Hypothalamic-Regulation-of-Appetite (1).docx

8/9/2019 Hypothalamic-Regulation-of-Appetite (1).docx

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Hypothalamic Regulation of AppetiteKatherine A. Simpson; Niamh M. Martin; Steve R. Bloom

Authors and DisclosuresPosted: 10 0! "00!; #$pert Rev #ndocrinol Meta%. "00!;&'():(**+(,". - "00!

uture Dru/s td.Abstract and Introduction

Abstract

he prevalence o2 o%esit3 is steadil3 risin/ and has hu/e health and 2inancial implications2or societ3. 4ei/ht /ain is due to an im%alance %et5een dietar3 inta6e and ener/3e$penditure and research has 2ocused on tr3in/ to understand the comple$ path5a3sinvolved in controllin/ these aspects. his revie5 hi/hli/hts the 6e3 areas o2 research inthe h3pothalamic control o2 appetite. he h3pothalamus consists o2 several nuclei that

inte/rate peripheral si/nals7 such as adiposit3 and caloric inta6e7 to re/ulate importantpath5a3s 5ithin the 8NS controllin/ 2ood inta6e. he %est characteri9ed path5a3s are theore$i/enic neuropeptide A/outi+related protein and the anore$i/enic pro+opiomelanocortin cocaine+ and amphetamine+related transcript neurons in the arcuatenucleus o2 the h3pothalamus. hese pro ect 2rom the arcuate nucleus to other 6e3h3pothalamic nuclei7 such as the paraventricular7 dorsomedial7 ventromedial and lateralh3pothalamic nuclei. here are also pro ections to and 2rom the %rainstem7 cortical areasand re5ard path5a3s7 all o2 5hich in2luence 2ood inta6e. he challen/e at present is tounderstand the comple$it3 o2 these path5a3s and tr3 to 2ind 5a3s o2 modulatin/ them inorder to 2ind potential therapeutic tar/ets.

Introduction

Epidemiology. estimates that over 1 %illion people are currentl3over5ei/ht and that over &00 million people are o%ese. ?1@ n the K7 the prevalence o2o%esit3 has more than tripled in the past "( 3ears7 and o%esit3 amon/ children has tripledin a decade. ?"""@ A 5ei/ht /ain o2 ust 16/ has %een sho5n to increase cardiovascular ris6%3 &.1C and dia%etes ris6 %3 .(+,C. ?"@ As e$pected7 o%esit3+related disorders have alsoincreased7 5ith !0C o2 o%ese adults havin/ at least one or more comor%idities7 includin/dia%etes mellitus7 h3perlipidemia7 h3pertension7 cardiovascular disease and certain 2ormso2 cancer. ?&7 @ Deaths related directl3 to o%esit3 have %een estimated at &"07000 per 3ear in#urope and &007000 in the SA .?"""@


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postulated that sleep deprivation and its e22ects on /ut hormone secretion has a role in thedevelopment o2 o%esit3 .?F@ he concept o2 the Gthri2t3 phenot3peG h3pothesis 5as 2irst coinedalmost (03ears a/o 5ith the o%servation that7 durin/ the hunter+/atherer da3s o2 man7possession o2 /enes that allo5ed one to survive despite 2amine7 con2ered an evolutionar3advanta/e .?*@ 8arriers o2 such /enes 5ould %e a%le to store ener/3 more e22icientl3 durin/

periods o2 a%undant 2ood suppl3 to increase their odds o2 survival durin/ 2amine. =o5ever7this Gthri2t3 /enot3peG %ecomes a disadvanta/e at times o2 a%undant ener/3 suppl37 suchas that seen in our current 4estern civili9ation7 resultin/ in o%esit3. amil37 t5in andadoption studies indicate that o%esit3 is hi/hl3 herita%le7 5ith the estimated /eneticcontri%ution ran/in/ 2rom F0 to ! C. ?!@ A series o2 comple$ s3stems re/ulate ener/3homeostasis so that su22icient ener/3 is availa%le and %od35ei/ht remains sta%le. ?,@ 8entralcircuits in the %rain rel3 on peripheral si/nals indicatin/ satiet3 levels and ener/3 stores7 as5ell as hi/her cortical 2actors7 such as emotional and re5ard path5a3s. he h3pothalamusis critical in the re/ulation o2 2ood inta6e and acts as a G6e3 controllerG 5ithin neural circuitr3to maintain ener/3 homeostasis. As illustrated in i/ure 17 the h3pothalamus is an inte/ral

part o2 the processin/ o2 a22erent si/nals7 such as those 2rom the /ut and %rainstem7 as5ell as the processin/ o2 e22erent si/nals that modulate 2ood inta6e and ener/3e$penditure. he h3pothalamus is su%divided into interconnectin/ nuclei7 includin/ thearcuate nucleus 'AR8)7 paraventricular nucleus 'PHN)7 ventromedial nucleus 'HMN)7dorsomedial nucleus 'DMN) and lateral h3pothalamic area ' =A). #arl3 lesionin/ studiesproposed a Gdual centerG h3pothesis7 5here%3 the ventromedial h3pothalamus acted as asatiet3 center and the lateral h3pothalamus 5as a G2eedin/ centerG. ?10711@he dual centerh3pothesis has no5 %een replaced %3 the concept o2 discrete neuronal path5a3s7 5hichare inte/rated into a comple$ neural net5or6 in 5hich speci2ic ore$i/enic and anore$i/enicneurotransmitters are released 2rom speci2ic neurons to in2luence 2ood inta6e and ener/3

e$penditure. he purpose o2 this revie5 is to hi/hli/ht the 6e3 pla3ers in the h3pothalamiccontrol o2 appetite7 the %rain circuitr3 involved and potential therapeutic tar/ets 2or o%esit3.

? 8 >S# 4 ND>4 @


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Figure 1.

Relationship %et5een the %rainstem7 h3pothalamus7 cortical areas and re5ard circuitr36no5n to modulate appetite control. $3ntomodulin; PI Peptide ; PHN I Paraventricular nucleus; HMN I Hentromedial nucleus.


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Hypothalamic Regions Important in Appetite Regulation

Arcuate Nucleus

he AR8 is a 6e3 h3pothalamic nucleus in the re/ulation o2 appetite. n mice7 lesions o2

the AR8 usin/ monosodium /lutamate produce o%esit3 and h3perpha/ia .?1"@ Anatomicall3related to the median eminence7 the AR8 is not 2ull3 insulated 2rom the circulation %3 the%lood+%rain %arrier and7 hence7 is strate/icall3 positioned to inte/rate a num%er o2peripheral si/nals controllin/ 2ood inta6e ' i/ure "). ?1&71 @ 5o ma or neuronal populations inthe AR8 are prominentl3 implicated in the re/ulation o2 2eedin/. >ne population7 locali9edmore mediall3 in the AR87 ?1(@ increases 2ood inta6e and coe$presses neuropeptide 'NP )and A/outi+related protein 'A/RP). he second population o2 neurons7 coe$pressin/cocaine+ and amphetamine+related transcript '8AR ) and pro+opiomelanocortin 'P>M8)7inhi%its 2ood inta6e and tends to cluster more laterall3 in the AR8. ?1F@ Neuronal pro ections2rom these t5o populations then communicate 5ith other h3pothalamic areas involved in

appetite re/ulation7 such as the PHN7 DMN and =A. ?1*+"0@ his net5or6 o2 neuronal circuitr3can %e modulated %3 peripheral si/nals7 such as leptin and insulin.

? 8 >S# 4 ND>4 @


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Figure 2.

he main h3pothalamic nuclei7 neuropeptides and path5a3s involved in the re/ulation o2appetite. 8irculatin/ hormones act on the AR87 5hich has an incomplete %lood+%rain%arrier and7 hence7 can a22ect do5nstream path5a3s7 5hich modulate appetite control. n

the AR87 ore$i/enic neurons coe$press NP and A/RP7 5hereas neurons coe$pressin/P>M8 and 8AR are anore$i/enic. n the AR87 activation o2 AMPK leads to increased2ood inta6e7 an e22ect that is inhi%ited %3 insulin and leptin. A/RP I A/outi+related protein;

AMPK I Adenosine monophosphate protein 6inase; AR8 I Arcuate nucleus; 8AR I8ocaine+ and amphetamine+related transcript; 8B1 I #ndocanna%inoid receptor 1; 88K I8holec3sto6inin; DMN I Dorsomedial nucleus; < P I JM I >$3ntomodulin; P>M8 I Pro+opiomelanocortin; P I Peptide ; PHN IParaventricular nucleus; HMN I Hentromedial nucleus.

Reward Mechanisms & Hypothalamic Appetite Regulation

Re5ard mechanisms pla3 a lar/e role in appetite re/ulation and are thou/ht topredominantl3 involve the mesolim%ic s3stem in the %rain. 8onditioned taste aversion'8 A) and lesionin/ e$periments su//est the or%ito2rontal corte$ and am3/dala areimportant in learnin/ and e$periencin/ 2ood and its su%seEuent e22ect on 2ood inta6e.Neuroima/in/ studies in humans have sho5n that pleasant and unpleasant odors activatedi22erent re/ions o2 the or%ito2rontal corte$ and cin/ulate /3rus7 areas that have directpro ections to the h3pothalamus ' i/ure 1). M8= and ore$in 2i%ers in the =A transmit andreceive in2ormation 2rom the cere%ral corte$. ?1""@ n addition7 the =A receives an inhi%itor3input 2rom the shell o2 the nucleus accum%ens7 5hich in turn receives inputs 2rom thepre2rontal corte$ .?1"&+1"(@ nterestin/l37 there is hi/h e$pression o2 8B1 receptors in thenucleus accum%ens and other re5ard circuitr37 such as the hippocampus and medial2ore%rain %undle. urthermore7 endocanna%inoids have %een 2ound to inhi%it e$citator3inputs to neurons in the shell o2 the nucleus accum%ens. ?1"F@

Endocannabinoids

#vidence to date su//ests that endocanna%inoids act as ore$i/enic si/nals viacanna%inoid 8B1 receptors in the 8NS. ?1"*@ Bloc6in/ 8B1 receptors inhi%its 2ood inta6e andcauses 5ei/ht loss in rodents. ?1"!@ he 5ei/ht+reducin/ e22ect o2 8B1 anta/onists 'e./.7rimona%ant) is accentuated in o%ese animals ?1",@ and has %een used in the treatment o2human o%esit3. 8B1 receptors are the most a%undant


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Insulin

8irculatin/ insulin rises in response to a /lucose load and7 as 5ith leptin7 circulatin/ levelsre2lect 2at mass. nsulin reaches the 8NS via receptor+mediated transport across the%lood+%rain %arrier. nsulin receptors are 5idel3 distri%uted in the %rain7 particularl3 in

h3pothalamic nuclei involved in the re/ulation o2 2ood inta6e. Neuron+speci2ic insulinreceptor+6noc6out 'N RK>) mice are o%ese and have increased 2ood inta6e as 5ell aselevated plasma leptin and insulin levels. ?1(!@ nsulin has an anorectic e22ect 5henadministered 8H or directl3 into the HMN. 8onsistent 5ith this7 insulin anti%odies increase2ood inta6e and %od35ei/ht 5hen administered directl3 into the HMN. ?1(,@ 8H+administeredinsulin acts via insulin receptors in the AR8 ?1F0@ and activates insulin receptor su%strate' RS) proteins and the P &K path5a3. he anorectic e22ect o2 insulin ma3 %e mediatedthrou/h IRS-2 7 since RS+"+null mice displa3 increased 2ood inta6e ?1F1@ and RS+" mRNA ishi/hl3 e$pressed in the AR8. he precise mechanism %3 5hich insulin inhi%its 2ood inta6eis still un6no5n. nsulin has %een sho5n to inhi%it NP A/RP neurons in the AR8.?"0@ =o5ever7 the anorectic e22ects o2 insulin ma3 also re2lect an interaction 5ith themelanocortin s3stem7 since insulin receptors are also present on AR8 P>M8 neurons and8H administration o2 insulin increases AR8 P>M8 mRNA e$pression. urthermore7 theanorectic actions o2 insulin are %loc6ed %3 melanocortin anta/onists. ?"071F"@

Interactions Between the Brainstem & Hypothalamus

Althou/h the h3pothalamus could %e re/arded as the G/ate 6eeperG o2 appetite si/nalin/7 itis important to remem%er that7 in addition to input 2rom hi/her %rain centers7 theh3pothalamus also receives si/nals 2rom the peripher3 ' i/ures 1 "). he de2icient

%lood+%rain %arrier o2 the AR8 ena%les circulatin/ 2actors re/ulatin/ appetite tocommunicate directl3 5ith the h3pothalamus. he %rainstem is another 6e3 8NS appetite+re/ulation center ?1F&@ and peripheral satiet3 si/nals can also act directl3 on %rainstemstructures such as the area postrema7 5hich also possesses an incomplete %lood+%rain%arrier. #$tensive reciprocal neuronal pro ections e$ist %et5een %rainstem andh3pothalamic 2eedin/ circuits to provide an alternative path5a3 throu/h 5hich circulatin/satiet3 2actors can communicate 5ith the h3pothalamus. ?1F 71F(@ he va/us nerve is the ma or neuroanatomical lin6 %et5een the < tract and the %rain. 8ell %odies o2 a22erent 2i%ers o2the a%dominal va/us nerve are located in the nodose /an/lia7 5hich pro ect onto the%rainstem. =ere7 the dorsal va/al comple$ 'DH8)7 consistin/ o2 the dorsal motor nucleus7

the area postrema and the sensor3 nucleus o2 the tractus solitarius 'N S)7 inter2aces 5ithh3pothalamic and hi/her centers. ?1F&@ A population o2 P>M8 neurons e$ist in the N S and ithas %een sho5n that over (0C demonstrate activation o2 S A +& in response to peripheralleptin administration. ?1FF@ =ence7 the va/us nerve provides an additional path5a3 via 5hichappetite+re/ulator3 si/nals 2rom the peripher3 can communicate 5ith the h3pothalamus tore/ulate ener/3 homeostasis.


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!"ynto#odulin

As 5ith < P+17 o$3ntomodulin is secreted 2rom intestinal cells postprandiall3 andreduces 2ood inta6e 5hen administered peripherall3 or 8H to rodents. ?1!"@ Peripheraladministration o2 o$3ntomodulin activates c-fos e$pression in the AR8 and its anorectic

e22ects can %e %loc6ed throu/h the use o2 a < P+1 anta/onist. ?1!"@ n mice7 man/anese+enhanced MR ?1! @ demonstrates that intraperitoneal in ection o2 o$3ntomodulin results inreduced rate o2 si/nal enhancement in the AR87 PHN and supraoptic nucleus7 5hereas< P+1 causes a reduction onl3 in the PHN7 3et an increase in the HMN. his su//ests that< P+1 and o$3ntomodulin act via di22erent h3pothalamic path5a3s.

Ghrelin


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2old. P is cleaved at the N+terminus %3 dipeptid3l peptidase H 'DPP+ H) to create thetruncated 2orm P &+&F. 4hereas 2ull+len/th P %inds to 17 " and ( receptors7 P &+&F is relativel3 selective 2or the " receptor. Peripheral administration o2 P &+&F reduces2ood inta6e in rodents and humans and PYY +6noc6out mice develop o%esit3. ?1,!71,,@ ncontrast to peripheral administration7 8H in ection o2 P &+&F stimulates 2ood inta6e7

possi%l3 throu/h 1 and ( receptors in the PHN.

he e$act mechanisms underl3in/ the anorectic e22ects o2 P &+&F are unclear. Severallines o2 investi/ation su//est a direct anorectic action o2 circulatin/ P &+&F on the AR8.Peripheral administration o2 P &+&F induces c-fos e$pression in the AR8 and directin ection o2 P &+&F into the AR8 inhi%its 2eedin/. ?1,!@ t has %een proposed that P &+&F e$erts its anorectic e22ect via the " receptor since this is a%olished in " receptor+6noc6out mice .?1,!@ he " receptor is hi/hl3 e$pressed on AR8 NP neurons and P &+&F ma3 reduce 2ood inta6e %3 inhi%itin/ NP release via autoinhi%itor3 " receptors. P &+&F decreases NP release and increases +MS= release in vitro 2rom h3pothalamic

e$plants. ?1,!@ #lectroph3siolo/3 studies su//est that P &+&F directl3 inhi%its the activit3 o2 AR8 NP neurons7 there%3 secondaril3 disinhi%itin/ anorectic P>M8 neurons. ?"00@=o5ever72urther studies su//est that the anorectic e22ects o2 P &+&F are more comple$ than asimple action on the AR87 since %oth POMC +null and MC4-R +null mice respond normall3to the anorectic e22ects o2 P &+&F.?"017"0"@ Recent 2indin/s support a va/al+%rainstem path5a3mediatin/ the e22ects o2 P &+&F on appetite7 since va/otom3 or lesionin/ o2 the %rainstem+h3pothalamic neuronal path5a3s a%olishes the anorectic e22ects o2 peripheral P &+&F.?1!07"0&@ his o%servation7 com%ined 5ith evidence 2or " receptor e$pression in the N S andnodose /an/lion o2 the va/us nerve7 ?"0&7"0 @ has led to the proposal that P &+&F ma3 re/ulate

AR8 neuronal activit3 indirectl3 via va/al+%rainstem path5a3s.

ancreatic olypeptide

he anorectic /ut hormone PP is released 2rom the pancreas into the circulation a2ter ameal and7 as 5ith P 7 is released in proportion to calories in/ested. Peripheral in ectiono2 PP to rodents and humans reduces 2ood inta6e .?"0(+"0*@ Peripheral PP administrationactivates neurons in the area postrema o2 the %rainstem7 an area 5ith a hi/h densit3 o2 receptors7 and reduces h3pothalamic NP and ore$in mRNA e$pression. ?"0(7"0!@ B3 contrast75hen /iven centrall37 PP stimulates appetite and increases h3pothalamic NP e$pression.?"0(@ hese contrastin/ e22ects o2 PP on 2eedin/ dependin/ on the route o2 administrationpro%a%l3 re2lect di22erential receptor distri%ution and activation. he anorectic e22ect o2peripheral administration o2 PP is li6el3 to arise 2rom activation o2 receptors7 5hereasthe receptor mediatin/ stimulator3 e22ects on appetite 2ollo5in/ central in ection is unclear.

utrient Sensing

here is evidence that the h3pothalamus can also sense nutrients and ad ust 2ood inta6eaccordin/l3. ?"0,@ 4hen cellular ener/3 stores are deplete7 the en93me AMPK is activated in


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order to increase su%strate upta6e. ?"10@ n the AR87 activation o2 AMPK leads to increased2ood inta6e and %od35ei/ht; an e22ect that is inhi%ited %3 %oth insulin and leptin.?1(&@ =o5ever7 h3pothalamic AMPK inhi%ition is essential 2or leptinGs e22ect on 2ood inta6eand %od35ei/ht. ?1(&@Recent evidence sho5s that /hrelin activates NP neurons in the AR8throu/h an AMPK path5a3 .?"11@ AMPK in the HMN also appears to pla3 a 6e3 role in the

detection o2 acute h3po/l3cemia and initiation o2 the /lucose counter+re/ulator3 response.?"1"@ here has also %een increasin/ evidence 2or a common path5a3 5ithin the PHNinvolvin/ AMPK. ntraperitoneal leptin and lateral ventricle administration o2 a melanocortina/onist causes a si/ni2icant decrease in AMPK activit3 in the PHN7 ?1(&@ 5hereas 8H A/RPcauses an increase.

here are considera%le data demonstratin/ the e22ects o2 circulatin/ car%oh3drates7 lipidsand amino acids in the h3pothalamic control o2 appetite. =3po/l3cemia itsel2 stimulates2ood inta6e and the h3pothalamus has 6e3 /lucose+sensin/ neurons in order to counteractthis. ?"1&@ nterestin/l37 acute h3po/l3cemia increases h3pothalamic NP and A/RP and

reduces P>M8 e$pression. ?"1 @Plasma lon/+chain 2att3 acids cross the %lood+%rain %arrierin a dose+dependent manner and can re/ulate 2ood inta6e via the h3pothalamus. 8Hadministration o2 the lon/+chain 2att3 acid oleic acid inhi%its 2ood inta6e %3 reduction o2

AR8 A/RP and NP e$pression. ?"1(@ Amino acids are also implicated in the h3pothalamicre/ulation o2 2ood inta6e7 and 8H administration o2 the amino acid leucine reduces 2oodinta6e in rats. eucine is thou/ht to mediate its e22ect throu/h increased h3pothalamicm >R activit3 that reduces AR8 NP e$pression. ?1( @ ntestinal chemosensors are ane$citin/ recent area o2 2ocus in understandin/ 2eed+2or5ard si/nals to the h3pothalamus tore/ulate ener/3 inta6e. ?"1F@

Clinical !herapeutic Applications

n conclusion7 the h3pothalamic control o2 appetite is comple$ and relies not ust onsi/nalin/ path5a3s 5ithin the %rain %ut also peripheral si/nals actin/ via the %rainstem andre5ard circuitries. As such7 there are multiple potential tar/ets 2or developin/ anti+o%esit3a/ents. ?"1*@ =o5ever7 due to the comple$it3 o2 neuronal circuits involved in appetite control7it is unli6el3 that tar/etin/ one speci2ic path5a3 5ill result in prolon/ed and clinicall3relevant 5ei/ht loss. nderstandin/ and hence modulatin/ several path5a3s7 includin/those a22ectin/ the %rainstem and /ut hormone pro2ile7 is li6el3 to %e a more success2ulapproach and ma3 provide real hope 2or e22ective treatments 2or o%ese patients.

"#pert Commentary

At present7 onl3 t5o dru/s are licensed and endorsed %3 the National nstitute o2 8linical#$cellence 'N 8#) in the K and the S DA 2or lon/+term therap3 a/ainst o%esit3: orlistatand si%utramine. inal appraisal documentation 2rom N 8# has also %een pu%lished andrecommends rimona%ant i2 orlistat and si%utramine are contraindicated or no response is


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