Karolo ea ghrelin ho ja lijo-motheo (2012)

PMCID: PMC3388148

NIHMSID: NIHMS360457

Mario Perelló, Ph.D.1 'me Jeffrey M. Zigman, MD, Ph.D.2,3

Moetso oa khatiso oa ho qetela oa mohatisi o fumaneha ho Biol Psychiatry

Sheba lihlooho tse ling ho PMC hore Qotsa sehlooho se hatisitsoeng.

Eya ho:

inahaneloang

The peptide hormone ghrelin e sebetsa tsamaisong ea methapo e kholo e le lets'oao le matla la orexigenic. Ha se feela hore ghrelin e amoheloa e le karolo ea bohlokoa ho fepheng lipotoloho tseo ho neng ho nahanoa hore li ama homeostasis ea mmele, empa palo e eketsehang ea lithuto tsa mahlale joale e supile ghrelin e le molaoli oa bohlokoa oa boits'ebetso ba ho ja moputso, o matla oa hedonic. Sehloohong sa hajoale, re hlahloba liketso tsa ghrelin tsa orexigenic, bopaki bo hokahanyang ghrelin le boits'oaro ba meputso ea lijo, mekhoa e ka sebelisoang ke eo ghrelin e arolelanang boitšoaro bo thehiloeng ho moputso, le lithuto tseo tse fanang ka maikutlo a karolo e tlamang bakeng sa ghrelin mekhoeng e fetotsoeng ea ho ja e tlisoang ke khatello ea maikutlo.

Keywords: Ghrelin, GHSR, hedonic, moputso, ho ja, khatello ea maikutlo

Ghrelin ke hormone ea peptide e hlophisitsoeng haholo ke sehlopha se ikhethileng sa lisele tsa endocrine tse fumanehang kahara gastric oxyntic mucosa (1). Ghrelin e sebetsa ka mokhoa oa "hormone" ea "agrog "receptor (" GHSR) "," "protein" e kopantsoeng le "protein" e kopantsoeng le "protein" e kopantsoeng le "protein"2). Li-GHSR li hlahisoa liseleng tse ngata tsa boko le litharollo tsa methapo, moo li arolelanang liketso tsa ghrelin sehlopheng se fapaneng sa mekhoa le boits'oaro (3). Tsena li kenyelletsa likarolo tsa kholo ea secretion ea hormone ea kholo, tsoekere ea mali homeostasis, ts'ebetso ea locomotor, prokinesis ea gastrointestinal le boits'oaro bo amanang le maikutlo, hara ba bang ba bangata (3-5). Ntle le moo, ghrelin e bohlokoa bakeng sa boima ba 'mele le melaoana ea ho leka-lekanya matla (6-9) 'me e amoheloa e le eona feela hormone e tsejoang ea orexigenic peptide (3). Ghrelin o ile a bonts'oa pele ho tsosa takatso ea lijo ka ho kenya lipotoloho tsa homeostatic hypothalamic (10). Li-circuits tsena tsa homeostatic li fana ka mokhoa oo ka oona ghrelin le matšoao a mang a ho fumaneha ha matla le ts'ebetso ea phepelo ea mpa e ka sebelisanang le tsamaiso ea methapo ea methapo ea methapo ea methapo ea methapo ea lijo le tšebeliso ea matla mme qetellong, ho boloka boima ba 'mele bo behiloeng (11). Bopaki ba morao-rao bo bonts'a hore ghrelin e boetse e laola li-circon tsa mesolimbic, ka lebaka leo, likarolo tse fapaneng tse sa jeng homeostatic, hedonic tsa ho ja (12-14). Hedonic, kapa ho ja moputso, ho kenyelletsa boits'oaro bo lebisang ho tšebeliso ea lijo tse monate, tseo batho ka bomong ba khothalletsoang ho li fumana ka mokhoa o phethahetseng (15). Mona, re shebisisa karolo ea ghrelin e le qoqotho ea orexigenic, ka ho shebisisa phello ea moea oa moea oa ho ja mabapi le lijo tse thehiloeng moputsong. Re boetse re bua ka litlamorao tsa 'mele oa ketso ena mme haholoholo, karolo ea ghrelin e le mokena-lipakeng oa boits'oaro bo susumetsang, bo thehiloeng moputsong.

Ketso tsa Orexigenic tsa ghrelin le kamano ea eona le boima ba 'mele

Liphello tsa Ghrelin mabapi le ho ja li thehiloe hantle [joalo ka ha ho hlahlojoa (8)]. Ghrelin ka bobeli lipontšo ebile e thusa ho arabela ho mebuso ea ho haella ha matla. Ho potoloha ha moea ho eketsa lijo pele ho lijo ho ea maemong a khothaletsang takatso ea lijo ha e hlahisoa ke tsamaiso ea lihomone tsa pherimitha (8). Methati ea eona e boetse e phahama ka lebaka la khaello ea lijo le ka mor'a ho theola boima ba 'mele bo amanang le boikoetliso le cachexia (16-22). Infusions ea ghrelin kapa GHSR agonists e eketsa boima ba 'mele ka liketso tsa pro-orexigenic le / kapa ho fokotseha ha ts'ebeliso ea matla (10, 23-26). Ketso ea bo-orexigenic ea Ghrelin e potlakile ebile e baka ho ja esita le ka linako tse jang lijo tse fokolang tsa boithati (8). Kamora ho potlaka ho fetang bosiu, bahanyetsi ba ghrelin ba thibela ho nona ho feta tekano (27). Phekolo e sa feleng e nang le "ghrelin" ea ntle le eona e ntlafatsa phepo le boima ba 'mele, ho fana ka maikutlo a hore ghrelin e nka karolo taolong ea boima ba' mele ba nako e telele (25). Le ha lithuto tse ling li bontšitse hore ha li na phello ea ho kena-kenana le liphatsa tsa lefutso kapa pharmacologic ka ho buoa ka ghrelin ho supa boima ba 'mele le takatso ea lijo (28, 29), liphuputso tse ling li supa hore ho ts'oaetsoa moea o matla oa ghrelin hoa hlokahala bakeng sa boits'oaro bo tloaelehileng ba ho ja le likarabo tsa boima ba 'mele, haholo-holo ho lijo tse matlafatsang tse nang le mafura a mangata (HFD) (6, 7, 27, 30). Mohlala, khaello ea GHSR e fokotsa ho nona haholo, boima ba 'mele le ho hlonepha ha motho a pepesehetse HFD ea pele (6, 30). Litoeba tsa Ghrelin tse ileng tsa pepesetsoa HFD bongoaneng li bontša mokhoa o tšoanang (7). Tse ling, empa ha se tsona kaofela, tsa mefuta e sa fetoleheng ea litoeba tsa GHSR le tsona li bonts'a litekanyo tse theohileng tsa 'mele ha motho a pepesetsoa lijo tse tloaelehileng tsa chow.6, 9, 31). Ho khahlisang ke hore phuputsong e 'ngoe, ha ho tlosa liphatsa tsa lefutso tsa lefutso kapa GHSR feela ho sa fella ka phetoho ea boima ba' mele ha motho a pepesetsoa chowon e tloaelehileng, ho tlosoa hoa liphatsa tsa lefutso ka bobeli ho ile ha fokotsa boima ba 'mele, ho fana ka maikutlo a ho ba teng ha likarolo tse ling tsa limolek'hule tsa sistimi ea li-ghrelin signaling (9).

Ghrelin e bohlokoa hape bakeng sa melao ea boima ba 'mele oa motho (32). Tsamaiso ea Ghrelin e eketsa phepelo ea lijo ho batho ba phetseng hantle, mme lits'oaetso tsa pele ho lijo tsa pele-pele li bonoa khafetsa ka letsatsi ha ho fuoa lijo ho baithuti ba tloaelitsoeng ho fepa (8, 17). Ntle le moo, ghrelin e bonahala e loketse mefuta e meng ea botena ba motho (32). Maqhubu a Ghrelin a phahama ho batho ka mor'a ho theola boima ba 'mele bo khothalletsoang ke ho ja,' me joalo ka kenya letsoho molemong oa ho eketsa boima ba 'mele bo tloaelehileng ho bonoang ho lijong33). Hape, ho fokotsa boima ba 'mele bo tšoaeang nako e telele le bo tšoarellang nako e telele ka lebaka la ho buuoa ka Roux-en-Y gastric bypass (RYGB) ho nahanoa ke ba bangata ho ntlafatsoa ka phokotso ea post-bypass ho ghrelin e potolohang. Joalo ka 1st tse tlalehiloeng ho 2002, li-profiles tsa 24-hr ghrelin tsa lithuto tsa RYGB li ne li le> 70% tse tlase ho feta tsa taolo e feteletseng (33). Liteko tse ngata tse ileng tsa latela tsa RYGB li netefalitse khaello ena ea ghypin, e amanang le ho phahama ha ghrelin e bonoang ka ho ja kapa maemong a mang a ho hloka matla (34-36). Ha batho ba bangata ba batenya haholo ba fokolitse maemo a mantlha a moea o potolohang ha o bapisoa le lithuto tse tloaelehileng.32), ho Prader-Willi Syndrome, maemo a phahameng a ghrelin a teng 'me a ngotsoe ke ba bang ho kenya letsoho ho hyperphagia e sa feleng le ho fumana boima ba' mele ka mofuta ona oa syndromic oa botena (37, 38).

Liphumano tsena li tšehelitse khopolo ea hore ho thibela ts'ebetso ea ghrelin e ka ba leano le sebetsang la ho fokotsa boima ba 'mele kapa ho thibela kholo ea botenya (39). Ha e le hantle, ho fokotsa moea o mongata oa bioava fumanehileng kapa tsamaiso ea letsatsi le letsatsi ea bahanyetsi ba GHSR ho fokotsa boima ba 'mele bo fokotsang' mele le ho fokotsa ho ja haholo (39-42). Ka mokhoa o ts'oanang, tsamaiso ho litoeba tsa mohanyetsi oa ghrelin O-acyltransferase, e thusang ho feto-fetoha ha moea oa phetoho ea bohlokoa kamora ho fetoleloa, e fokotsa haholo phaello ea boima ba 'mele ka lebaka la lijo tse matlafalitsoeng ka har'a li-ketane tsa "triglycerides" (43).

Ka lehlakoreng le fapaneng la sefahleho, litoeba le / kapa batho ba nang le cachexia ea etiology e fapaneng le anorexia mothosa ba na le ghrelin e phahameng ea ho potoloha (19, 22). Re kholoa hore litlolo tse phahameng tsa tlhaho tsa "mele" tse amanang le cachexia le anorexia mothosa li sebetsa ka mokhoa oa ts'ireletso khahlanong le seo e neng e tla ba mofuta oa phenotype o matla le ho feta. Maemong a joalo, ghrelin e ka ba e sebelisang karolo e ts'oanang ea ts'ireletso joalo ka ha e ngotsoe nakong ea khatello ea maikutlo le kelello; ke hore, ghassin e phahameng e hlahisoang ke khatello ea maikutlo e thusa ho fokotsa boits'oaro bo amanang le khatello ea maikutlo bo amanang le khatello ea maikutlo (bona ka tlase bakeng sa puisano e ngoe hape) (44). Ebile, le ha maemo a phahameng a ghrelin a hlaha ka tlhaho maemong a cachexia a kenyellelitsoeng, mohlala, ka tsamaiso ea moemeli oa chemotherapeutic cisplatin ho likhoto kapa ho kenngoa ha sarcomas likotong, litekanyetso tsa meriana tse phahamisang maemo a ghrelin mefuteng ena li ntlafatsa le ho feta boima ba 'mele le eketsa tšebeliso ea lijo (22, 45). Ka hona, liphetoho tse teng tsamaisong ea ghrelin li bonahala li sebetsa bakeng sa boima bo fapaneng ba 'mele,' me phekolo ea nakong e tlang bakeng sa mathata a fapaneng a boima ba 'mele e ka kenyelletsa tse amanang le boits'oaro bo itlhommeng pele ba lijo tsa moea oa ghrelin.

Litlamorao tsa Ghrelin ho likarolo tsa hedonic tsa ho ja

Mechini e sebelisang lijo tse matlafatsang lijo tse matlafatsang, 'me ha e kenyelle feela lijo tse matlafatsang tsa lijo, empa hape e ntlafatsa mehloli e metle ea lijo tse itseng tseo moeti a etsang boiteko bo matla ba ho fumana lijo tse khahlisang (27, 46-51). Joalokaha ho hlalositsoe ka tlase, polelo ea GHSR le tšebelisano ea ghrelin le likarolo tse 'maloa tsa boko tse kenyelletsang ts'ebetsong ea moputso li tšehetsa taba ea hore ghrelin e laola likarolo tse ling tsa ho ja (12, 52). Ho shebella mekhoa ena ea ho bua ho lebisitse bafuputsi ho tsebahatsa litlamorao tsa litlamorao tsa boits'oaro ba lijo.

Liphuputso tse 'maloa li hlahlobile karolo ea karolo ea ghrelin ho hlalosang khetho ea lijo. Ghrelin e fetisetsa khetho ea lijo ho lijo tse nang le mafura a mangata (25, 49). Ka mokhoa o ts'oanang, ghrelin e eketsa tšebeliso ea tharollo e ntle ea saccharin mme e eketsa khetho ea lijo tse nang le tatso ea saccharin ka mofuta oa hlaha empa eseng litoeba tse haelloang ke GHSR (47). Ho matlafatsa liphumano tsena, litoeba tse haelloang ke GHSR le litoeba tse khahlanong le GHSR li sebelisa botoro e tlase ea peanut le Ensure® empa ha li fokotse tšebeliso ea kamehla ea letsatsi ka har'a protocol ea khetho ea mahala (48). Ka mokhoa o ts'oanang, mohanyetsi oa GHSR ka nakoana le ka mokhoa o khethang o fokotsa ho kenella ka likhoto tsa 5% sucrose tharollo ka har'a protocol ea metsi a nang le botlolo tse peli tsa botlolo.53). GHSR antagonist e boetse e blunts saccharin tharollo ea boits'oaro ka litoeba (53).

Ntle le ho ntlafatsa khetho ea lijo tse monate le tse mafura, ghrelin e sebelisana le mekhoa e rarahaneng haholoanyane ea ho ja. Mohlala, tlhahlobong ea sebaka se ratang lijo (CPP), nako eo liphoofolo li e sebelisang tikolohong eo li kileng tsa fumana lijo tse monate e bapisoa le nako e sebelisoang tikolohong e ikhethileng e amanang le chow kapa tloaelo lijo. . Tsamaiso ea pharmacologic ea ghrelin le keketseho ea matla ho ghrelin e susumetsoang ke lithibelo tsa caloric ka bobeli li thusa ho fumana CPP bakeng sa HFD (27, 46, 50). Ka lehlakoreng le leng, litoeba tsa mofuta oa hlaha tse tšoaroang ke mohanyetsi oa GHSR nakong ea boemo le maemo 'me litoeba tsa GHSR-null ka bobeli li ile tsa sitoa ho bonts'a CPP bakeng sa HFD ka tloaelo e bonoang tlasa thibelo ea khalori (27). Mohanyetsi oa GHSR o boetse o thibela CPP bakeng sa li-pellets tsa chokolete litekong tse khabisitsoeng (48).

Litlamorao tsa Ghrelin mabapi le boitšoaro bo thehiloeng ho moputso le tsona li se li hlahlobiloe ho sebelisoa mochini o hatellang kapa o tsamaisang nko, o tsepamisang maikutlo molemong oa moputso (27, 51, 54). Ghrelin e eketsa mochini o hatisang mochini oa sucrose, li-sucrose tsa peanut-flavored le li-pellets tsa HFD ka litoeba (27, 51, 55, 56). Ka lehlakoreng le leng, mohanyetsi oa GHSR o fokotsa ts'ebetso e arabelang tharollo ea 5% sucrose (53). Ho joalo, botenya bo khothalletsoang ke ho ja bo fokotsa ts'ebetso e sebelisang moputso bakeng sa meputso ea lijo (51). Mabapi le hona, phello e hlabisang lihlong ea takatso ea phepo e mabapi le tšebelisano ea moea oa boipheliso ka lijo tse ts'oanang le ho hanana le bohato ba ghrelin ba orexigenic bo bonoang ke litoeba tse amanang le phepo (57, 58).

Ketso ea Ghrelin mabapi le moputso oa lijo le eona e bohlokoa ho batho. Haholo-holo, tsamaiso ea ghrelin ho batho ba batho nakong ea ts'ebetso ea ts'ebetso ea matla a matla a matla a khoheli e eketsa karabelo ea neural litšoantšong tsa lijo libakeng tse 'maloa tsa boko tse kentsoeng phepelong ea hedonic, ho kenyelletsa le amygdala, orbitofrontal cortex, hippocampus, striatum, le sebaka sa likarolo tsa Vortal (VTA) (59, 60).

Li-substrates tsa Neuronal le li-circuits tse tsamaisang liketso tsa ghrelin ka moputso oa lijo

Lilemong tse leshome tse fetileng, bafuputsi ba 'maloa ba sebelitse ho fumana palo ea manonyeletso le likhase tse tšoaeang mahlo tse ikarabellang bakeng sa ho fetola liketso tsa ghrelin mabapi le ho ja lapeng, tlhahiso ea lihormone tsa kholo le tlhahiso ea mali ea tsoekere ea glucose [joalo ka ha e hlahlojoe ho (2, 61)]. Litla-morao tsa li-neuronal le li-circuits tse arolelanang moea oa boipheliso oa lijo tse sa tsoa qala ho hlakisoa, mme ho tla buisanoa ka tsona mona (Setšoantšo sa 1).

Setšoantšo sa 1 Faele e kantle e nang le setšoantšo, papiso, joalo-joalo Lebitso la ntho ke nihms360457f1.jpg

Mohlala oa ketso ea ghrelin ho mesolimbic moputso circry bokong ba methapo

Dopamine

Dopaminergic neurons tse hlahang morerong oa VTA ho ea bokong ba li-nucleus (NAc), amygdala, preortalal cortex le hippocampus (11, 15). Litebello tsena li na le tsela ea mesolimbic mme li khanna ka matla boits'oaro ba meputso ea mefuta e fapaneng. Mabapi le bohlokoa, li-GHSR li hlahisoa haholo ho VTA, ho kenyelletsa le dopaminergic VTA neurons (12, 52). Tsamaisong ea ghrelin, likhoto tse nang le VTA-lesioned li jella botoro e nyane ea peanut empa e ja tse lekanang tsoekere e tšoanang, joalo ka ha e bapisoa le liphoofolo tse nang le sham-lesion (48). Likhoto tse nang le leseli la VTA ha li qete nako e nyane ho feta likhoto tse sham-lesioned tse hlahlobang li-tubes tse nang le botoro ea peanut ho arabela ts'ebetsong ea intracerebroventricular ghrelin (48). Ho kokota ka mokhoa o ikhethileng oa polelo ea GHSR ho likhoto tsa transgenic tse hlalosang mofuta oa antisense oa GHSR ho lisele tse nang le lisele tsa tyrosine hydroxylase (tse kenyeletsang dopaminergic VTA neurons) li fokotsa ho ja haholo (62). Hape, tsamaiso e sa fetoheng ea li-ghrelin e susumetsa polelo ea gene ea li-receptor tse 'maloa tsa dopamine ka har'a potoloho ea VTA-NAc (63).

Ghrelin e ka ama ka kotloloho ts'ebetso ea methapo ea dopaminergic VTA (12, 52). Mohlala, exoemea ghrelin e etsa hore ho lokolloe dopamine ho li-neuron tsa VTA morerong oo ho ea ho NAc, mme ghrelin e eketsa khafetsa mohato o ka bang teng methapong ena ea methapo ea kutlo (5, 12, 14, 64, 65). Ntle le moo, tsamaiso ea intra-Vta ea ghrelin le / kapa bahanyetsi ba GHSR ba fetolela mokhoa oa ho ja oa kamehla o tloaelehileng, khetho ea lijo, boitšoaro bo khothatsang ba meputso ea lijo, le liketso tse ling ho kenyelletsa boitšisinyo. Ha ho le joalo, ghrelin microinjection ho VTA e eketsa lijo tse fumanehang ka bolokolohi, ha VTA microinjection ea mohanyetsi oa GHSR e fokotsa tšebeliso ea lijo ka lebaka la ghrelin e sa ts'oaneng.12, 13). Tsamaiso ea ghrelin e sa foleng ka hara lethal dose ea VTA-ka ts'epahalo e eketsa tšebeliso ea kamehla e fumanehang ea kamehla mme e eketsa boima ba 'mele (66). Direct ghrelin microinjection ho VTA le eona e eketsa ho kenella ha botoro ea peanut ka holim'a chow e tloaelehileng.48). Ka mokhoa o ts'oanang, tsamaiso ea intra-VTA ea mohanyetsi oa GHSR e fokotsa ts'ebetso ea HFD, 'me ha e na tšusumetso ea ho ja lijo tse nang le protheine e ngata haholo kapa tse nang le nama ea nama ea nama ea khomo e nang le lik'habohaedreite, tseo ba nang le phihlello e lekanang (66). VTA microinjection ea ghrelin e eketsa mochini o sebetsang o hatellang bakeng sa meputso ea sucrose le li-pellets tse latsoitsoeng ka banana.12, 13, 48, 55, 56, 67), ha VTA microinjection ea mohanyetsi oa GHSR e fokotseha ts'ebetso e arabelang bakeng sa sucrose eo hangata e susumetsoang ke ho potlakisa bosiu (12, 55). Litlamorao tse ntle li bonoa litulong tse sa thibeloang lijo, tseo ho tsona ho tsamaisang 'mala o sa thekeseleng oa VTA nako le nako ha o tsamaisoa ka tšohanyetso a ntse a sebetsana le li-pellets tse nang le tatso ea chokolete e sa tsubang.66). Ho feta moo, striatal dopamine depletion, joalo ka ha e hlahisoa ke ho fana ka Vil e sa sebetseng hantle ea neurotoxin 6-hydroxydopamine, e fokotsa litlamorao tsa moea tse tsamaeang le VTA bakeng sa moputso o matla oa phepelo bakeng sa meputso ea lijo (67). Litlamorao tse matlafatsang tsa ghrelin le tsona li thibetsoe ho intra-VTA GHSR ea li-antagonist tsamaiso (68).

Boithutong ba ho etsa lipatlisiso tsa karolo ea ts'ebetso ea ghrelin ka kotloloho ho VTA, re ile ra tšela litoeba tsa GHSR-null, tse nang le mofuta oa "loxP-flanked transsetal blocking" tse kenang ka har'a mofuta oa GHSR, ho ea litoeba moo polelo ea Cre recombinase e tsamaisoang ke morekisi oa tyrosine hydroxylase (50). Lice tse nang le likopi tse peli tsa GHSR-null allele le kopi e le 'ngoe ea trans transgene li hlahisa li-GHSR ka mokhoa o ikhethileng liseleng tse nang le li-tyrosine hydroxylase hangata li hlophisitsoe ho hlahisa GHSR le tyrosine hydroxylase ka bobeli. Tsena li kenyelletsa, le ha li sa thibeloe, sephutheloana sa VTA dopaminergic neurons. Ghrelin e tšoaea ka kotloloho li-neurons tsena tse atisang ho ba li-dopaminergic ha e mamelle feela bokhoni ba tšebetso ba ghrelin ba ho tsosa takatso ea ho ba teng kamehla ka chow, empa hape e lekane ho hokahanya liketso tsa eona ho CPP bakeng sa HFD (50). Ka kakaretso, lithuto tsena tse ngata li fana ka maikutlo a karolo ea bohlokoa ea li-neurons tsa GTA tsa GHSR tse nang le dopaminergic VTA bakeng sa diketso tsa ghrelin mabapi le lijo le moputso oa lijo.

Li-opioids

Li-opioids li kanna tsa bapala karolo e hlahelletseng ea taolo bakeng sa li-dopaminergic neurons tsa methapo ea methapo ea kutlo. Pele ho intracerebroventricular tsamaiso ea μ-opioid receptor e khethang mohanyetsi, naltrexone, li-opereishene tse arabelang bakeng sa li-pentets tsa sucrose ke likhoto tse fuoeng ghrelin intracerebroventricular (56). Haholo-holo, infusion ea ghrelin e bohareng e eketsa polelo ea μ-opioid receptor mRNA ka har'a VTA (56). Hape, mosebeletsi ea arabelang sucrose e susumetsoang ke VTA microinjection e tobileng ea ghrelin e thibetsoe pele ho VTA microinjection ea naltrexone (56). Ho khahlisang ke hore, le ha ts'ebetso e eketsehileng ea tšusumetso ea moea e fumanehang ka bongata le eona e koetsoe ke naltrexone ha metsoako ena ka bobeli e laoloa intracerebroventricularly, ha e sa bonoa ka kotloloho ho VTA microinjection ea likomporo (56). Kahoo, li-opioid li bohlokoa liketsong tsa ghrelin ho litheko tsa lijo le moputso oa lijo, empa libaka tsa anatomic tsa liserekisi tse laolang lits'ebetso tsena li kanna tsa fapana ka tsela e fapaneng.

NPY

Li-neuron tse arabelang ka Vrel tsa Ghrelin li ka boela tsa angoa ke arcuate hypothalamic neuropeptide Y (NPY) neurons. Hoa tšoana le liphuputso tse boletsoeng ka holimo tsa naltrexone, NPY-Y1 receptor antagonist LY1229U91 (LY) literaka tse buoang li-ghrelin tse kentsoeng li arabela bakeng sa li-pentets tsa sucrose ha LY le ghrelin li sa sebetse ka mokhoa o hlakileng oa ts'ebetso ea bobeli le ea bobeli.56). Ho fapana le naltrexone, LY e blunts ghrelin e tsosang takatso ea ho fumaneha ka bolokolohi hore na ka bobeli ba ente intracerebroventricularly kapa intra-VTA (56). Ka hona, joalo ka ha ho ile ha bonoa bakeng sa li-opioids, ho supa ha NPY ho bohlokoa ho liketso tsa ghrelin tsa orexigenic le liketso tsa eona moputsong oa lijo, le ha liserekisi tse laolang lits'ebetso tsena li fapana ka mokhoa o fapaneng.

Li-Orexins

Tlatsetso e 'ngoe e ka bang teng potolohong ea ghrelin-VTA ke li-orexins (hypocretins). Li-Orexins li nka karolo hantle ka ho ba karolo ea li-neuropeptide ka boits'oaro bo botle. Ketso ea Ghrelin mabapi le moputso oa lijo e hloka ho tšoaetsoa ka mokhoa o hlakileng ke orexin, joalo ka ha ho pakahala ho se atlehe ha litoeba tsa orexin-knockout kapa litoeba tsa mofuta o hlaha tse fuoang XXUMX antagonist SB-1 intraperitoneally ho fumana CPP bakeng sa HFD ho arabela kalafo ea ghrelin (27). E boetse e bonts'a ho rarahana ha li-circuits tsena tsa neuronal, litoeba tsa SB-334867-tse entsoeng esale pele le litoeba tse haelloang ke orexin ka bobeli li bonts'a likarabo tse felletseng tsa orexigenic ho ghrelin (27).

NAChR

Ketso tsa Ghrelin ka moputso oa lijo le tsona li angoa ke ho tšoaetsoa ke cholinergic. Tsamaiso e kenelletseng ea mochini o sa sebetseng oa nicotine acetylcholine receptor (nAchR) o khahlanong le takatso ea lijo e kenang ka har'a litoeba mme o fokotsa bokhoni ba moputso oa lijo o thehiloeng ho chokolete ho beha maemo sebakeng seo a se ratang.69). Haholo-holo, ente ea masapo ea mecamylamine e fokotsa tšebeliso ea lijo tse kenang ka hare ho litoeba (69). Tsamaiso e kenelletseng ea mecamylamine kapa 18-methoxycoronaridine, mohanyetsi ea khethiloeng oa li-receptor tsa nicotinic tsa α3β4, e fokotseha dopamine ea intracerebroventricular ghrelin e kenyellelitseng dopamine e ngata ho NAc (5), intra-VTA e laoloang ke dopamine ea ghrelin-induction e tlisoang ke dopamine e ngata ho NAc (64), le / kapa lijo tsa moea tse kenang kahare-VTA e laoloang ke moea (69). Hape, mofuta o sa foleng oa intracerebroventricular ghrelin modulates nAChRb2 le polelo ea mofuta oa nAChRa3 litseleng tsa mesolimbic (63). Bopaki bo totobetseng ba ts'usumetso ea cholinergic phetohelong ea moputso oa ghrelin bo tsoa thutong eo ho eona mecamylamine e ileng ea etsa hore ho be le lijo tse fumanehang ka bongata ka sejo sa moea (CPP)47), le e 'ngoe moo Tsamaiso ea ho potoloha ea 18-methoxycoronaridine e thibetseng keketseho ea intra-VTA ghrelin-ikiwa le keketso ea tharollo ea 5% nakong ea protocol e fihlelletsoeng ka libotlolo tse peli.64).

Liphuputso tse mabapi le karolo ea ho senoloa ha nachR ho tšebetso ea ghrelin li sibollotse sebaka se seng se ikhethileng sa ts'ebetso - sebaka sa hamorao sa thuto-morao (LDTg) - litlamorao tsa ghrelin moputsong oa lijo. LDTg ke sebaka se tsebahalang sa polelo ea GHSR (52, 69, 70), moo GHSR mRNA e sebelisana 'moho le choline acetyltransferase mRNA (69). Tsamaiso ea Intra-VTA ea mohanyetsi oa nAChR, α-conotoxin MII, e thibela li-NAc dopamine tse fetang tse tlisoang ke LDTg-regrel ghrelin (65). Kahoo, bonyane litlamorao tsa eona, ghrelin e ka sebetsa ka kotloloho ho LDTg cholinergic neurons projeke eo ho VTA.

Glutamate

Tekanyetso ea khatello ea meriana ea tlhahiso ea glutamatergic, joalo ka ha e fihletsoe ke tsamaiso ea intra-VTA ea N-methyl-D-aspartic acid receptor antagonist AP5, e thibela li-dopamine tsa ghrelin tse kenyellelitsoeng ho hlohlelletsoa hoa NAc le ghrelin-induction locomotor (68). Kahoo ho na le monyetla oa hore tlhahiso ea glutamatergic ho VTA le eona e ama bokhoni ba ghrelin ba ho fetola boitšoaro ba moputso oa lijo.

Endocannabinoids

Endocannabinoids e eketsa takatso ea lijo le khothaletso ea ho ja lijo tse fumanehang habonolo (71). Sekhahla se bohareng sa ghrelin ho mofuta oa li-endocannabinoid receptor mofuta oa 1 knockout se hloleha ho eketsa takatso ea lijo, ho fana ka maikutlo a hore mokhoa oa ho saena oa endocannabinoid o hlokahala bakeng sa phello ea orexigenic ea ghrelin hape e ka boetse ea kenella liketsong tsa hedonic tsa ghrelin (72).

Karolo ea ghrelin joalo ka mokena-lipakeng oa khatello ea maikutlo e bakang khatello ea maikutlo

Bohlokoa ba 'mele ba litlamorao tsa phello ea ghrelin moputsong oa lijo bo bonahala ka ho hlaka haholo maemong ao ho' ona moea oa plasma hangata o phahamisoang, joalo ka linako tsa ho hloka matla (73, 74). Mohlala, CPP ea HFD e ts'oaroa ke litoeba tsa mofuta o hlaha ka thibelo e telele ea caloric (27, 54), ha tsamaiso ea bokhopo ba GHSR e ea ho litoeba tsa mofuta o hlaha kapa ho seng joalo, ho tlosoa hoa liphatsa tsa lefutso, e thibela boitšoaro bona bo amanang le moputso oa lijo tse amanang le caloric.27, 54). Tsamaiso ea antagonist ea GHSR e boetse e thibela ts'ebetso e amanang le "caloric limited" e amanang le "lever"63). Motho a ka pheha khang ea hore sisteme ea ghrelin e bile teng ho thusa liphoofolo ho sebetsana le maemo a ho hloka matla ka ho rata ho ja lijo tse matlafatsang tsa khalori.

Ho phahamisoa ha ghrelin le hona ho bonoa holim'a khatello ea maikutlo (44, 75-81). Mohlala, maemo a phahameng lipuong tsa mofuta oa gastric ghrelin gene le plasma ghrelin li etsahala karabong ea litoeba mabapi le khatello ea mohatla le khatello ea phepelo ea metsi (75, 76). Litlhaselo tse phahameng tsa plasma ghrelin le tsona li fumaneha ka litoeba tse hatisoang ke ho pepesetsoa ntloana e nang le likhohola e sa khaotseng kapa tikolohong e batang (44, 50, 77, 82). Ts'ebetso e sa feleng ea khatello ea kelello ea khatello ea maikutlo (CSDS), e sebelisang litoeba tse tona khafetsa tsa ho ts'oaroa ke setlamo ke mohanyetsi e moholo le e moholo, e lebisa maemong a phahameng a plasma ghrelin (44, 50, 83). Ka mokhoa o ts'oanang, ho pepesetsoa litoeba ho protocol ea khatello ea kelello ea 14 ea matsatsi a sa tsitsang le e sa tsitsang ho tsosa plasma ghrelin (81). Batho ba imetsoe haholo khatello ea kelello kapa tlhahlobo e lekantsoeng ea khatello ea maikutlo ea sechaba le bona e bonts'a plasma ghrelin (78, 80). Mekhoa e ikarabellang bakeng sa keketseho ena e amanang le khatello ea maikutlo mochineng o potolohang ha e e-so tsejoe empa e ka kopanngoa ka karabelo ea kutloelo-bohloko, joalo ka ha ho khothaletsoa ke lithuto tse hokahanyang ts'ebetso ea ts'ebetso ea methapo ea kutloelo-bohloko le / kapa tokollo ea li-catecholamine ho secretion ea ghrelin le ho hokahanngoa. karabelo ea khatello ea maikutlo84-86).

Batho ba bangata ba nang le khatello ea maikutlo ba tlaleha phetoho mekhoeng ea bona ea ho ja - ba bang ba ja haholo 'me ba bang ba ja ka tlase ho khatello ea maikutlo pele ho khatello ea maikutlo (87, 88). Ntle le moo, batho ba na le keketseho ea ho ja lijo tse matlafatsoang ntle le karabelo ea lijo ka kakaretso taolong ea khatello ea maikutlo (87, 88). Mekhoa e rarahaneng ea ho ja e amanang le khatello ea maikutlo e kanna ea kenya letsoho keketsehong ea ho ata ha botenya le botenya har'a batho ba pepesehileng khatello ea maikutlo. Ho khahlisang ke hore ho nyoloha ho bakoang ke khatello ea maikutlo holima ghrelin e fumanoang ho "ba jang haholo maikutlong" - ho thoeng ka lebaka la litakatso tsa bona tsa boiphihlelo tsa lijo le ts'ebeliso e eketsehang ea lijo tse nang le lik'habohaedreite le mafura ho arabela maikutlo a mabe le khatello ea maikutlo - li hloleha ho theoha hampe kamora lijo ts'ebeliso (80). Hona ha ho tšoane le karabelo ea moea oa moea o bonoang ho litheko tsa lijo ho batho ba tlalehang phetoho e nyane mekhoeng ea bona ea ho ja ha ba le khatello ea maikutlo (80), 'me ka hona, e fana ka maikutlo a karolo ea ghrelin mekhoeng ea ho ja e thehiloeng ho khatello ea maikutlo.

Re sebelisitse CSDS ho fuputsa ka ho khetheha karolo ea ghrelin mabapi le liphetoho tse bakang khatello ea maikutlo mokhoeng oa moputso oa lijo. CSDS, e boletsoeng kaholimo e phahamisa ghrelin e potolohang, e amahanngoa le hyperphagia ea fumanehang ka bolokolohi e fumanehang ka mehla ka nako le bonyane khoeli e le ngoe kamora nako ea ho hloloa (44, 89, 90). Hyperphagia ena, e sa bonoeng litoebeng tse haelloang ke li-GHSR, e ka kenya letsoho phaellong e phahameng ea 'mele e bonoang ho litoeba tsa mofuta oa hlaha oa CSDS (44, 89, 90). Ha se CSDS feela e khothalletsang karabelo ea hyperphagic ho litoeba tsa mofuta o hlaha, empa e eketsa le CPP bakeng sa HFD (50). Karabo e joalo e bakiloeng ke khatello ea lijo e itšetleha ka ho supa li-ghrelin, hobane CPP ea HFD ha e bonoe ho litoeba tse senotsoeng tsa CSDS GHSR-null (50). Ntle le moo, polelo ea li-GHSRs ka mokhoa o ikhethileng oa li-neuron tse nang le tyrosine hydroxylase (eo, joalo ka ha ho hlalositsoe kaholimo, e kenyelletsa dopaminergic VTA neurons) e lumelletsoe ho kenyelletsa mekhoa ea ho ja hedonic ke protocol ea CSDS (50). Hape ho ka etsahala hore li-glucocorticoids li bapala karolo ea tšehetso ho kopaneng ha ghrelin ho lijo tse thehiloeng ho khatello ea maikutlo, joalo ka ha maemo a phahameng a corticosterone a bonoa ho litoeba tsa mofuta o hlaha tse pepesitsoeng ho CSDS ho feta GHSR-null litterlings tse tšoanang. Sena se bonahala se nepahetse phapusing ea lijo tse amanang le khatello ea maikutlo le lijo tse thehiloeng ho moputso tse bonoang ke mofuta o hlaha ha o bapisoa le GHSR-null litterlings kaha secretion ea glucocorticoid e matlafatsa boits'oaro bo botle ebile e eketsa lijo tse matlafatsang haholo (88).

Se fumanoeng ka holimo sa CSDS ho mofuta oa hlaha le liphoofolo tsa GHSR-null se fapane le se bonoang mohlaleng oa khatello ea maikutlo o sa fetoheng o sa lebelloang oa khatello ea maikutlo e sa foleng.81). Le ha CSDS le khatello ea maikutlo e sa reroang e sa lebelloang ka bobeli e phahamisa ghasine ea plasma, boiphihlelo ba litoeba tse sa lebelloang bo sa bonahaleng bo fokotse takatso ea lijo le phaello ea boima ba 'mele nakong ea nako ea kalafo, ha litoeba tse sa sebetseng tsa GHSR tse haelloang ke phetoho lipapisong tsena (81). Ho hlokahala mosebetsi o mong hape oa ho hlakisa matla a ka bang teng phakeng ea lijo tse fumanehang phepelong ea lijo, moputso oa lijo le boima ba 'mele har'a mefuta e fapaneng ea lijo tse thehiloeng ho khatello ea maikutlo (91-96) le hara batho ba nang le karabelo e fapaneng ea boits'oaro ba karabelo ho khatello ea maikutlo.

Sephetho le maikutlo

Boithuto ba morao tjena bo senotse mathata a mangata a amanang le karolo eo ghrelin e etsoang ho fetoleng lijo, le boleng bo khotsofatsang ba lijo tse fumanehang habonolo. Boholo bo totobatsa bohlokoa ba litsela tsa mesolimbic liphellong tsena. Ho khahlisang, litlamorao tsa ghrelin tsamaisong ea mesolimbic le tsona li fetela mekhoeng e amanang le lithethefatsi le joala, ho fana ka maikutlo a hore ghrelin e ka ba khokahano lipakeng tsa khaello ea lijo le / kapa khatello ea maikutlo ka keketseho ea boleng ba hedonic ba meputso e mengata ka (97-99)]. Ghrelin ka boeona e tsejoa e le moputso oa tlhaho (100). Litsela tsa Mesolimbic le tsona li bohlokoa bakeng sa litlamorao tsa ghrelin ho mongobo. Haholo-holo, ka ho sebelisa mehlala ea litoeba, re bonts'itse hore ho eketseha ha maemo a moea a potolohileng ka matsatsi a 10 a thibelo ea khalori kapa ka ente e matla ea maiketsetso ho hlahisa karabo e kang ea antidepressant litekong tse qobelloang tsa ho sesa (44). Leha ho le joalo, thibelo ea khalori ha e sa hlohlelletsa karabelo ho litoeba tse haelloang ke li-GHSR, e fana ka maikutlo a hore ho kena-kenana le ghrelin ho supang ho nyenyefatsa boits'oaro bo kang ba antidepressant bo amanang le thibelo ea khalori (44). Hape, ha motho a pepesetsoa CSDS, litoeba tsa GHSR-null li bonts'a ho ikhetholla ho batho ba bang (letšoao le leng la boits'oaro bo tepelletsang) ho feta batho ba tloaetseng ho tlatlapa (44). Ka hona, re khothalelitse hore ts'ebetso ea ts'ebetso ea ghrelin signachingways ha e sebetsana le khatello ea maikutlo e sa fetoheng e ka ba tloaelo ea lapeng e thusang batho ho sebetsana le khatello ea maikutlo. Ntle le lits'ebetso tse ling re ile ra khona ho hlahisa li-neurons tsa moea tse arabelang ka sebuelellong (ghrelin-reactionate catecholaminergic neurons), li-ghrelin tse otlolohileng ka ho toba ka li-GHSRs tse fumanehang sebakeng sa catecholaminergic neurons (ho kenyelletsa le likarabo tse boletsoeng pejana tsa VTA dopaminergic neurons) le tsona li lekane bakeng sa likarabo tse tloaelehileng tsa kamora ho latela khatello ea maikutlo e sa foleng.50).

Ka lebaka la liketso tsena tse ngata tsa ghrelin le tse shebahalang li potoloha li-circonal tsa neuronal, motho a ka nahana ka ketsahalo eo ho eona ts'ebetso ea ghrelin e etsisang batho ba nang le bothata ba ho ipolaisa tlala ho phekola bocha ho ka thibela marotholi a amanang le ghrelin e potolohang. Molumo o latelang oa li-circuits tse kenelletseng ka moea o matla o ka thusa ho hlohlelletsa lijo, oa fokotsa se ka fokolisang khatello ea maikutlo (boemo bo lulang bo le bobe pakeng tsa lithuto tsa anorexia amanosa), 'me oa lebisa ho phetseng hantle (ka lebaka la thepa ea tlhaho e ruisang ea ghrelin).

Ka lehlakoreng le leng, mesolimbic pathways e tsamaisang bonyane litlamorao tse ling tsa ghrelin ka ho ja lapeng, ho ja ka hedon, le moea o fokotsang ts'ebetso ea tsona joalo ka sepheo sa ho fokotsa lithethefatsi. Sebopeho se kopantsoeng sa methapo ea methapo ea methapo se kopanyang karabelo ea boitšoaro bo kopanetsoeng se ka bolela esale pele pheletso e tšoanang le ea lithethefatsi tse felisang botenya Rimonabant, e sa kang ea fumana tumello ea FDA ka lebaka la litlaleho tse eketsehang tsa khatello ea maikutlo e matla, bakeng sa likhomphutha tse ling tse khahlanong le botenya. Boitšoaro bo joalo bo shebahalang bo hokahane bo totobatsa le ho feta bohlokoa ba lithuto tse reretsoeng ho khetholla litsela tsa neuroanatomical tse laolang liketso tsa ghrelin ka boitšoaro ba ho ja bo amanang le boima ba 'mele homeostasis, moputso, khatello ea maikutlo le maikutlo. Leha sena se ka re khutlisa, re lumela hore datha tsohle tse fumanehang tse amanang le ghrelin le boits'oaro ba moputso oa lijo li tšehetsa ka matla mohopolo oa ho shebisa lits'ebetso tsa ghrelin e le leano le hlakileng la ho phekola le / kapa ho thibela kholo ea boima ba 'mele bo feteletseng.

lumela hore baa fokola

Bangoli ba ka thabela ho amohela thuso ea Dr. Michael Lutter bakeng sa litlhaloso tsa hae tse ngata tse thusang nakong ea ho hlophisoa ha buka ena e ngotsoeng ka letsoho. Boithuto bona bo tšehelitsoe ke Florencio Fiorini Foundation, Mokhatlo oa Lipatlisiso oa Brain oa Machabeng le lithuso tsa PICT2010-1954 ho MP le R01DA024680 le R01MH085298 NIH lithuso ho JMZ.

Mongolo o botlaaseng ba leqephe

Liphatlalatso tsa Lichelete

Bangoli ha ba tlalehe litabeng tsa lichelete kapa litabeng tse ka 'nang tsa e-ba le thahasello.

Boitlhotlhollo ba Mohoeletsi: Ena ke faele ea PDF ea mongolo o ngotsoeng ka letsoho o sa amoheloang o amoheletsoeng bakeng sa ho hatisoa. Joaloka tšebeletso ho bareki ba rona re fana ka phetolelo ena ea pele ea mongolo o ngotsoeng ka letsoho. Mongolo o ngotsoeng ka letsoho o tla ba le ho kopitsa, ho kenya lihlopha le ho hlahloba bopaki bo hlahang pele o hatisoa ka mokhoa oa oona oa ho qetela. Ka kopo hlokomela hore nakong ea mekhoa ea tlhahiso ea lihlahisoa e ka fumanoa e ka amang litaba, le litsebiso tsohle tsa molao tse sebetsang koranteng e amanang le eona.

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