Review Article Obesity and Appetite Control - Hindawi Publishing Corporation

20 Pages·2014·1.38 MB·English

HindawiPublishingCorporation
ExperimentalDiabetesResearch
Volume2012,ArticleID824305,19pages
doi:10.1155/2012/824305
Review Article
Obesity and Appetite Control
KeisukeSuzuki,ChannaN.Jayasena,andStephenR.Bloom
SectionofInvestigativeMedicine,ImperialCollegeLondon,CommonwealthBuilding,DuCaneRoad,LondonW120NN,UK
CorrespondenceshouldbeaddressedtoStephenR.Bloom,[email protected]
Received15March2012;Accepted20June2012
AcademicEditor:BernardThorens
Copyright©2012KeisukeSuzukietal.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,
whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Obesity is one of the major challenges to human health worldwide; however, there are currently no effective pharmacological
interventions for obesity. Recent studies have improved our understanding of energy homeostasis by identifying sophisticated
neurohumoralnetworkswhichconveysignalsbetweenthebrainandgutinordertocontrolfoodintake.Thehypothalamusisa
keyregionwhichpossessesreciprocalconnectionsbetweenthehighercorticalcentressuchasreward-relatedlimbicpathways,and
thebrainstem.Furthermore,thehypothalamusintegratesanumberofperipheralsignalswhichmodulatefoodintakeandenergy
expenditure.Guthormones,suchaspeptideYY,pancreaticpolypeptide,glucagon-likepeptide-1,oxyntomodulin,andghrelin,are
modulatedbyacutefoodingestion.Incontrast,adipositysignalssuchasleptinandinsulinareimplicatedinbothshort-andlong-
termenergyhomeostasis.Inthispaper,wefocusontheroleofguthormonesandtheirrelatedneuronalnetworks(thegut-brain
axis)inappetitecontrol,andtheirpotentialsasnoveltherapiesforobesity.
1.Introduction In addition to local paracrine actions and peripheral
endocrine effects mediated through the bloodstream, gut
Despite recent progress in our understanding of the phys- hormonesplayapivotalrolerelayinginformationonnutri-
iological mechanisms regulating body weight and energy tionalstatustoimportantappetitecontrollingcentreswithin
expenditure, obesity remains a major worldwide health thecentralnervoussystem(CNS),suchasthehypothalamus
crisiswithanarrayofvascular,metabolic,andpsychosocial andthebrainstem.
consequences[1,2].Overweightorobeseindividuals(body In this article, we will summarise our current under-
mass index 25–30) have an increased risk of developing standing of the physiological interactions between the gut
diabetes, coronary heart disease, and hypertension [2, 3]. andbrain,termedthe“gut-brainaxis,”focussingparticularly
Adults with a body mass index of 40 or higher have been ontheinteractionsofguthormoneswiththeCNSandvagus
associatedwithahighriskofdevelopingdiabetes,hyperten- nerve[6].Wewillnotdiscusssignaltransductionpathways,
sion,dyslipidaemia,asthma,arthritis,andpoorhealthstatus, enteric nervous systems related to controlling food intake,
whencomparedwithnormalweightindividuals[4]. or neural signalling pathways in organs associated with the
Bodyweightistightlyregulatedbycomplexhomeostatic gastrointestinaltractsuchasliverorpancreas.
mechanisms. Obesity is a state in which energy intake
chronically exceeds energy expenditure. Even a subtle mis-
match(lessthan0.5%)incaloricintakeoverexpenditureis 2.GutHormones
sufficient to cause weight gain [5]. The rising prevalence of
obesityislikelytoresultfromcontemporaryenvironmental 2.1.PancreaticPolypeptide-FoldPeptides. ThePP-foldfamily
and lifestyle factors such as increased access to palatable comprises neuropeptide Y (NPY), peptide YY (PYY), and
foodsandreducedrequirementsforphysicalexercise,when pancreaticpolypeptide(PP).Theyarecomposedofachain
compared with ancient hunter-gatherer lifestyles charac- of 36 amino acids residue and share amino acid homology,
terisedbyunpredictableperiodsoffeastandfamine. amidatedC-terminalends.ThetertiarystructurePP-foldis
2 ExperimentalDiabetesResearch
Ushapedwithanextendedpolyprolinehelixandanαhelix nervosa when compared withcontrol subjects[24]. Studies
connectedbyaβturn[7].Inaddition,ahairpin-likePP-fold of circulating levels of PYY in obese and lean people have
motifisvitalforreceptorbinding.PYYandPParesecreted yielded inconsistent results [25, 26]; however, a blunted
from gastrointestinal tract, whereas NPY is predominantly, postprandialriseinPYYinobesesubjectssuggestsapossible
widelydistributedinCNS[8].ThisfamilyactsviaGprotein- associationwithimpairedpostprandialsatietyduringobesity
coupledreceptors;Y1,Y2,Y4,Y5,andY6[9].TheY3receptor [21].
hasnotyetbeencloned,andtheY5receptorhasbeenfound PYY exerts anorectic effects via a direct action in
3–36
asanonfunctionaltruncatedform. thehypothalamicarcuatenucleus(ARC).Peripheraladmin-
istration of PYY increases c-fos expression (a marker
3–36
2.2.PeptideTyrosineTyrosine(PYY). PYYisanappetitesup- of neuronal activation) in the ARC and direct injection of
pressing hormone, which was isolated originally from PYY intotheARCinhibitsfoodintake.Thiseffectislikely
3–36
porcine upper small intestine [8]. Its name is derived from to be mediated through the Y2 receptor since the anorectic
its characteristic tyrosine (Y) residues at both the C and N effect of peripheral PYY administration is blocked in
3–36
terminals.PYYisreleasedfromtheLcellsofthedistalgutin Y2 receptor-null mice, and intraarcuate injection of a Y2
responsetoingestednutrientswithtwootherguthormones, receptor selective agonist also supresses food intake [16].
GLP-1 and OXM. PYY immunoreactivity is highest in the Although conflicting results have been reported [27], the
rectum, and decreases proximally to low levels in the duo- vagal-brainstem may also signal the actions of PYY on
denumandjejunum.PYYimmunoreactivityisalsofoundin food intake. Two independent laboratories have observed
the CNS regions such as the hypothalamus, medulla, pons, that vagotomy abolishes anorexia c-fos activation following
and spinal cord [10]. Two endogenous circulating forms, peripheralPYY administration[28,29].
3–36
PYY andPYY ,aresynthesizedwithinthegut.PYY Incontrasttotheanorecticeffectsobservedbyperipheral
1–36 3–36 1–36
is the biologically active major circulating form, which is andintraarcuatePYY administration,directadministra-
3–36
produced by cleavage of the N-terminal tyrosine-proline tion of PYY into the third ventricle of the brain [30] or
3–36
residues from PYY by the enzyme dipeptidyl-peptidase paraventricularnucleus(PVN)[31]increasesinfoodintake.
1–36
IV (DPP-IV) [11]. PYY has affinity to all Y receptors, This paradoxical action may be explained by considering
1–36
whilePYY actsmainlyviathehigh-affinityhypothalamic that such effects might be endogenously mediated by the
3–36
Y2receptor. orexigenicCNS-distributedpeptide,NPY,throughanaction
The PYY secretion pattern suggests a role in satiety. on Y1 receptor and Y5 receptors [32]. PYY may also act in
Circulating PYY concentrations are low in fasted state and thebrainareasotherthanthehypothalamusandbrainstem.
increase rapidly following a meal with a peak at 1-2 hours In a clinical study using functional MRI by Batterham et
and remain elevated for several hours [12]. PYY release is al. [33], PYY infusion modulated neural activity within
3–36
increased in proportion to calorie intake [12]. PYY may corticolimbicandhighercorticalbrainregions.
have a role in the pathogenesis of a number of anorectic ExogenousPYY andexendin-4,aGLP-1receptor
conditionssuchasinflammatoryboweldisease,steatorrhea, agonist, have syner3g–i3s6tiNcHe2ffects to suppress food intake in
tropical sprue, and cardiac cachexia, since plasma PYY mice [34]. Furthermore a recent study utilizing functional
levels are elevated in patients with these conditions [13– MRIbyDeSilvaetal.[35]showedthatcoadministrationof
15]. Peripheral PYY administration shows a reduction PYY andGLP-1 tofastedhumansubjectsresults
3–36 3–36 7–36amide
in food intake and body weight gain in rats [16]. In both insimilarreductionsinsubsequentenergyintakeandbrain
leanandobesehumansubjects,intravenousadministration activity,asobservedphysiologicallyfollowingfeeding.
of PYY reduces appetite and food intake [16, 17] with NeuropeptideY2receptorshavecardiovasculareffectsin
3–36
observed plasma PYY levels similar to the physiological additiontotheirmetaboliceffects.Y2agonismisimplicated
3–36
levels after a meal; this data suggests that the physiological inthepathogenesisofhypertensioninhypertensiverats[36].
effectofPYYistosuppressfoodintake.Ofnote,nonausea Nordheim and Hofbauer [37] reported that Y2 receptor
was reported in subjects following PYY administration. stimulation by PYY demonstrated cardiovascular effects
3–36 3–36
Thissuggeststhat,unlikeleptin,thesensitivityofsubjectsto of endogenous NPY in rats on different dietary regimens.
PYYispreservedinobesesubjects.Someinvestigatorsfailed In food-restricted rats, PYY increased mean arterial
3–36
toshowananorecticeffectofPYY,possiblyduetoinadequate pressure and heart rate, whereas PYY did not influence
3–36
acclimatizationofcontrolandtreatedanimals[18]. mean arterial pressure and heart rate in high-fat diet rats.
The “ileal brake” is the negative feedback mechanism However,humanstudiesthusfarhavenotdemonstratedany
in which the presence of nutrients into the colon inhibits hypertensivechangesasaresultofPYYadministration.
motility and transit of further nutrients within the upper
gastrointestinaltract[19].Fatisknowntobethemostpotent 2.3.PancreaticPolypeptide(PP). PPissecretedfromPPcells
triggeroftheilealbrake.GLP-1andPYYmaycontributeto inthepancreaticisletsofLangerhansinresponsetoameal.
thisphenomenon[20]. AnorecticeffectsofPParethoughttobemediatedbydirectly
PYY has been reported to regulate energy expenditure, throughtheY4receptorinthebrainstemandhypothalamus.
delay gastric emptying, reduce acid secretion, and inhibit In addition, it may act also via the vagus nerve, as the
gallbladder contraction and pancreatic exocrine secretions anorecticeffectsofPPareabolishedbyvagotomyinrodents
[21, 22]. Circulating PYY levels are low in obese subjects [38]. PP has a high affinity for the Y4 receptor, of which
[17, 23], and they are higher in patients with anorexia expression is found in the area postrema (AP), nucleus
ExperimentalDiabetesResearch 3
of the tractus solitarius (NTS), dorsal motor nucleus of In addition, GLP-1 is distributed within the CNS.
7–36amide
vagus (DVN), ARC, and PVN [39]. An autoradiography Immunoreactive neurons for GLP-1 are located
7–36amide
study also identified saturable PP binding sites at the in the PVN, DMN, NTS, dorsal vagal complex (DVC),
interpeduncularnucleus,AP,NTS,andDVN[40].LikePYY, pituitary, and thalamus [57]. GLP-1 receptor mRNA is
paradoxical effects on food intake are observed following distributedthroughouttherostrocaudalhypothalamus,with
PP injection, depending on its route of administration. In denseaccumulationintheARC,PVN,andsupraopticnuclei
contrast to the anorectic effects observed with peripheral [58].WhileperipheraladministrationofGLP-1inratsleads
PP administration, central PP administration stimulates to increased c-fos expression in the ARC [28], intracere-
food intake [41]. Although the exact mechanism of this broventricular (ICV) administration results in increased c-
phenomenon is unclear, these differential effects may be fos expression in the PVN, NTS, and AP [59]. Ascending
mediated by activation of distinct populations of receptors. NTS-PVNprojectionscontainGLP-1[60]areimplicatedin
PP also has other physiological effects, such as delaying controllingfoodintake.IntheCNS,leptinreceptor(Ob-Rb)
gastricemptying,attenuatingpancreaticexocrinesecretion, was expressed in GLP-1-containing neurons in the NTS in
andinhibitinggallbladdercontraction[42]. animals and leptin activated GLP-1 containing neurons in
PlasmaPPlevelsshowdiurnalvariations:lowestlevelsare the NTS [61]. Signals arising from the hepatoportal GLP-
observed in the early morning and highest in the evening. 1R promote glucose clearance, which are independent of
The release of postprandial PP is biphasic. Circulating PP changesininsulinsecretion[62,63].
concentrations increase after a meal in proportion to the GLP-1 exerts its effect by activation of the GLP-1R
caloric intake, and increased levels remain for up to 6 to stimulate adenylyl cyclase activity and thereby cAMP
hours postprandially [43]. Circulating PP levels seem to be production [64]. GLP-1R is widely distributed particularly
inverselyproportionaltoadiposity;higherlevelsarereported in the brain, gastrointestinal tract, and pancreas [64, 65].
in subjects with anorexia nervosa [44]. Some, but not all In the brain, binding sites for GLP-1Rs have been found in
[45, 46], studies have demonstrated significant reductions thehypothalamus,striatum,brainstem,substantianigra,and
in circulating levels of PP in obese subjects [47, 48]. subventricular zone among other structures [64, 66]. GLP-
Furthermore, obese patients with Prader-Willi syndrome 1Rs are present on both glia and neuronal cell types [66].
(PWS) have been reported to have reduced PP release both In addition, GLP-1Rs are expressed in the nodose ganglion
basallyandpostprandially[49]. [67]. Furthermore bilateral subdiaphragmatic total truncal
Inmice,acuteandchronicperipheralPPadministration vagotomyorbrainstem-hypothalamicpathwaytransetioning
resultsinreducedfoodintake.Inleptin-deficientob/obmice, abolishes the suppressing actions of GLP-1 on food intake
repeatedintraperitonealPPinjectiondecreasesbodyweight [28];thissuggeststhatthevaguscontributestotheactionsof
gain and improves insulin resistance and hyperlipidaemia GLP-1onfoodintake.
[38]. Furthermore, transgenic mice overexpressing PP have Circulating GLP-1 levels rise postprandially and fall in
reduced food intake when compared with wild-type con- the fasted state. Recent evidence also suggests that GLP-
trols [50]. In normal-weight human subjects, intravenous 1 levels rise in anticipation of a meal [68]. GLP-1 not
infusion of PP achieved three times higher circulating PP only reduces food intake, but also suppresses glucagon
concentrations when compared with postprandial levels in secretion and delays gastric emptying [69]. Intravenous
the same subjects after a buffet lunch (which reduced food administrationofGLP-1isassociatedwithadose-dependent
intakeby25%over24hours)[51].Furthermore,twice-daily reduction of food intake in both normal weight and obese
infusion of PP in volunteers with PWS resulted in a 12% subjects[70],althoughobesesubjectsmaybelessresponsive
reduction in food intake [52]. Agonists to the Y4 receptor [64].
designedtomimictheactionsofPPhavebeendevelopedand GLP-1possessesapotentincretineffectinadditiontoits
are under further investigation as potential novel therapies anorecticaction;itstimulatesinsulinsecretioninaglucose-
forobesity. dependent manner following ingestion of carbohydrate.
However, its use as obesity treatment was limited for many
yearsbyitsshortplasmahalf-lifeof1-2minutes[71],which
2.4. Proglucagon-Derived Peptides. The proglucagon gene is
ispartlyattributedtoenzymaticdegradationbyDPP-IVand
expressedinthepancreas,intheL-cellsofthesmallintestine
renal clearance that rapidly inactivate and remove GLP-1
and in the NTS of the brainstem [53, 54]. GLP-1, GLP-
fromplasmacirculation[72,73].Continuoussubcutaneous
2, OXM, and glucagon are proglucagon-derived peptides.
infusionofGLP-1topatientswithtype2diabetesfor6weeks
Glucagonisthemainproductinthepancreas,whereasOXM,
reducesappetite,andbodyweight,andimprovesglycaemic
GLP-1, and GLP-2 are the major products in the brain and
control [74]. However, DPP-IV-resistant analogues of GLP-
intestine[55].
1 have been developed. Exendin-4 (exenatide), a naturally
occurring peptide originally isolated from the saliva of the
2.4.1.Glucagon-LikePeptide-1(GLP-1). GLP-1iscosecreted Gila monster lizard, is a DPP-IV-resistant GLP-1R agonist
with PYY from the L cells in the intestine in response to [75]. Exenatide improves glycaemic control and decreases
nutrientingestion.GLP-1hastwobiologicallyactiveforms, body weight in patients with type 2 diabetes. [76]. GLP-1
GLP-1 and GLP-1 . The latter truncated form possesses trophic effects on pancreatic beta cells in animal
7–37 7–36amide
is the major circulating form in humans, although both models[77].GLP-1andexendin-4havebeenrecentlyshown
active isoforms of GLP-1 have equivalent potency [56]. topromotecellulargrowthandreduceapoptosisinnervous
4 ExperimentalDiabetesResearch
tissues[78],buttrophiceffectsonpancreaticbetacellshave in response to hypoglycaemia. Glucagon enhances the
not been demonstrated clinically in human subjects. GLP- body’sphysiologicalresponsetostress,byincreasingenergy
1 agonists are, therefore, a good example of how research expenditure[95,96].However,glucagonadministrationalso
in this area has been translated into clinical practice. A decreases food intake, possibly by modulating vagal tone
three-year duration of treatment with exenatide has been andgastricemptying[97,98].Schulmanetal.[99]reported
reported to improve beta cell function; however, when that glucagon reduces food intake and body weight but
adjusting for weight loss associated with exenatide therapy, caused hyperglycemia. However, the administration of the
thiseffectremainsspeculative[79].DPP-IVinhibitors,such dualagonistsstimulatingbothglucagonandGLP-1receptors
as sitagliptin and vildagliptin, which are licensed for the achieved improvement of diet-induced obesity and glucose
treatmentoftype2diabetes,donotresultindecreaseinbody intolerance [100, 101]. It is, therefore, plausible that dual
weight. This may be explained by considering that DPPIV agonism of glucagon and GLP-1 receptors may offer novel
is also involved in the modification of other gut hormones targetsforantiobesitytreatment.
suchasPYY,andcytokineswhichmayhaveoppositeeffects
toGLP-1[80].
GLP-1-based therapies are promising novel treatments 2.5.Ghrelin. Ghrelinwasidentifiedoriginallyasanendoge-
for type 2 diabetes, however, long-term outcome data nous ligand for the growth hormone secretagogue receptor
are not yet available. The reported side effects of GLP-1 (GHS-R) in rat stomach [102]. Ghrelin comprises a chain
agonistsarenauseaandvomiting.Animalsafetystudieswith of 28 amino acids with esterification of the hydroxyl group
liraglutide have identified C-cell carcinoma of the thyroid. of the third serine residue by octanoic acid, and it is the
Acutepancreatitishasbeenreportedinhumanstreatedwith only known orexigenic gut hormone. Ghrelin is principally
liraglutide or exenatide [81]. Further outcome data will, secreted from X/A-like cells within gastric oxyntic glands
therefore, be important in confirming the long-term safety [103]. In keeping with this, gastrectomy results in an 80%
ofGLP-1-basedtherapies. reductionofplasmaghrelinlevels;theremainderissecreted
from the intestine, pancreas, pituitary, and colon [104].
Ghrelin also acts as a neurotransmitter, being expressed
2.4.2. Oxyntomodulin (OXM). OXM is a 37-amino acid
withintheARCandperiventricularareaofthehypothalamus
peptideoriginallyisolatedfromporcinejejunoilealcellsand
[102,105].
is found to show glucagon-like activity in the liver [82].
Serum ghrelin levels are increased by fasting and
OXM is another product of the proglucagon gene and is
decreased by refeeding or oral glucose administration, but
cosecreted with GLP-1 and PYY by the L-cells of the distal
they are not decreased by water ingestion [106]. In rats,
gastrointestinal tract, in response to ingested food and in
ghrelinlevelsshowadiurnalpattern,withthebimodalpeaks
proportiontocaloricintake[83].OXMhasanorecticeffects
occurring before dark and light periods [107]. In humans,
andshowsincretinactivitywithamuchlowerpotencywhen
ghrelin levels have a diurnal rhythm which is identical to
compared with GLP-1 [84]. OXM also inhibits gastric acid
the diurnal rhythm of leptin, with both hormones rising
secretionanddelaysingastricemptying[85].
throughout the day to a zenith at 0100h, then falling
Administration of OXM is associated with decreased
overnighttoanadirat0900h[108].
foodintakeandincreasesenergyexpenditureinbothrodents
Levels of circulating ghrelin rise preprandially and fall
andhumans[86–88].TheanorecticeffectofOXMisblocked
rapidly in the postprandial period [108]. Both central and
by the GLP-1R antagonist, exendin [89], and is not
9–39 peripheral administration of ghrelin increase food intake
observed in GLP-1R null mice [90]; this suggests that the
andbodyweightalongwithareductioninfatutilisationin
anorectic effects of OXM may be mediated by the GLP-1R.
rodents[106,109].Negativecorrelationsbetweencirculating
However, OXM has relatively low in vitro affinity for the
ghrelin levels and body mass index are found in human.
GLP-1R which is 50 folds lower than the affinity of GLP-
Fasting plasma levels of ghrelin are reported to be high in
1 for GLP1R, despite the anorectic potency of OXM being
patientswithanorexianervosa[110]andsubjectswithdiet-
comparable to the potency of GLP-1 [91]. Several actions
induced weight loss [111]. In contrast, obese subjects show
of OXM seem independent of the GLP-1R [87, 92, 93];
a less marked drop in plasma ghrelin after meal ingestion
the cardiovascular effects of OXM are preserved in GLP-
[112]. In patients with heart failure, increased levels of
1R knockout mice [92]. These data suggest that a further
plasma ghrelin are reported in cachectic patients when
receptor through which OXM mediates its anorectic effect
compared with noncachectic patients [113]. Furthermore,
hasyettobeidentified. Furthermore,directadministration
in patients with PWS, elevated circulating ghrelin levels are
of the GLP-1R antagonist, exendin , to the ARC fails to
9–39 found,whencomparedwithindividualswithnonsyndromic
inhibit the anorectic effects of OXM but inhibits that of
formsofobesity[114].
GLP-1 [87]. Like GLP-1, OXM is inactivated by DPP-IV.
Ghrelin mediates its orexigenic action via stimulation
OXM analogues resistant to DPP-IV degradation are being
ofNPY/agouti-relatedpeptide(AgRP)coexpressingneurons
developedaspotentialobesitytreatments[94].
withintheARCofhypothalamus.Peripheraladministration
ofghrelinincreasesc-fosexpressionintheARCNPY/AgRP
2.4.3.Glucagon. Theroleofglucagoninglucosehomeostasis neurons[115]andablationofbothAgRPandNPYneurons
is well established; glucagon is produced by alpha cells of completely abolishes the orexigenic effect of ghrelin [116].
the pancreatic islets and increases glucose concentration The brainstem and vagus nerve may also contribute to the
ExperimentalDiabetesResearch 5
effects of ghrelin on food intake. ICV injection of ghrelin 2.8.Amylin. Amyliniscoreleasedwithinsulininresponseto
induces c-fos expression in the NTS and AP [117]. GHS-R mealingestion,anditmayfunctionasananorectichormone.
is found to be expressed in the vagus nerve. Furthermore, Circulatinglevelsofamylinarefoundtobehigherinobese
blockade of gastric vagal afferents in rats abolishes ghrelin- than lean subjects [133, 134]. Administration of amylin
inducedfeedingandpreventstheghrelin-inducedriseinc- is associated with reduced food intake and body weight
fosexpressionwithintheARC[118].Inadditiontoitspotent [135]. The anorectic effects of amylin may be mediated
orexigenic property, ghrelin also increases gastric motility, by modulating activity of the serotonin, histamine, and
upstimulates the hypothalamo-pituitary-adrenal axis, and dopaminergic system in the brain as well as inhibition
possesses cardiovascular effects such as vasodilatation and of NPY release [133]. Administration of pramlintide, a
enhancedcardiaccontractility[104]. synthetic analogue of human amylin, improves glycaemic
Ghrelin may promote food intake in part by enhancing control and causes weight loss in type 2 diabetes patients
the hedonic responses to food cues, which is demonstrated using insulin [136]. Therefore, amylin replacement with
by the recent study by Malik et al. [119]. In their study, pramlintide as an adjunct to insulin has been reported as
functional MRI was performed during exposure to food a novel physiological approach toward improved long-term
pictures, and the study results demonstrated increased glycaemicandbodyweightcontrolinpatientswithdiabetes
activation in the amygdala, orbitofrontal cortex, anterior [137].
insula,andstriatum,duringintravenousinfusionofghrelin.
3.PeripheralAdipositySignals
2.6. Obestatin. Obestatin is a 23-amino acid peptide hor-
mone which is derived from posttranslational cleavage of 3.1.Insulin. Circulatinglevelsofinsulinandleptinpositively
preproghrelin, and released from the stomach [120]. In correlate with adipose tissue mass within the body. Both
contrasttoghrelinwhichhasorexigenicproperties,obestatin insulinandleptinareimplicatedinthelong-termregulation
may have anorectic effects by decreasing food intake, of energy balance. Insulin is synthesized in the ß cells of
delaying gastric emptying, and reducing body weight in thepancreasandissecretedrapidlyafterameal,withwell-
rodents[121].However,thepotentialanorecticofobestatin characterisedhypoglycaemiceffects[138].However,insulin
remainscontroversial,sinceotherinvestigatorshavefailedto alsoactsasananorecticsignalwithintheCNS.ICVadmin-
demonstrateeffectsonfoodintakeinleanorobeserodents istration of insulin results in a dose-dependent suppression
[122]. offoodintakeandbodyweightgaininbaboonsandrodents
[139, 140]. Intrahypothalamic insulin injection to the PVN
alsoresultsindecreasedfoodintake[141].Insulinentersthe
2.7.Cholecystokinin(CCK). CCKwasthefirstguthormone CNS through a saturable and receptor-mediated transport
found to be implicated in appetite control [123]. CCK is process [142]. Insulin receptors are widely expressed in the
secreted postprandially by the I cell of the small intestine brain,particularlyinhypothalamicnuclei,suchastheARC,
intocirculation[124],withashortplasmahalf-lifeofafew DMN, and PVN, which are involved in control of food
minutes. Plasma CCK levels rise within 15 minutes after intake [143]. Although the mechanism of insulin-mediated
mealingestion[124].InfusionofC-terminaloctapeptideof anorexia has not been fully elucidated, hypothalamic NPY
CCKdecreasedfoodintakein12leanmen[125].However, seemstobeinvolved.ICVadministrationofinsulininhibits
intermittent prandial CCK infusion reduces meal size in thefasting-inducedincreaseinNPYmRNAexpressioninthe
rats but causes a compensatory increase in meal frequency PVN and ARC in rats. This suggests that fasting increases
[126].A2-weekcontinuousintraperitonealinfusionofCCK NPY biosynthesis through an ARC-PVN pathway in the
failed to suppress food intake at any time point [127]. hypothalamusviaamechanism whichisdependentonlow
Other physiological functions of CCK include stimulating insulinlevels[144].
the release of enzymes from the pancreas and gall bladder,
promotingintestinalmotility,anddelayinggastricemptying.
There are two CCK receptor subtypes known; CCK1 and 3.2. Leptin. Leptin is the product of the ob gene, and it is
CCK2receptors,previouslyclassifiedasCCKAandCCKB. predominantlysecretedbyadipocyteswithcirculatinglevels
TheanorecticactionofCCKappearstobemostlymediated proportional to fat mass [145]. Levels of circulating leptin
via CCK1 receptors on the vagal nerve [128, 129]. CCK 1 haveadiurnalandpulsatilepattern,withpeaklevelsatnight
and2receptorsarewidelydistributedinbrainincludingthe [146]. Leptin is transported across the BBB by a saturable
brainstemandhypothalamus[130]. transportersystem[147],anditexertsitsanorecticeffectvia
Some studies suggest that leptin and CCK may interact theARC,wherebothNPY/AgRPandpro-opiomelanocortin
synergisticallytoinduceshort-terminhibitionoffoodintake (POMC)/cocaine- and amphetamine-regulated transcript
and long-term reduction of body weight [131]. Leptin- (CART) neurons express leptin receptors [148]. Leptin
deficientmiceareinsensitive tothemeal-terminatingeffect inhibits NPY/AgRP neurons and activates POMC/CART
ofCCKadministration.Furthermore,leptinsignallingpath- neurons [149, 150], resulting in reduced food intake [149]
ways to brain are dampened in the absence of interaction and increased energy expenditure [151]. The effects of gut
with CCK release after a meal or in the setting of CCK-A satiation signals such as CCK can be amplified by leptin
receptorblockade[132]. whichactsintheCNS,includingtheARCinparticular[152].
6 ExperimentalDiabetesResearch
Therearethreetypesofleptinreceptorsidentified:long, Cleavageofaprecursorprotein,calledPOMC,produces
short,andsecretedform[153].Amongthose,Ob-Rbrecep- α-melanocyte-stimulating hormone (α-MSH), which binds
tor, which is highly expressed in the hypothalamus [154], to melanocortin-3 receptor (MC3R) and melanocortin-4
is thought to act as the main receptor involved in appetite receptor(MC4R)tosuppressfoodintake[167].TheMC4R
control.Thedb/dbmouse,withaninactivatingmutationin is highly expressed in the hypothalamus and is thought to
theOb-Rbreceptor,hasanobesephenotype[155,156],and have a major role in suppressing food intake compared to
leptin-deficientob/obmiceexhibithyperphagiaandobesity, the MC3R. MC4R knock-out mice have hyperphagia and
whichcanbereversedbyleptinadministration[157]. obesity [167]. MC3R-deficient mice also have increased fat
Subcutaneous administration of recombinant leptin mass and reduced lean body mass [168]; however, selective
reduces fat mass, hyperinsulinaemia, and hyperlipidaemia MC3Ragonistsfailtosuppressfeeding[169].
in obese children with congenital leptin deficiency [158]. CART is the third most abundant transcript identified
However, obese individuals often have high leptin levels, within the hypothalamus and is mostly colocalized with
which result in a failure to respond to exogenous leptin. POMCintheARC.ICVadministrationofCARTsuppresses
Thisleptinresistanceseverelylimitsthetherapeuticutilityof feeding,whereasICVinjectionofCARTantiserumincreases
leptin,anditislikelytoresultfromreducedleptinreceptor foodintake[170].However,CARTinjecteddirectlyintothe
signaltransduction[159]oranimpairedabilityoftheBBB PVNorARCoffastedratscausesanincreaseinfoodintake
totransportleptin[160]. at 1-2 hours postinjection [171], which suggests opposing
effects of CART on food intake can be observed depending
on the site of administration. Hence, the physiological role
4.NeuralPathwaysRelatedto
ofCARTinenergyhomeostasisisunclear.
theAppetiteControl
NPY/AgRP neurons extensively project to the adjacent
hypothalamic nuclei, such as the PVN, DMN, and LHA.
Feeding and energy expenditure are controlled by com-
AgRPandNPYareexclusivelycolocalizedinARCneurons,
plex neural networks distributed throughout the forebrain bothofwhichexertorexigeniceffects[172].NPYisthemost
and brainstem. Reward-related neural brain regions have
abundant neuropeptide in the CNS [173]. ICV injection
been implicated in the nonhomeostatic control of feeding
of NPY stimulates food intake in rats [41] and repeated
behaviour[161].Bycontrast,homeostaticfeedingbehaviour
daily bilateral PVN injection of NPY for 10 days causes an
isintegratedwithinthehypothalamus.Keyperipheralsignals
approximately two-fold increase in daily food intake and
of energy status such as gut hormones and adipokines
a six-fold increase in the rate of body weight gain [174].
either signal to the hypothalamus directly or signal to
The orexigenic effect of NPY appears to be mediated by
the hypothalamus indirectly via the brainstem and vagal
afferent fibres. Adiposity signals such as insulin and leptin stimulationofhypothalamicY1andY5receptors.AGRPwas
isolatedbyitshigh-sequencehomologywiththeAgouticoat
are involved in the long-term energy homeostasis, and gut
colourgenewhichisassociatedwithyellowcoat,obesity,and
hormones such as PYY, GLP-1, PP, OXM, and ghrelin are
increased body length in mice. AgRP is a potent-selective
implicated in the short-term regulation of meal ingestion
[162–164]. antagonistattheMC3RandMC4R[175].
The PVN receives projections of NPY/AgRP and
POMC/CART from the ARC and contains neurons which
5.TheHypothalamus express the anorectic factors, thyrotropin-releasing hor-
mone,andcorticotropin-releasinghormone.Microinjection
Thehypothalamuscontrolsfeedingbyintegratingperipheral
oforexigenicoranorexigenicsignals,suchasghrelin,orexin-
humoral signals that influence food intake and energy
A, CCK, leptin, and GLP-1 into the PVN alter food intake
expenditure, with neural signals from the brainstem and
and body weight [163]. While ICV injection of NPY into
highercorticalcentres.Theimportanceofthehypothalamus
thePVNcauseshyperphagiaandobesity[174],destruction
inenergyhomeostasiswasfirstsuggestedbyclassiclesioning
of the PVN causes hyperphagia and obesity [176]. This
experiments in rodents [165]; subsequent studies have
finding implies that the PVN may have an inhibitory role
suggested a role of hypothalamic nuclei, such as arcuate
in food intake and body weight. The LHA also receives
nucleus (ARC), paraventricular nucleus (PVN), ventrome-
projectionsfromtheARCandcontainstwoorexigenicneu-
dial nucleus (VMN), dorsomedial nucleus (DMN), and
ropeptides, melanin-concentrating hormone (MCH), and
lateralhypothalamicarea(LHA)inenergyhomeostasis.
orexin (hypocretin). Transgenic mice overexpressing MCH
In the ARC, there are two important discrete neu-
develop obesity and insulin resistance [177]. Furthermore,
ronal populations: neurons which coexpress neuropeptide
transgenic mice which are deficient in the prohormone
Y (NPY) and agouti-related peptide (AgRP) stimulate food
intake,whereasneuronscoexpressingpro-opiomelanocortin precursor of MCH or the MCH 1 receptor are lean [178].
(POMC) and cocaine- and amphetamine-regulated tran- Hypocretins1and2areproducedbythegroupsofneurons
script (CART) suppress food intake (Figure1). The ARC in the LHA [179]. These neurons project extensively to
is located at the base of median eminence which may be theolfactorybulb,cerebralcortex,thalamus,hypothalamus,
accessed by circulating hormones likely due to its deficient brainstem, locus coeruleus, tuberomamillary nucleus, and
blood-brain barrier (BBB) [166] or by carrier-mediated raphenucleus.Inadditiontotheorexigeniceffectsonfood
transport. intake,orexinseemstoalsohavearoleinotherphysiological
ExperimentalDiabetesResearch 7
Higher brain centres
Hunger
ARC
Brainstem PVN ↑ONPreYx/iAgegnRi Pc ↓APOnoMreC x/iCgeAnRi cT
Brain
BBB Periphery
V
a
g
u
s
PP from PYY, GLP-1 Ghrelin
↓ pancreas ↓OXM from ↑ from
intestine stomach
Fasting/preprandial state
(a)
Higher brain centres
Satiety
ARC
PVN ↓Orexigenic ↑Anorexigenic
Brainstem NPY/AgRP POMC/CART
Brain
BBB
Periphery
V
a
g
us
PP from PYY, GLP-1 Ghrelin
↑pancreas ↑OXM from ↓ from
intestine stomach
Postprandial state
(b)
Figure1:Theguthormonesignallingtothebrainunderfasted(a)andfedstates(b).(a)Duringthefasting/preprandialstate,ghrelinrelease
fromthestomachactsupontheARCandvagustostimulatehunger.(b)Inthepostprandialstate,releaseofanorectichormones,PYY,GLP-1,
OXM,andPPfromintestineactupontheARC,brainstem,andvagustocausesatiety.ARC,arcuatenucleus;NPY/AgRP,neuropeptideYand
agoutirelatedpeptide;POMC/CART,pro-opiomelanocortin,andcocaine-andamphetamine-regulatedtranscript;PVN,paraventricular
nucleus;GLP-1,glucagon-likepeptide-1;PP,pancreaticpolypeptide;PYY,peptideYY;OXM,oxyntomodulin.
functions such as regulation of blood pressure, the neu- DMNlesionscausehyperphagiaandobesity,whichsuggests
roendocrinesystem,bodytemperature,andthesleep-waking a suppressive role in appetite [185]. In diet-induced mice,
cycle[180].Animpairmentofhypocretinneurotransmission an approximately 40-fold increase in NPY expression is
hasbeenassociatedwiththepathologyofhumannarcolepsy, observed in the DMN and VMN when compared with
which is a chronic sleep disorder characterized by excessive controls [186]. In the VMN, brain-derived neurotrophic
daytime sleepiness, cataplexy, hypnagogic hallucinations, factor (BDNF) is highly expressed, and VMN BDNF neu-
and sleep paralysis [181]. MCH-R1 antagonists may have rons suppress food intake through MC4R signalling [187].
therapeuticpotentialforthetreatmentofobesity[182],but Increased signalling in the VMN following an oral glucose
further work is required to determine if their use would load has been observed [162]. Selective deletion of BDNF
be associated with adverse effects attributable to the other neurons in the VMN and DMN of adult mice results in
biologicalactionsoforexin. hyperphagiaandobesity[188].
TheDMNreceivesNPY/AgRPprojectionsfromtheARC Glucose sensing plays an important role of the brain.
[183]andprojectstheα-MSHfibretothePVN[162,184]. Conventionally, glucose sensing is thought to involve
8 ExperimentalDiabetesResearch
glucokinase-dependentmetabolismofglucosetoATP,which to that seen in the hypothalamus [193]. POMC neurons
then alters membrane excitability by modulating ATP- exist within the NTS, which show STAT-3 activation in
dependent channels or transporters, such as ATP-inhibited response to leptin administration to suppress food intake
K+ channels (KATP). Recent studies, however, suggest that [196].AdministrationofleptinintotheDVCsuppressesfood
glucose-excited and glucose-inhibited neurones are able intake[193].
to sense glucose irrespective of such metabolic pathways. Inadditiontothehypothalamus,thevagusnerveplaysa
Brain glucose sensors, specialized neurones which respond centralroleinregulatingthefeeding.Vagalafferentneurons
to fluctuations in local extracellular glucose concentration, have been shown to express a variety of receptors within
have been found only in a few brain regions, in particular, thebrainstem,whichincludecholecystokinin(CCK)1Rand
the hypothalamus and brainstem. Hypothalamic glucose- CCK2R (at which both CCK and gastrin act [197]), Ob-
sensing neurones are found in the LHA, ARC, and VMN, R [198], Y2R [29], GLP-1 [67], and GLP-2R [199], growth
and responsive neurons have been identified which either hormone secretagogue receptor (GHS)-R1 where ghrelin
increase firing rate (glucose-excited neurones) or decrease acts[118],andtheorexinreceptor,OX-R1[200].
firing rate (glucose-inhibited neurones) in response to ex- The vagal stretch and tension sensors detect nutrients
tracellularglucose[189]. stored in the stomach. The vagus nerve also helps to
transmit gut hormones signals such as CCK, ghrelin, PYY,
6.Brainstem PP, and GLP-1, which are released by anticipation of meals
and the presence of food in the upper gastrointestinal
Withinthebrainstem,thedorsalvagalcomplex(DVC)plays tract. Cell bodies of afferent fibres of the abdominal vagus
an important role in relaying peripheral signals via vagal nerve are located in the nodose ganglia, which project
afferent fibres from the gut to hypothalamus. The DVC to the DVC of brainstem. In rats, infusion of saline into
has projections to the hypothalamus and higher cortical the stomach has been observed to reduce food intake to
centres [190] and comprises the dorsal motor nucleus of similar extents to infusion of nutrients into the stomach
vagus (DVN), area postrema (AP), and the nucleus of the [201]; this phenomenon is likely to be attributable to vagal
tractussolitarius(NTS).NTSisanidealpositiontointegrate nervefunction.Thevagusnerveparticipatesintransmitting
peripheralsignalsduetoitscloseproximitytotheAP,which the food-induced negative-feedback signals important for
hasanincompleteBBB[163]. determining meal size. Transection of all gut sensory vagal
Other than ascending brainstem-hypothalamus path- fibres results in increased meal size and meal duration, but
ways,descendinghypothalamicprojectionstothebrainstem doesnotblockgastricpreload-inducedfeedingsuppression,
are also important in control of food intake. α-MSH implyingthatvagalafferentsignalshaveasignificantrolein
projections from POMC neurons in the ARC terminate satietyduringspontaneousmeals[202,203].Randichetal.
in close anatomical proximity to neurons in the NTS, [204]utilizedextracellularrecordingsfromthevagusnerve,
which respond to gastric distension [191]. Furthermore, andfoundthatittransmitsasatietysignalfromthejejunum,
descending projections from the LHA to the NTS contain followingactivationbyinfusionoffattyacids.
orexinandMCH,anddescendingARC-parabrachialnucleus The importance of the role of the vagus nerve in
pathways have been identified [152]. The PVN projects transmitting peripheral signals has been demonstrated by
regions of the midbrain such as the ventral tegmental area, vagotomyorcapsaicintreatmenttoabolishitseffect,andby
Edinger-Westphalnucleus,ventrolateralperiaqueductalgray vagusnervestimulation(VNS)toenhanceitsactivity[205].
matter, reticular formation, pedunculopontine tegmental Low-frequency VNS in rats fed with a standard diet results
nucleus, and dorsal raphe nucleus. The PVN also projects indecreasedfoodintakeandbodyweight[206].Compared
to the prelocus coeruleus in the dorsal pons as well as the
withtheshamgroup, obeseminipigs receivedVNS did not
nucleus ambiguous and NTS in the ventral medulla. The
gain body weight and showed decreased food intake by
medial NTS receives the most extensive projections of the 18%—the effects lasted for 14 weeks [207]. Gil et al. [208]
PVN,substantiallymorethantheDVNorAP[192].
reported that chronic VNS with 10Hz electrical impulses
Theimportanceofthehindbraininenergyhomeostasis
in rats fed with a high-fat diet significantly decreased food
is highlighted by considering that chronically maintained
intake and body weight gain. In their study, significant
decerebrate rats, with complete high mesencephalic tran-
neuronalresponsesintheNTSanddecreasedserumleptin,
section, remain responsive to taste stimuli and respond to
butincreasedghrelinlevels,wereobservedandalsonesfatin-
intake-inhibitory feedback from the gut; however, hyper-
1levelstendedtoincreasefollowingVNS.Thissuggeststhat
phagicresponsetofooddeprivationisnotobservedinthese
VNSresultsinreductionsinfoodintakeandbodyweightby
animals [193]. Direct delivery of leptin to the lateral or
increasingbrainsatietysignalsthroughthevagalafferents.
third ventricle as well as the fourth ventricle significantly
The close association of the vagal efferent, sympa-
suppresses food intake up to 24h after treatment [193].
The effects of various gut hormones on food intake are thetic, and enteric systems makes it difficult to selec-
attenuatedbylesionsoftheareapostrema[194]orvagotomy tively manipulate the vagus nerve. Genetic approaches to
[28, 29, 118, 195]. Taken together, these findings suggest modulate signalling of neurotrophin factors (e.g., BDNF
brainstem-mediatedmechanismsoncontrollingfoodintake. and neurotrophin-3), which are essential for vagal afferent
The expression of leptin and insulin receptors, and of development, may help to further elucidate the regulatory
glucose sensing mechanisms in the brainstem, is similar roleofthevagusnerveingutphysiology[209].
ExperimentalDiabetesResearch 9
7.RewardSystems to odours and fat rich food when compared with lean
subjects[220].
Inhumans,environmentalcues,cognitive,reward,andemo-
tional factors play an important role in food intake which
mayoverridehomeostaticrequirements[210].Thecorticol- 8.NutrientsanditsRelatedSignals
imbicpathwaysareresponsibleforreward-associatedfeeding
ModulatingAppetite
behaviour, which include the striatum, ventral tegmental
area, nucleus accumbens, insular cortex, anterior cingulate
Althoughlow-energydensitydietsinduceshort-termweight
cortex, and orbitofrontal cortex. The orbitofrontal cortex
loss [221], they are usually associated with rebound weight
is associated with regulating gustatory, olfactory, visual,
gain.SomedietarypatternssuchastheMediterranean-type
and somatosensory function, and sensory factors, such as
dietareassociatedwithadecreasedrateofcardiacdeathand
taste and smell, and has an important role in reward-
nonfatal myocardial infarction compared with a Northern
relatedfeeding[211].Inpatientswithfrontotemporallobar
European or North American dietary pattern [222]. In the
degeneration,hyperphagiaisreportedtobeassociatedwith
Mediterranean diet, monounsaturated fat is substituted for
atrophyintheanterolateralorbitofrontalcortex[212].
saturated and trans-fats, and intake of fruits, vegetables,
The endocannabinoid and opioid systems have wide
fibre,andwholegrainsarehigh,isrecommended[223].Itis,
receptor distributions within the CNS and play important
therefore, interesting to consider whether specific nutrients
rolesinreward-relatedfeeding[213].Administrationofaμ-
withindietsareabletomodulatefoodintake,inadditionto
opioid receptor agonist into the nucleus accumbens prefer- effectsassociatedwiththeirdirectnutritionalvalue.
entially stimulates intake of high-fat diet regardless of diet
The amino acid L-Glutamate is involved in multiple
preferenceatbaseline,whenbothfatandcarbohydratediets
physiologic functions, which include taste perception, car-
are displayed simultaneously [214]. Increased expression of
bohydratemetabolism,andexcitatoryneurotransmissionin
orexin in the hypothalamus has been observed following the brain [224]. L-Glutamate stimulates its receptors in gut
administrationofopioidμ-receptoragonistsintothenucleus epithelialcells,whichactivatecerebralregionssuchasbasal
accumbens[215].Preadministrationofacannabinoidrecep- ganglia, limbic systems, and hypothalamus through vagal
tor (CB1) antagonist prevents the orexigenic effect of the afferent nerve [225]. Kondoh et al. [226] reported that rats
endocannabinoidagonist,anandamideonfoodintake[213]. with chronic ad libitum administration of monosodium
Leptin has been shown to reduce endocannabinoid levels L-glutamate had reduced weight gain, fat deposition, and
in the hypothalamus [216]. This suggests that hypothala- plasmaleptinconcentrationswhencomparedwithcontrols.
mic endocannabinoids may act via CB1 to increase food In rodents, long-chain omega-3 polyunsaturated fatty
intake through a leptin-regulated mechanism. The nucleus acids supplementation has been shown to improve obesity
accumbens (NAs) is a key region of limbic pathway and [227]. In a recent study using a mouse model of diet-
may be implicated in regulation of hedonistic feeding and induced obesity, ICV administration of unsaturated fatty
homeostaticfeeding[210]. acids reduced hypothalamic inflammation, hypothalamic
The ventral striatum and population of dopamine neu- andwholebodyinsulinresistance,andbodyadiposity[228].
ronsofthesubstantianigraareinvolvedintherewardsystem Free fatty acids exert insulin-like effects in key brain areas
in human and nonhuman primates. The ventral striatum for energy homeostasis, including the ARC, possibly by
receivesinputfromtheorbitofrontalcortexandanteriorcin- favouringintracellularaccumulationofthelong-chainfatty
gulatecortex,whichincludetheNAandthebroadcontinuity acyl-CoA(LCFA-CoA)[229].
Unsaturated free fatty acid may, therefore, be beneficial
betweenthecaudatenucleusandtheputamenandtheolfac-
totreatobesity,althoughevidenceinhumanisstilllimited.
torytubercle[217].Dopamineappearstobeassociatedwith
Fructose is being increasingly used in processed foods
reward-related food intake and with behaviours required
withintheWesterndiet.However,itseffectsmaybedistinct
to maintain feeding essential for survival. Mice lacking
to those of the related sugar, glucose. As glucose levels
dopamine, caused by the selective inactivation of tyrosine
enteringtothebrainincrease,foodintakeissuppressed.In
hydroxylase, develop fatal hypophagia; and replacement of
contrast, fructose increases food intake when metabolized
dopamine in these animals to the caudate putamen or NA
in the brain. Fructose has the opposite effect of glucose on
restores preference for sucrose or palatable chow [218].
theAMPactivatedkinase/malonyl-CoAsignalingsystemand
However, dopamine may have more complex effects on
therebyenhancesfeedingbehaviour[230].
feeding,sincedopaminesignallingintheDMNandARCof
Serotoninhasaroleinappetitecontrol.5HT-containing
hypothalamusmayinhibitfoodintake[149].
neurons are organized into nine nuclei (B1–B9) which
In a recent positron emission tomography study, meal
are located in the midbrain and hindbrain. In particular,
ingestion was associated with greater activation of the the midbrain dorsal raphe (B7) contains a substantial
midbrain and middle-dorsal insula, and lesser activation portion of the total brain 5HT neurons, with distinct
in the posterior cingulate cortex, temporal cortex, and or- projectionstohypothalamicnucleiandotherfeeding-related
bitofrontal cortex following a meal in obese individuals forebrain areas [231]. 5-HT-stimulating drugs reduce food
when compared with lean individuals [219]. In addition, intake partly mediated through the 5-HT receptor [232].
2C
a study utilizing functional magnetic resonance imaging Although its effects on eating behaviour remain to be
(MRI)suggestedthatobeseindividualshadgreaterresponses characterised,lorcaserin,aselective5-HT receptoragonist
2C
10 ExperimentalDiabetesResearch
Table1:Thesummaryoftheroleofguthormonesonappetiteregulationandotheractions.
Guthormones Feeding Receptor Majorsecretionsite Otheractions
Delaysgastricemptying,inhibitsgallbladdercontraction,pancreatic
PYY ↓ Y2 Lcellsingut
3–36 exocrinesecretions,andgastricacidsecretion
Delaysgastricemptying,attenuatespancreaticexocrinesecretion,
PP ↓ Y4,Y5 PPcellsinpancreas
andinhibitsgallbladdercontraction
Incretin,decreasesbloodglucose,delaysgastricemptying,and
GLP-1 ↓ GLP-1 Lcellsingut
neurotrophiceffect
OXM ↓ GLP-1 Lcellsingut Inhibitsgastricacidsecretionandgastricemptying
Glucagon ↓ GCGR Pancreaticαcells Enhancingphysiologicalresponsetostress
Gallbladdercontraction,relaxationofsphincterofOddi,and
CCK ↓ CCK1,2 Icellofsmallintestine
pancreaticenzymesecretion
Growthhormonesecretion,promotesgastricmotility,vasodilatation,
Ghrelin ↑ GHS stomach
andincreasescardiaccontractility
Amylin ↓ AMY1-3 pancreaticβcells Adipositysignals
PYY:peptideYY,PP:pancreaticpolypeptide,GLP-1:glucagon-likepeptide-1,OXM:oxyntomodulin,CCK:cholecystokinin,GCGR:glucagonreceptor.
isreportedtobeanovelantiobesitydrugreducingbothfood of weight loss with an acceptable level of risk. RYGB
intakeandbodyweight. is thought to achieve its beneficial effects through the
Tasteaffectsfoodpreferenceandintake.Lingualproteins BRAVE effects: Bile flow alteration, Reduction of gastric
CD36 and GPR120 are reported to be responsible for size, Anatomical gut rearrangement and altered flow of
the spontaneous preference for lipid-rich foods [233] and nutrients, Vagal manipulation, and subsequent Enteric gut
have been identified in human taste buds [234]. The gut hormone modulation [241]. A decrease in levels of the
hormones such as GLP-1 and CCK and neurotransmitters orexigenichormoneghrelin,andanincreaseinlevelsofthe
are also produced locally in taste buds [235]. Sweet and anorectic hormones PYY and GLP-1 have been observed
umami taste are mediated by T1R family (T1R1, T1R2, following bypass surgery [111, 242, 243]. An increase in
T1R3) which belongs to family C of GPCRs including energy expenditure may play a role in part in weight loss
metabotropic glutamate receptors, calcium sensing recep- aftergastricbypasssurgery[244].Moreover,microbialshifts
tors, and V2r pheromone receptors. In the intestine, there towards substantially higher concentrations of Proteobace-
are different sweet taste cells (enteroendocrine, brush cells) ria, specifically Enterobacter hormaechei, are demonstrated
within the epithelial layer. These sweet taste receptors may following RYGB surgery [241]. Gastric bypass surgery is
signal through vagal afferent fibres to alter food intake and associated with greater improvements in glycaemic control
delay gastric emptying [236]. It has been shown that leptin inpatientswithtype2diabetes,whencomparedwithgastric
selectively suppresses sweet taste sensitivity or taste cells bandingprocedures[245].Furthermoretheseimprovements
through Ob-RB, whereas endocannabinoids enhance sweet inglycaemicstatusoftenprecedeweightloss,whichimplies
tastesensitivityoftastecellsviaCB1receptor[237]. that bypass surgery may have effects in ameliorating type 2
diabeteswhichareadditionaltotheireffectsonbodyweight.
9.BariatricSurgery
Whereas pharmacological and behavioural treatments are 10.GutMicrobiota
usuallyassociatedwithweightlossfollowedbyweightregain,
bariatricsurgeryprovidesweightlossforatleast15years,in A potential association between gut microbiota and the
patientswithobesity[238,239].Bariatricsurgeryisclassified pathogenesis of obesity has been recently recognised [246].
into 3 types of surgical procedures; malabsorptive surgery, The human gut harbours a large number of 1000 to 1150
restrictive surgery, and mixed procedures. Malabsorption- bacterial species collectively termed gut microbiota [247].
based procedures include the jejuno-ileal bypass, which Adult germ-free mice have 40% less total body fat than
results in decreased nutrients absorption by shortening the micewithnormalmicrobiota;andreplacingthemicrobiota
functional small bowel length, and by allowing nutrients in adult germ-free mice is associated with a 60% increase
to pass directly from the proximal jejunum to the terminal in body fat content and insulin resistance within 14 days
ileum. Restrictive bariatric surgery includes the laparo- of replacement [248]. In contrast to mice with normal
scopic application of an adjustable gastric band, which is gut microbiota, germ-free mice may be protected against
associated with lower comorbidity when compared with high fat diet-induced metabolic changes; increased fatty
malabsorption-based procedures [240]. Roux-en-Y gastric acid metabolism, elevated levels of fasting-induced adipose
bypass (RYGB) is a combined restrictive and malabsorp- factor,Fiaf,knownasangiopoietin-likeprotein-4,asecreted
tive procedure, which yields long-term, sustained period lipoprotein lipase inhibitor, and increased AMP-activated