteral
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ThematicReview LVANBLOEMENDAAL,JSTENKULVE EffectsofGLP-1onappetiteand 221:1 T2
andothers bodyweight
administration,degradation-resistantGLP-1receptorago- expenditure and glucose metabolism. In normal physi-
nists(GLP-1RA)havebeendevelopedthatcanbeinjected ology,theintegrationofallperipheralsignalswillresultin
s.c. once daily (QD) or twice daily (BID) or even once energy intake matching the organism’s energy
weekly (QW) (Fineman et al. 2012). These agents are expenditure.
currentlysuccessfullybeingemployedinthetreatmentof The homeostatic signals arising from peripheral
T2DM (Drucker & Nauck 2006). GLP-1RA improves organs convey different aspects of the energy regulatory
glycaemic control and stimulates satiety, leading to processtotheCNS:long-term(‘static’)informationabout
reductionsinfoodintakeandbodyweight.Thepresence energy stores and acute, meal-related (‘dynamic’) infor-
of GLP-1 receptors in the CNS and findings from animal mation(Schwartzetal.2000,Havel2001).Adipose-tissue-
and human studies indicate that the GLP-1RA-induced derivedleptin,whichissecretedinproportiontoadipose
satietyandweighteffectsmaybe,atleastinpart,mediated mass,conveys‘static’informationtotheCNSaboutlong-
by their actions on the brain. This review focuses on term energy stores. In normal physiology, central leptin
current evidence for a physiological role of GLP-1 in the signalling has an anorectic effect (Cohen et al. 2001),
central regulation offeeding behaviour. Also, weprovide
and central leptin resistance has been postulated to be
an overview of presently available data on pharma-
a contributing factor to the development of obesity
cological stimulation of GLP-1 pathways leading to CNS
(Considine et al. 1996, Levin & Dunn-Meynell 2002,
activation,changesinfoodintakeandweightloss.
Enriori et al. 2007). Insulin secreted from pancreatic
b-cells displays both tonic (basic) 24h and meal-related
CNS regulation offeeding secretion (Polonsky et al. 1988). Thus, insulin may relay
bothlong-termandacuteinformationandwasshownto
Foodintakeisregulatedbycomplexinteractionsbetween
y actinthebraintoreducefoodintake(Woodsetal.1979,
nolog nbruatirnienatrse,ahs.orTmheonreesg,unlaetuiroonpeopftidfeeesdainngd sceavnerbaleddififveirdeendt Bruning et al. 2000, Benedict et al. 2008). In obesity and
ri over-nutrition, peripheral insulin resistance results in
oc in homeostatic and non-homeostatic feeding (Lutter &
d chronic hyperinsulinaemia. Interestingly, a study using
n Nestler 2009). Homeostatic feeding controls energy
E 18-fluoro-deoxy-glucose (18FDG) positron-emission
of balance by adjusting food intake to promote stability in
nal the amount of energy stores. However, non-homeostatic tomography (PET) indicated the existence of central
r insulinresistanceinobeseindividualswiththemetabolic
ou orhedonicfeedingcanoverridethishomeostaticpathway
J syndrome,whichiscompatiblewiththegenerallygreater
resulting in overeating. It has been postulated that this
caloric intake in these individuals (Anthony et al. 2006).
is caused by the rewarding (palatable) properties of
Theabove-mentionedmeal-relatedgut-derivedhormones
food (Wang et al. 2004, Volkow & Wise 2005, Trinko
(ghrelin, CCK, PYY, OXM and GLP-1) signal dynamic
etal.2007).
information about the changes in nutritional status to
Homeostaticcontroloffeedingconsistsofthesensing
theCNS.
and integration within the CNS of changes in nutrients,
In contrast to homeostatic control of feeding
hormones and neuropeptides, reflecting changes in
behaviour, non-homeostatic feeding behaviour is not
energybalanceandtheensuingalterationsinfoodintake.
regulated by hunger and satiety signalsbut rather by the
The brainstem and hypothalamus are important CNS
rewardingpropertiesandmotivationrelatedtofoods,and
structureswithintheregulatorypathwaysofhomeostatic
feeding as they receive, convey and integrate peripheral involves reward, cognitive and emotional factors. Thus,
signals. The area postrema (AP) and nucleus tractus corticolimbiccircuitsinhumans(including thestriatum,
solitarii (NTS) in the brainstem convey these peripheral amygdala, insula, nucleus accumbens (NAc) and orbito-
signals, consisting of nutrients, hormones and vagal frontalcortex)areimplicatedinnon-homeostaticeating.
afferent activation, to the arcuate nucleus (ARC) of the Within the CNS, pathways for homeostatic and non-
hypothalamus (Bailey 2008). The ARC consists of orexi- homeostatic control of feeding comprise multiple inter-
genic neurons (expressing neuropeptide Y and agouti- connected brain regions. The above-described hormonal
related peptide) and anorexigenic neurons (expressing regulatorsofhomeostaticfeedingmayalsoinfluencebrain
pro-opiomelanocortin), which collectively regulate rewardsystemsand mayincreaseordecreasethereward-
homeostatic control of eating (Gao & Horvath 2008). In ing value of food depending on energy requirements
this process, the hypothalamus acts as a gatekeeper, as it (Berthoud2011,Kenny2011).Palatablefoodcanactivate
additionally controls body temperature, energy brainrewardcircuits,andtheserewardingeffectscanbea
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ThematicReview LVANBLOEMENDAAL,JSTENKULVE EffectsofGLP-1onappetiteand 221:1 T3
andothers bodyweight
powerful motivation for food consumption and may Exenatide is currently available in two formulations for
overrulesignalsregulatinghomeostaticfeeding. thetreatmentofT2DM,i.e.ashort-actingcompoundfor
The studies summarised above show that both BIDs.c.injection(half-life2.4h,tobeadministeredbefore
homeostatic and non-homeostatic factors influence breakfast and dinner) and a long-acting extended-release
feeding behaviour and that there is an extensive cross- formulation for QW administration. Exenatide BID was
modulationofsignalswithinthesepathways.Leptinand approvedbytheUSFoodandDrugAdministration(FDA)
gut-derivedhormoneshavebeenstudiedinthesearchfor in2005andbytheEuropeanMedicinesAgency(EMA)in
therapeutictargetsforthetreatmentofobesity,butthese 2006. Exenatide QW was approved by the FDA and EMA
attempts were not successful (Crawley & Beinfeld 1983, in 2012 and 2011 respectively. Liraglutide is a GLP-1RA,
Jordanetal.2008,Costantinietal.2011,Moonetal.2011, which, due to its 97% amino acid homology to native
Cummings 2013), except for GLP-1RA. Although not GLP-1, incontrast toexenatide,isa trueGLP-1 analogue
approved for the treatment of obesity, administration (Knudsen et al. 2000). Addition of a C16 fatty acid chain
of GLP-1RA consistently results in body weight loss in prolongs absorption from the subcutaneous depot and
humans. promotes albumin binding, collectively resulting in a
prolonged (13h) circulating half-life after s.c. injection.
Consequently, liraglutide is suitable for QD adminis-
GLP-1RA treatment and body weight in tration. Liraglutide was approved in 2009 by the EMA
humans andin2010bytheFDA.LixisenatideisaGLP-1RAbased
on exendin-4 that is DPP-4-resistant due to C-terminal
Theincretinsystem:fromphysiologytopharmacology
modificationwithsix lysine residuesanddeletionofone
Following meal ingestion, GLP-1 is secreted into the proline(Barnett2011).LixisenatidewasapprovedbyEMA
y
og circulationbyenteroendocrineL-cellslocatedinthedistal in 2013 and will be submitted to the FDA in the near
nol jejunum and ileum and contributes to postprandial future. Although the half-life of lixisenatide is similar to
ri
oc glucose regulation, as it augments meal-related insulin that of exenatide BID, and lixisenatide is regarded as
d
n secretion from the pancreas (Kreymann et al. 1987, ashort-actingGLP-1RA,ithasfourfoldhigheraffinityfor
E
of Mojsov et al. 1987). Also GLP-1 promotes insulin gene the GLP-1 receptor than GLP-1 and therefore can be
nal transcription (Drucker et al. 1987). Also, GLP-1 improves administeredQD(Werneretal.2010).
r
ou pancreaticb-cellglucoseresponsiveness(Holzetal.1993). Short-acting GLP-1RA are more effective in lowering
J
Other glucose-lowering mechanisms of GLP-1 involve postprandialhyperglycaemia,whilelong-actingGLP-1RA
inhibition of glucagon secretion and deceleration of ratherreducebasalhyperglycaemia(Finemanetal.2012).
gastric emptying and gut motility. In addition to An important determinant of postprandial hyperglycae-
pancreaticislets,GLP-1receptorshavebeendemonstrated miaistherateofgastricemptying.Rapidtachyphylaxisof
in the gut, heart, vasculature, kidney, muscle and lung gastricemptyingdeceleration,resultingfromcontinuous
(Sivertsen et al. 2012), indicting so-called pleiotropic stimulationoftheGLP-1receptorbylong-acting(butnot
effects of GLP-1, i.e. effects beyond glucose lowering. short-acting) GLP-1RA, may explain their lack of efficacy
Many excellent reviews have been published describing withrespecttomeal-relatedhyperglycaemia(Naucketal.
thephysiologicalroleofGLP-1inglucoseregulationand 2011).Inasmuchasgastricemptyingdelayalsopromotes
the pleiotropic effects (Baggio & Drucker 2004, Drucker the most common side effect of GLP-1RA, i.e. nausea
2006, Holst 2007, van Genugten et al. 2009, Vilsboll & and occasional vomiting, these side effects are more
Garber2012). frequently observed with short-acting GLP-1RA than
Exenatide, the first GLP-1RA developed for human long-acting GLP-1RA (Drucker et al. 2008, Buse et al.
use, is a synthetic form of exendin-4, a 39-amino acid 2009). The occurrence of these side effects may limit
peptide isolated from the salivary secretions of the Gila the possibility of higher dosing of GLP-1RA and possible
monster (Heloderma suspectum). Exendin-4 shares 53% greater improvement of glycaemic control and body
sequence identity with GLP-1. Substitution of alanine by weight reduction. The effects of GLP-1RA on gastric
glycineatthesecondpositionoftheNH -terminusmakes emptying and nausea and their possible influence on
2
exendin-4 resistant to DPP-4-mediated degradation GLP-1RA-induced satiety will be discussed in more detail
(Nielsen et al. 2004). Exendin-4 has greater effective laterinthisreview.
receptor affinity than native GLP-1 and is therefore a Several other GLP-1RA, mainlylong-acting GLP-1RA,
potentGLP-1RA(Raufmanetal.1992,Youngetal.1999). including albiglutide, semaglutide and dulaglutide are
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ThematicReview LVANBLOEMENDAAL,JSTENKULVE EffectsofGLP-1onappetiteand 221:1 T4
andothers bodyweight
currentlyunderadvancedclinicaldevelopment(Fineman (Astrup et al. 2009, 2012). These seemingly more robust
et al. 2012), but the preliminary clinical data are beyond weight effects may be due to the higher doses of
thescopeofthisreview. liraglutide used and higher BMI (w35kg/m2) at baseline
ascomparedwiththephase-3trialsinT2DMpopulations
(BMIw32–33kg/m2).Asmall-sizedstudyinseverelyobese
GLP-1RAandtheireffectonbodyweight
non-diabetic individuals with impaired glucose metab-
GLP-1RAareapprovedforthetreatmentofT2DMbecause olism(baselineBMIw40kg/m2)showedameanplacebo-
oftheirglucose-loweringeffects.Asanadditionalbenefit, adjusted weight reduction of 3.3kg after 24 weeks of
treatmentwithGLP-1RAisassociatedwithsustaineddose- exenatide 10mg BID (Rosenstock et al. 2010). It is worth
dependentweightlose.Ameta-analysisof21trials(6411 noting that, currently, GLP-1RA have not been officially
participants)showedaweightedmeandifferenceinbody approvedforthetreatmentofobesity.
weightofK2.9kg(95%CI,K3.6toK2.2)achievedwith Takingalltheseclinicalresultstogether,GLP-1RAare
the highest dose of GLP-1RA compared with the control associated with weight loss. This has consistently been
treatment (Vilsboll et al. 2012). Mean weight changes in shown during treatment with short-acting and long-
trialscomparingexenatideBIDorliraglutideatthehighest actingGLP-1RAinbothT2DMandobeseindividuals.
dosetoplaceboasadd-ontreatmenttooralblood–glucose-
loweringagentsduring20–30weeksrangedfromK3.1to
Effects of GLP-1 and GLP-1RA on energy
K0.2kginthetreatmentgroupcomparedwithK1.4toC
balance
0.6kgintheplacebogroup(Table1).Intrialscomparing
exenatide BID, exenatide QW or liraglutide with basal or Toattainbodyweightloss,achievinglong-termnegative
biphasicinsulin,thusachievingsimilarglycaemiccontrol energy balance by reduction in appetite and energy
y
og in both intervention groups, the weight differences intake,orbyanincreaseinenergyexpenditureorbothis
nol wereevenmoreprominent.WeightlossduringGLP-1RA required.
ri
oc treatment ranged from 1.8 to 4.1kg, while weight Preclinical data indeed show an inhibiting effect of
d
n gain with insulin therapy varied between 1.0 and 4.1kg GLP-1 administration on food intake. Acute i.p. or s.c.
E
of (Table 1). In phase-3 trials, weight loss effects of administrationofGLP-1andexendin-4resultedinadose-
nal lixisenatide were relatively modest (up to a mean of dependentinhibitionoffoodintakeinrodents(Rodriquez
r
ou 1.0kgvsplacebo;Petersen&Christensen2013;Table1). de Fonseca et al. 2000, Abbott et al. 2005, Talsania et al.
J
TheobservedGLP-1RA-relatedweightlosswasassoci- 2005), which also persisted during prolonged adminis-
atedwithreductionintotalbodyfat,particularlytrunkor tration of i.p. exendin-4 BID (Szayna et al. 2000). The
visceral fat (Jendle et al. 2009, Bunck et al. 2010). When reductions in food intake with GLP-1 and exendin-4 are
on treatment, the achieved weight loss with GLP-1RA attributedtodecreasesinmealsize(Scott&Moran2007,
persisted over 52 weeks (Nauck et al. 2007, Bunck et al. Ruttimannetal.2009).However,GLP-1infusionduringa
2009,Garberetal.2009)andinopen-labelextensiontrials 3hperiodreducedthecumulativefoodintakenotonlyby
up to 2–3 years (Bunck et al. 2011, Garber et al. 2011, reducing meal size but also meal frequency (Chelikani
Macconell et al. 2013). Although open-label extension etal.2005).
trials with GLP-1RA may be flawed by selection bias Also in humans, GLP-1 was shown to reduce food
towards responders, the observed sustained weight loss intake, appetite, and hunger and to promote fullness
over time seems different to weight loss through dietary and satiety (Flint et al. 1998, 2001, Naslund et al. 1998,
restriction,whereonlyasmallminorityofobeseindivid- Gutzwilleretal.1999,Verdichetal.2001).Itisnoteworthy
ualsmaintainweightlossinthelongterm(Andersonetal. that satiation and satiety are commonly used as syno-
2001).Itisworthyofnote,however,thatwhenexenatide nyms, but need to be distinguished (Mithieux 2013).
BID was discontinued after 3 years of exposure, patients Satiationistheincreasingsensationoffullnessthatoccurs
started to regain weight during the 12-week washout duringdigestionandabsorptionofameal.Satietyisastate
period (Bunck et al. 2011). Thus, no durable effects are ofno-hungerthatoccurssometimeafterthelastmealand
presentunlesspatientsareonactiveGLP-1RAtreatment. moderatestheinitiationofthefollowingmeal.Aplacebo-
In non-diabetic obese individuals, placebo-adjusted controlled study in healthy normal-weight individuals
weight loss after 20-week treatment with liraglutide, at investigating the effects of i.v. administration of GLP-1
dosesof1.2,1.8,2.4and3.0mgQD,rangedfromamean duringa5hperiodshowedthatGLP-1atpharmacological
of2.1–4.4kg,whichpersistedthrough2yearsoftreatment levelsdecreasedhungerandenhancedsatietyandfullness
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ThematicReview LVANBLOEMENDAAL,JSTENKULVE EffectsofGLP-1onappetiteand 221:1 T5
andothers bodyweight
Table 1 Weight changes during GLP-1RA treatment for 20–30 weeks compared with placebo or insulin. Weight changes from
baselineto20–30weeksduringphase-3trials(noextensiontrials)comparingapprovedGLP-1RAwithplaceboorinsulininT2DM
patientsandobese(non-diabetic)individuals
Mean(S.E.M.)
No.of Duration Study weightchangesin
Study patients (weeks) populations Compound/dosing kgfrombaseline Pvalue
Add-onGLP-1RAtreatmentvsplacebo
Buseetal.(2004) 377 30 T2DM Exenatide5mgBID K0.9(0.3) NS
Exenatide10mgBID K1.6(0.3) !0.05
Placebo K0.6(0.3) –
DeFronzoetal.(2005) 137 30 T2DM Exenatide5mgBID K1.6(0.4) !0.05
Exenatide10mgBID K2.8(0.5) !0.001
Placebo K0.3(0.3) –
Kendalletal.(2005) 733 30 T2DM Exenatide5mgBID K1.6(0.2) !0.01
Exenatide10mgBID K1.6(0.2) !0.01
Placebo K0.9(0.2) –
Morettoetal.(2008) 232 24 T2DM Exenatide5mgBID K2.8(0.3) 0.004
Exenatide10mgBID K3.1(0.3) !0.001
Placebo K1.4(0.3) –
Astrupetal.(2009) 371 24 Obese,non-diabetic Liraglutide1.2mgQD K4.8(0.5) 0.003
Liraglutide1.8mgQD K5.5(0.5) !0.0001
Liraglutide2.4mgQD K6.3(0.5) !0.0001
Liraglutide3.0mgQD K7.2(0.5) !0.0001
Placebo K2.8(0.5) –
Marreetal.(2009) 1041 26 T2DM Liraglutide0.6mgQD C0.7(0.0) !0.05
gy Liraglutide1.2mgQD C0.3(0.0) NS
olo Liraglutide1.8mgQD K0.2(0.0) !0.05
n Placebo K0.1(0.1) –
ri
c Naucketal.(2009) 1091 26 T2DM Liraglutide0.6mgQD K1.8(0.2) NS
o
d Liraglutide1.2mgQD K2.6(0.2) !0.01
n
E Liraglutide1.8mgQD K2.8(0.2) !0.01
f
o Placebo K1.5(0.3) –
nal Russell-Jonesetal.(2009) 581 26 T2DM Liraglutide1.8mgQD K1.8(0.3) 0.0001
ur Placebo K0.4(0.4) –
o
J Zinmanetal.(2009) 533 26 T2DM Liraglutide1.2mgQD K1.0(0.3) !0.0001
Liraglutide1.8mgQD K2.0(0.3) !0.0001
Placebo C0.6(0.3) –
Rosenstocketal.(2010) 163 24 Obese,non-diabetic Exenatide10mgBID K5.1(0.5) !0.001
Placebo K1.6(0.5) –
Bollietal.(2011) 482 24 T2DM Lixisenatide20mgQD K2.7(0.3) 0.0025
Placebo K1.6(0.3) –
Seinoetal.(2012)a 311 24 T2DM Lixisenatide20mgQD K0.4(0.3) 0.086
Placebo C0.1(0.3) –
Pingetetal.(2013) 484 24 T2DM Lixisenatide20mgQD K0.2(0.3) NS
Placebo C0.2(0.3) –
Riddleetal.(2013)a 446 24 T2DM Lixisenatide20mgQD C0.3(0.3) 0.0012
Placebo C1.2(0.3) –
AddonGLP-1RAvsinsulintreatment
Heineetal.(2005) 551 26 T2DM Exenatide10mgBID K2.3(0.2) !0.0001
Insulinglargine,titratedQD C1.8(0.2) –
Bergenstaletal.(2009) 372 24 T2DM Exenatide5mgBID K2.0(0.3) !0.001
InsulinBIAsp70/3012UQD C2.9(0.3) –
InsulinBIAsp70/306UBID C4.1(0.9) –
Daviesetal.(2009) 49 20 T2DM Exenatide10mgBID K2.7(0.3) !0.001
Insulinglargine,titratedQD C3.0(0.3) –
Russell-Jonesetal.(2009) 581 26 T2DM Liraglutide1.8mgQD K1.8(0.3) !0.0001
Insulinglargine,titratedQD C1.6(0.3) –
Diamantetal.(2010) 456 26 T2DM Exenatide2mgQW K2.6(0.2) !0.05
Insulinglargine,titratedQD C1.4(0.2) –
Gallwitzetal.(2011) 363 26 T2DM Exenatide10mgBID K4.1(0.2) !0.001
InsulinBIAsp70/30,titrated C1.0(0.2) –
BIAsp,biphasicinsulinaspart;BID,twicedaily;NS,notsignificant;T2DM,type2diabetesmellitus;QD,oncedaily;QW,onceweekly.
aThesestudiesaddedGLP-1RAtoinsulintherapy.
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ThematicReview LVANBLOEMENDAAL,JSTENKULVE EffectsofGLP-1onappetiteand 221:1 T6
andothers bodyweight
scoresafteranenergy-fixedbreakfast,measuredbyvisual although the later had smaller effects (Hwa et al. 1998,
analogue scale (VAS) questionnaires, and reduced caloric Osaka et al. 2005), indicating that peripheral effects of
intakeby12%duringasubsequentadlibitumlunch(Flint GLP-1arealsoimportant.Incontrast,acutei.c.v.exendin-
et al. 1998). However, there were no differences in the 4 administration in mice resulted in a rapid decrease in
subjective ratings of taste, visual appeal, smell, aftertaste oxygen consumption (Baggio et al. 2004b), but vehicle
andoverallpalatabilityofthemeal.Similarreductionsin administrationalsoresultedinalargedecreaseinoxygen
hunger and increases in satiety scores were described in consumption, making the results difficult to interpret.
studieswithasimilardesigninobeseandT2DMindividuals Furthermore, 4 week i.c.v. treatment with a selective
(Naslund et al. 1998, Gutzwiller et al. 1999). In a meta- GLP-1receptorantagonist(exendin9–39)inmiceresulted
analysis of studies in humans evaluating acute effects inahigheroxygenconsumption(w22%)comparedwith
ofGLP-1infusiononfoodintake,ameandecreaseof11.7% vehicle, but the exendin 9–39-induced increase in food
was reported in the amount of ad libitum energy intake consumption(w83%)(Knaufetal.2008)couldcontribute
compared with saline(Verdich etal. 2001). Interestingly,
to the observed increase in oxygen consumption. More
reductions in VAS-score hunger ratings were not only
specifically, GLP-1 seems to affect thermogenesis. I.v.
present with pharmacological levels, but also with infu-
administration of GLP-1 in rats increased body tempera-
sions attempting to achieve physiological postprandial
ture by 0.38C. The effect of GLP-1 on body temperature
GLP-1levels(w50pmol/l;Flintetal.2001).However,atthe
was not altered by decerebration, whereas cervical spinal
latter GLP-1 concentration, there were no statistically
transectionattenuatedthethermogenicresponsetoGLP-1
significanteffectsonadlibitumfoodintake.
(Osaka et al. 2005), indicating involvement of the lower
Studies observing prolonged GLP-1 administration
brainstem but not forebrain areas in this mechanism.
over more than one day are limited. Two small studies,
y Moreover,i.c.v.GLP-1administrationinmiceresultedin
nolog utoswinagrdascroendtuinceudouhsusn.cg.eirnafnudsieonnhpaunmcepd,fsuhlolnweesdsatennddseanticeiteys an increase in brown adipose tissue (BAT) thermogenesis
ri (Lockie et al. 2012). Interestingly, BAT thermogenesis
oc scoresmeasuredwithVASquestionnaires.Inasmallstudy
d changes did correlate with an increased activity of
n with six T2DM patients, GLP-1 administration over 48h
E sympathetic fibres innervating BAT. As peripherally
of resulted in an average tendency towards a decrease in
nal hunger and increase in satiety throughout the days, but administered GLP-1 did not alter BAT thermogenesis,
r it is likely that the thermogenic effects of GLP-1 are
ou this effect only reached statistical significance just before
J mediated by the brain. Taken together, these preclinical
thestartofthenextmeal(lunchanddinner;Toft-Nielsen
findings indicate that GLP-1 might have effects on the
et al. 1999). Furthermore, a hallmark proof-of-concept
central regulation of energy balance by affecting energy
study,duringwhichGLP-1wasadministeredviacontinu-
expenditure and specifically thermogenesis, but the
ous s.c. infusion for 6 weeks in seven T2DM patients
resultsarenotfullyconclusive.
reported a trend towards reduction in overall appetite
In humans, the reported effects of GLP-1 on energy
scoresmeasured2hafterthemeal(Zanderetal.2001).
expenditure are more inconsistent. During acute GLP-1
Taken together, these observations regarding food
infusion, energy expenditure caused by diet-induced
intake in humans show that GLP-1 administration has
thermogenesis was decreased in both healthy lean and
consistent acute effects on hunger, fullness and satiety
obeseindividuals(Flintetal.2000,2001).Aftertreatment
measures. Longer-term studies in small groups indicate
of 4 weeks with liraglutide in T2DM patients, the
that a persistent reduction in appetite and food intake
may mediate the effects of GLP-1RA treatment on estimated 24h resting energy expenditure tended to
bodyweight. increase (Horowitz et al. 2012), but this effect was not
The body-weight-reducing effects of GLP-1RA treat- confirmed in trials with a treatment duration of
ment could also be due to increased energy expenditure, 8–10 weeks with liraglutide or exenatide (Harder et al.
leading to a negative energy balance. However, the 2004,Bradleyetal.2012).
reported effects of GLP-1 on energy expenditure from Given the lack of consistency in the effects of GLP-1
animal data are not consistent. Energy expenditure andGLP-1RAonenergyexpenditureinhumans,ithasbeen
depends on oxidation of substrates and consists of concludedthatthetreatment-relatedbodyweightlosscan
differentelements,suchasrestingmetabolicrate,physical ratherbeattributedtoadecreaseinenergyintake.Various
activity and thermogenesis. Both i.v. and i.c.v. adminis- mechanisms and routes of action of GLP-1 are involved
tration of GLP-1 in rats increased oxygen consumption, andcontributetotheinhibitoryeffectonfoodintake.
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ThematicReview LVANBLOEMENDAAL,JSTENKULVE EffectsofGLP-1onappetiteand 221:1 T7
andothers bodyweight
GLP-1effectsontheregulationofappetite:the administration observed in fasting human subjects
role of delayed gastric emptying (with an empty stomach) (Gutzwiller et al. 1999). Taken
together, other mechanisms than delayed gastric empty-
An important factor in the regulation of appetite and
ing alonecontributetotheappetite-suppressingeffectof
satiationduringfoodintakeisgastricmechanosensation.
GLP-1RAtreatment.Theseeffectsmaypartlybemediated
Distension of the stomach induces satiation signals by
by actions of GLP-1 on CNS networks involved in the
activation of gastric mechanoreceptors, which relay
regulationofappetite.
informationviavagalnervestotheNTSinthebrainstem.
The amount of gastric distension due to food intake is
GLP-1 effects on the CNS regulation of appe-
partly influenced by the rate of gastric emptying, which
tite and satiety
affects postprandial glycaemic excursions. The role of
gastric motility in appetite and satiation regulation and
GLP-1/GLP-1RA exerts their effects on glucose homeo-
the effects of GLP-1/GLP-1RA on gastric and gut motility
stasis,feedingbehaviourandbodyweight,bothviadirect
has been extensively reviewed (Janssen et al. 2011,
andindirectpathways,whicharelargelymediatedbythe
Marathe et al. 2011). GLP-1 delays gastric emptying and
CNS(Fig.1).
gut motility not only in healthy lean but also in obese
ExperimentaldataindicatethatGLP-1mayalsoexert
subjects and patients with T2DM (Nauck et al. 1997,
actionsinthebrainbeyondthesewell-establishedeffects,
Naslund etal. 1998, Schirra etal. 2002, Meier etal. 2003,
by influencing neuronal health, cognition and neuro-
Little et al. 2006). Delayed gastric emptying affects the
inflammation(Duringetal.2003,Lietal.2009,McClean
extentofgastricdistension,therateofnutrientexposure
etal.2011,Tweedieetal. 2013). Thelatter CNS effectsof
of the gut and, consequently, gut hormones secretion,
GLP-1arebeyondthescopeofthisreview.
y
og whichinturninfluencespostprandialglucoseexcursions. AphysiologicalroleforGLP-1inthecentralregulation
nol Although usually transient, gastrointestinal symp- of feeding was suggested when GLP-1 receptors were
ocri toms, most notably nausea and occasional vomiting, are localised in many parts of the rat brain, including areas
nd themostcommonlyreportedsideeffectsduringGLP-1RA thatareimplicatedinthecontroloffoodintake(including
E
of treatment.Onemightspeculatethatchangesinsignalling areas important for reward processing and motivated
nal due to delayed gastric emptying and nausea are the sole behaviour)andenergybalance,suchasthehypothalamus,
r
ou causeofGLP-1-inducedchangesinappetiteandsatiation NTS, AP, dorsal striatum and NAc (Shugrue et al. 1996,
J
and of GLP-1RA treatment-induced weight loss. In Merchenthaler et al. 1999). In addition, administration
rodents,acuteinfusionwithGLP-1RAinducedadelayin of GLP-1 into the lateral ventricle resulted in powerful
gastric emptying, associated with a decrease in food inhibition of feeding when fasted male rats were refed,
intake. However, after 14 days of continuous GLP-1RA which was accompanied by c-Fos expression, a marker of
infusion, gastric emptying was similar to that of animals neuronal activation, in both the paraventricular nucleus
receiving a vehicle infusion, but food intake was still (PVN) of the hypothalamus and the central nucleus of
reduced (Jelsing et al. 2012). Also in humans, the the amygdala (Turton et al. 1996). This effect was dose-
inhibitory effect of GLP-1 on gastric emptying is subject dependent and was blocked by i.c.v. administration of
to tachyphylaxis (Nauck et al. 2011). In spite of the exendin 9–39, a highly selective antagonist of the GLP-1
observed tachyphylaxis of delayed gastric emptying, the receptor.Moreover,administrationofGLP-1intothethird
weight-lowering effect of GLP-1RA treatment persists ventriclealsosignificantlyinhibitedfoodintakeinfasted
over periods up to 3 years (Macconell et al. 2013). Other maleratsinadose-dependentfashion(Schicketal.2003).
observationsmakingitlesslikelythatGLP-1RAeffectson Asi.c.v.GLP-1administrationinGLP-1receptorknockout
gastricemptyingaretheonlycauseofappetiteandweight mice failed to reduce food intake, the GLP-1 receptor
loss include the observed weight reduction during seems to be implicated in these GLP-1-induced effects.
GLP-1RA treatment in the absence of nausea (Buse et al. Interestingly, GLP-1-receptor deletion itself did not alter
2004,DeFronzoetal.2005,Naucketal.2009,Russell-Jones body weight or feeding behaviour (Scrocchi et al. 1996).
et al. 2009, Garber et al. 2011, Shyangdan et al. 2011); Direct administration of GLP-1 into the PVN, lateral
similar or even greater weight loss with long-acting hypothalamus, dorsomedial hypothalamus and the
GLP-1RA,despitetheirreducedeffectongastricemptying ventromedial hypothalamus significantly reduced food
relative to short-acting GLP-1RA (Jelsing et al. 2012); intake,whereasinjectionoftheGLP-1receptorantagonist
and the reported reduction in appetite after GLP-1 exendin 9–39 into the lateral hypothalamus augmented
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ThematicReview LVANBLOEMENDAAL,JSTENKULVE EffectsofGLP-1onappetiteand 221:1 T8
andothers bodyweight
= GLP-1 receptor
= Afferent neuronal signal
(GLP-1-stimulated)
Cortical brain = Afferent neuronal signal
PVN Hyp centres (nutrient-stimulated)
= Afferent neuronal signal
DMH (gastric distension)
VMH = Circulation
NAc
ARC Hyp = Efferent neuronal signal
ANgPRYP/ POMC VTA
{
BS GLP1
AP –
NTS
Brown adipose Pancreas Stomach GLP-1
tissue ↑Insulin ↓Gastric emptying 10–15%
↑Thermogenesis ↓Glucagon
Food intake
Systemic
Liver circulation
Intestinal vagal
↑Insulin action GLP-1 afferents/ENS
Hepatic vagal ?
25% branch
+
Portal
y circulation
g
o
ol
n GLP-1
ri
c
o
d Gut
n
E
f
o
al
n
r
u
o
J Figure1
ProposedroutesofactionofGLP-1inthecentralregulationoffeedingandglucosemetabolism.Gut-derivedGLP-1mayaffectthebrainbyseveralroutesof
action,i.e.indirectly,vianeuralafferents,anddirectly,byenteringthebrainviathesystemiccirculationandbycrossingtheblood-brainbarrier.Other
potentialmediatorsconstitutingthegut–brainaxisincludenutrientsandsignalsarisingfrommeal-relatedgastricdistension.GLP-1secretedfromintestinal
L-cellsinresponsetomeal-ingestion,diffusesacrossthebasallaminaintothelaminapropria,atwhichleveltheuptakebycapillariesandthedegradationby
DPP-4occurs.Subsequently,endogenousGLP-1activatesintestinalvagalafferents,locatedinthegutorportalcirculation,partlybelongingtotheenteric
nervoussystem(ENS),whichmayactivateGLP-1-producingneuronsinthenucleustractussolitarii(NTS).Additionalactivationofintestinalorportalvagal
afferentsbynutrients,othergut-hormonesorgastricdistensionmayalsoactivatetheseGLP-1-producingneurons.Theseneuronsprojecttoseveralfood-
regulatingareas,mostofwhichcontainGLP-1receptors.Theseareasincludetheventraltegmentalarea(VTA),thenucleusaccumbens(NAc)andthe
hypothalamus(Hyp).Throughoutthehypothalamus,theGLP-1receptorispresent,particularlyintheparaventricularnucleus(PVN),dorsomedial
hypothalamus(DMH)andthearcuatenucleus(ARC),withagreaterdensityonpro-opiomelanocortin(POMC)neurons(anorexigenicneurons)thanonthe
agouti-relatedpeptide(AgRP)/neuropeptideY(NPY)neurons(orexigenicneurons).Todate,noreceptorshavebeenfoundintheventromedial
hypothalamus(VMH).Lessisknownaboutthehighercorticalcentresthatextendthecircuitrybeyondthehypothalamus,VTAandnucleusaccumbens.Only
25%ofthegut-derivedGLP-1reachestheportalcirculation,whereitcanactivateafferenthepaticvagalnerves,whilemerely10–15%ofgut-derivedGLP-1
entersthesystemiccirculationandmayaccessthebrainthroughareaswithapermeableblood-brainbarrier,suchastheareapostrema(AP)andARC.
Efferentpathways,amongothers,originatinginthebrainstem(BS),subsequentlysignaltoperipheralorganstoclosetheloopoffeedingbehaviourand
glucosemetabolismregulation,bothofwhichmaybepartlyinterlinked.Accordingly,GLP-1lowersbloodglucosebystimulatingpancreaticinsulinsecretion
andproduction,andbysuppressingglucagonsecretionfromthepancreasandbyenhancinghepaticinsulinactioninaglucose-dependentmanner.Also,
GLP-1-relatedeffectspromotinggastricemptyingdelayseemtobepartofthisregulatoryloop.Theseactionsmaybeduetodirecteffectsofcirculatinggut-
derivedGLP-1but,giventheshortcirculatinghalf-lifeoftheincretinhormone,indirect,neurallymediatedeffectsmaycontribute,eventoagreaterextent,
totheefferentoutputtotheseorgans.
foodintakeinsatiatedrats.Despitethereportedpresence homeostatic feeding, but also due to effects on the
of GLP-1 receptors, injections of GLP-1 directly into the rewarding value of food that are exerted at the level of
ARCdidnotaffectfoodintake(Sandovaletal.2008).The themesolimbicrewardsystem.Microinfusionofexendin-
effects of GLP-1 on food intake may not only be due to 4 in key mesolimbic structures, ventral tegmental area
effectsonhypothalamicandbrainstemcircuitsregulating and NAc, resulted in decreased motivated behaviour for
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ThematicReview LVANBLOEMENDAAL,JSTENKULVE EffectsofGLP-1onappetiteand 221:1 T9
andothers bodyweight
sucrose in rats (Dickson et al. 2012). Also, injection i.c.v. administration. Albiglutide, injected i.p., was more
of exendin 9–39 into the NAc resulted in significant effective in lowering hyperglycaemia than inducing
hyperphagiainrats,indicatingaphysiologicroleofGLP-1 satiety.Althoughc-FosactivationindifferentCNSnuclei
receptorsintheNAcforthecontroloffoodintake(Dossat was similar after peripheral albiglutide administration, it
et al. 2011). Collectively, these preclinical data show was less robust compared with the pattern induced by
that central GLP-1 induces satiety by affecting both exendin-4.Theseexperimentsindicatedthatbothperiph-
homeostatic and reward-associated food intake and that eral and central mechanisms are involved in the GLP-1
theseeffectsseemtobeGLP-1receptor-mediated. receptor-mediated effects on glucose and energy
homeostasis.
StudiesusingtheGLP-1receptorantagonistexendin9–
RoutesofactionofGLP-1:directandindirecteffects
39 provide further insights into the routes of action of
ontheCNS
GLP-1.Peripheraladministrationofexendin9–39increased
The inhibitory effects of GLP-1 on food intake may be foodintakewhengiventosatiatedrats(Williamsetal.2009).
due to both direct and indirect effects on the CNS To differentiate between central and peripheral pathways
(Fig. 1), but the exact routes of action are largely involved, exendin 9–39 was injected either centrally or
unknown. Gut-derived GLP-1 may enter the brain peripherally before both central and peripheral injection
through the AP, at the level of which the blood–brain ofGLP-1.AnorexiainducedbyperipheralGLP-1wastotally
barrier is permeable. A radiolabelled GLP-1 analogue has blocked by peripheral, but not central i.c.v. pretreatment
beendemonstratedtoeasilycrosstheblood–brainbarrier with exendin9–39, whereas the opposite was true for the
in mice (Kastin et al. 2002). But due to its short anorectic effect of central GLP-1, which was not blocked
circulating half-life (Kieffer et al. 1995), it is likely that byperipheralexendin9–39.ThesedataindicatethatGLP-1
y
og only a small amount of gut-derived GLP-1 reaches the releasedbytheintestineactsasaphysiologicalsatietysignal
nol brain. Therefore, it is unclear whether peripherally by activating peripheral GLP-1 receptors, whereas central
ri
oc released GLP-1 needs to enter the brain to affect food GLP-1affectsfeedingthroughGLP-1receptorsinthebrain.
d
n intake, or whether other routes of action are involved Interestingly, these findings also imply that the anorectic
E
of in its effects on feeding behaviour. Based on in situ effectsofperipheralGLP-1donotdependoncentralGLP-1
nal hybridisation experiments, preproglucagon-encoding receptors. However,giventhe previouslymentioneddata,
r
ou mRNA was found in a single population of neurons it seems likely that the GLP-1 systems in the CNS and in
J
in the caudal portion of the NTS, indicating that local the periphery work together in the regulation of feeding
GLP-1 synthesis in the brainstem which could serve to behaviour.
amplify peripherally generated GLP-1 signals (Larsen BecauseGLP-1receptorshavebeenobservedonvagal
et al. 1997). However, more recent work has shown fibres (Vahl et al. 2007), it has been suggested that the
that after i.p. administration of exendin-4 in male rats vagalnerveplaysanimportantroleinthecommunication
the majority of GLP-1-containing neurons in the NTS between gut and brain. This hypothesis was supported
werenotc-Fos-positive(Guetal.2013).Interestingly,i.p. by experiments with vagotomised animals. The effects
administration of exendin-4 resulted in extensive c-Fos of i.p. injected GLP-1 on food intake and activation of
expression in regions where a high density of GLP-1- hypothalamic ARC feeding neurons were abolished after
immunoreactive terminals originating from the NTS bilateralsubdiaphragmatictotaltruncalvagotomyaswell
were localised. Therefore, it remains undetermined as after brainstem–hypothalamic pathway transectioning
whether the GLP-1-containing neurons in the NTS inrats(Abbottetal.2005).However,theseexperimentsdid
have a role in amplifying or relaying gut-derived GLP-1 not allow the identification of the exact portion of
signals to the central GLP-1 networks. the vagal nerve (intestinal or hepatic) involved in the
TherelativeimportanceofperipheralvscentralGLP-1 GLP-1-mediatedeffects.Gut-derivedGLP-1diffusesacross
networks for control of satiety was studied in mice by thebasallaminaofthegutintothelaminapropria,where
acute peripheraland central administration of exendin-4 theuptakebycapillariesandthedegradationbyDPP-4take
and the large GLP-1–albumin fusion protein albiglutide place.Only25%ofthegut-derivedGLP-1reachestheportal
(Albugon),whichisunabletocrosstheblood–brainbarrier circulationand10–15%ofthesecretedamountleavesthe
(Baggio et al. 2004a). Exendin-4 and albiglutide both liverandentersthesystemiccirculation(Holst&Deacon
reduced glycaemic excursions, which inhibited food 2005). As the portal circulation has the highest GLP-1
intake and gastric emptying after peripheral as well as levels, vagal afferents in the portal branch may be an
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ThematicReview LVANBLOEMENDAAL,JSTENKULVE EffectsofGLP-1onappetiteand 221:1 T10
andothers bodyweight
important site of action of GLP-1. Indeed, intraportal Functional magnetic resonance imaging (fMRI) is
infusion of DPP-4 inhibitor was shown to suppress food currently used to assess neuronal activation in a resting
intake in rats and to increase c-Fos expression in several state, but also in response to different tasks or stimuli.
areas of the brain and these responses were blocked by Intragastric nutrient infusion in male rats reduced fMRI-
hepaticvagotomy(Fujiwaraetal.2012).Moreover,itwas measured activation in homeostatic (hypothalamus and
shownthatfoodintakesuppressioninducedbyi.p.GLP-1 NTS) and non-homeostatic (cortico-limbic) brain areas
wasbluntedinratswithcompletesubdiaphragmaticvagal andtheseeffectswereinverselycorrelatedwithcirculating
deafferentation, but not in rats with selective ablation of GLP-1 plasma concentrations (Min et al. 2011). Injection
thecommonhepaticbranchofthevagalnerve(Hayesetal. of GLP-1 i.p. into fasted mice reduced fMRI signal
2011).Theseresultsunlikethatthehepaticbranchofthe intensity in the PVN, increased signal intensity in the
vagusisnottheonlyrouteviawhichGLP-1induceseffects VMHandresultedinnoalterationsintheARC.Adlibitum
on food intake. There may be paracrine-like GLP-1 fed rats (without exogenous GLP-1 administration) also
signallingonGLP-1receptorsexpressedonvagalafferents showedareducedactivationinthePVN,butaswellasin
innervatingthegastrointestinaltractandactionsofGLP-1 theARC, andelicitednochanges intheVMH (Chaudhri
in the portal area as well as on gastrointestinal vagal et al. 2006). Taken together, this indicates that feeding-
afferents may reduce food intake. Recently, truncally inducedchangesinPVNactivitymayberelatedtoGLP-1.
vagotomised male subjects showed no reduction in ad Ad libitum feeding resulted in a decrease in ARC signal
libitumfoodintakeduringexogenousi.v.GLP-1adminis- intensitythatcouldnotbereplicatedbyexogenousGLP-1
tration, unlike healthy control subjects (Plamboeck et al. infusions,indicatingthatchangesinARCactivityduring
2013). Similar to rodents, these findings indicate an feedingprobablyresultfromothersignalsthanGLP-1.
involvement of vagal afferent signalling in peripheral The effects of GLP-1 infusion on fMRI-measured
y
og GLP-1-mediatedregulationoffeedinginhumans. neuronal activity have also been studied in humans
nol Inconclusion,effectsofGLP-1intheCNSmaybedue (DeSilvaetal.2011).Inhealthynormal-weightindividuals
ri
oc to both direct and indirect routes of action. However, (11malesandfivefemales),themeanfMRIsignalchange
d
n it seems that GLP-1 more probably exerts its actions on was described in a priori selected brain regions involved
E
of the brain by indirect pathways, i.e. via vagal afferents inrewardprocessingandhedonicfeeding(dorsalstriatum,
nal originating in the intestine and portal circulation. NAc, insula, amygdala and orbitofrontal cortex). Mean
r
ou However, additional information regarding the activity in these regions was attenuated when viewing
J
interaction between the various circuits involved is food pictures in the fed as compared with the fasted
neededinfuturestudies. state. Interestingly, GLP-1 infusion in the fasted state
attenuated neuronal activity to an extent similar to that
observed after feeding. The effect of exenatide vs saline
infusiononhypothalamicconnectivitywasstudiedusing
GLP-1effectsonfood-relatedbrainresponses;
fMRI in obese males and ‘responders’ (i.e. those who
neuroimaging studies
showedreductioninadlibitumfoodintakeafterexenatide
With the development of neuroimaging techniques, infusion)vs‘non-responders’werecompared(Schlogletal.
recent studies substantiate the effects of GLP-1 on brain 2013).Duringscanning,differentpictures(foodandnon-
areas related to feeding, in both animals but particularly food) were presented and subjects were asked to rate the
inhumansinvivo.Anobservationalstudyusing15O-water picturesfortastiness.Whileratingthefoodpictures,only
PET for cerebral blood flow (CBF) measurement showed the group of responders showed a higher connectivity of
that the postprandial increase in GLP-1 concentration the hypothalamus during exenatide infusion compared
correlatedwiththepostprandialregionalCBFincrements with placebo. Connectivity is a proxy for the influence
in the hypothalamus and left dorsolateral prefrontal of this brain region on the rest of the brain. The effect
cortex(Pannacciullietal.2007).Using18FDGPET,GLP-1 of exenatide on connectivity was not observed in the
infusion in lean individuals reduced glucose metabolism non-responder group nor in the responder group while
inthehypothalamusandbrainstem(Alvarezetal.2005). rating non-food pictures, supporting the hypothesis of a
These findings demonstrate that exogenous GLP-1 is hypothalamic exenatide effect specific to states when
associated with altered cerebral glucose metabolism, but networksofappetiteandfeedingcontrolareactive.
therelationshipofthesecerebralchangeswithfoodintake Taken together, these studies indicate that periph-
andappetiteisnotclear. erally administered GLP-1 affects brain activity in areas
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