Ọrụ nke ghọrọ na nri iri nri (2012)

PMCID: PMC3388148

NIHMSID: NIHMS360457

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

Mbubre ọhụụ nke onye bipụtara edemede a dị na Ọrịa Ọrịa

Hụ ihe ndị ọzọ na PMC na ebe isiokwu e bipụtara.

Gaa:

nkịtị

The peptide hormone ghrelin na-arụ ọrụ na etiti ụjọ usoro dị ka ihe ike orexigenic mgbama. Ọ bụghị naanị na a ghọtara ghrelin ka ọ na-ekere òkè dị mkpa n'inye nri sekit a na-eche na ọ na-emetụta homeostasis arọ ahụ, mana ọnụ ọgụgụ ọmụmụ sayensị na-agbakọta ugbu a achọpụtala ghrelin dị ka onye na-achịkwa isi ihe na-adabere na ụgwọ ọrụ, omume iri nri hedonic. N'isiokwu dị ugbu a, anyị na-enyocha omume orexigenic nke ghrelin, ihe akaebe na-ejikọta ghrelin na omume ụgwọ ọrụ nri, usoro nwere ike iji ghrelin na-edozi omume iri nri dabeere na ụgwọ ọrụ, yana ọmụmụ ndị ahụ na-atụ aro ọrụ dị mkpa maka ghrelin na mgbanwe omume iri nri nke nrụgide kpatara.

Keywords: Ghrelin, GHSR, hedonic, ụgwọ ọrụ, iri nri, nchekasị

Ghrelin bụ hormone peptide emebere nke ọma site na otu dị iche iche nke sel endocrine dị n'ime mucosa gastric oxyntic (1). Ghrelin na-arụ ọrụ site na onye na-anabata ihe nzuzo nke homonụ uto (GHSR), onye nnabata G-protein jikọtara ya na mbụ bụ ebumnuche nke secretagogues hormone uto synthetic.2). A na-egosipụta GHSR n'ọtụtụ ụbụrụ ụbụrụ na anụ ahụ dị n'akụkụ, ebe ha na-edozi omume ghrelin na otu usoro na omume dị iche iche.3). Ndị a gụnyere ọrụ na nzuzo nzuzo nke homonụ na-eto eto, glucose homeostasis ọbara, ọrụ locomotor, prokinesis eriri afọ na omume metụtara ọnọdụ uche, n'etiti ọtụtụ ndị ọzọ.3-5). Na mgbakwunye, ghrelin dị mkpa maka ịdị arọ ahụ na nhazi nguzozi ike (6-9A na-amata ya dị ka naanị hormone peptide orexigenic mara (3). E gosipụtara Ghrelin na mbụ ka ọ na-akpali iri nri site na ịgbalite sekit hypothalamic homeostatic (10). Sekit homeostatic ndị a na-enye ụzọ nke ghrelin na akara ndị ọzọ nke nnweta ike na ọrụ eriri afọ nwere ike iji sistemu ụjọ nke etiti megharịa oriri na mmefu ume na n'ikpeazụ, jikwaa ịdị arọ ahụ.11). Ihe akaebe na-adịbeghị anya na-egosi na ghrelin na-achịkwa sekit mesolimbic na, n'ihi ya, akụkụ dị iche iche na-abụghị homeostatic, akụkụ hedonic nke iri nri.12-14). Hedonic, ma ọ bụ iri nri dabere n'ụgwọ ọrụ, gụnyere omume ndị na-eduga na iri nri na-atọ ụtọ, nke ndị mmadụ na-akpali iji nweta nke ọma (15). N'ebe a, anyị na-enyocha ọrụ ghrelin dị ka hormone orexigenic, na-elekwasị anya na mmetụta ghrelin na iri nri dabere na ụgwọ ọrụ. Anyị na-atụlekwa ihe gbasara physiological nke omume a na karịsịa, ọrụ ghrelin dị ka onye ogbugbo nke nrụgide na-akpata, omume iri nri dabeere na ụgwọ ọrụ.

Omume orexigenic nke ghrelin na mmekọrịta ya na ibu ahụ

Mmetụta Ghrelin na iri nri bụ nke ọma [dị ka enyochala (8)). Ghrelin na-egosi ma na-enyere aka ịzaghachi ọnọdụ enweghị ike. Na-ekesa ghrelin na-abawanye tupu nri ruo ọkwa nke na-akpali iri nri mgbe nchịkwa nke homonụ na-emepụta.8). Ọkwa ya na-ebilikwa na-esochi ụkọ nri yana mgbe mbelata ibu ya jikọtara ya na mmega ahụ na cachexia (16-22). Infusions nke ghrelin ma ọ bụ GHSR agonists na-abawanye ibu ahụ site na omume pro-orexigenic na / ma ọ bụ ibelata mmefu ike10, 23-26). Omume orexigenic nke Ghrelin na-adị ngwa ngwa ma na-akpalite iri nri ọbụlagodi n'oge obere nri na-enweghị onwe ya (8). Mgbe o buchara ọnụ abalị, ndị na-emegide ghrelin na-egbochi iribiga nri ókè (27). Ọgwụgwọ na-adịghị ala ala na exogenous ghrelin na-akwalitekwa nri na uru ahụ, na-atụ aro na ghrelin na-ekere òkè na nhazi ịdị arọ ahụ ogologo oge.25). Ọ bụ ezie na ụfọdụ ọmụmụ egosila ntakịrị na enweghị mmetụta nke mkpụrụ ndụ ihe nketa ma ọ bụ ọgwụ ọgwụ na ghrelin na-egosi na ịdị arọ ahụ na oriri (nri).28, 29), ọmụmụ ndị ọzọ na-atụ aro na achọrọ akara ghrelin na-emebi emebi maka omume iri nri na nzaghachi ịdị arọ nke anụ ahụ, ọkachasị maka nri nwere oke abụba (HFD) na-akwụghachi ụgwọ (HFD).6, 7, 27, 30). Dịka ọmụmaatụ, ụkọ GHSR na-ebelata oriri, ịdị arọ ahụ na adiposity n'oge mkpughe HFD.6, 30). Ụmụ oke Ghrelin knockout kpughere HFD n'oge ndụ ha na-egosi ụdị phenotype (7). Ụfọdụ, ma ọ bụghị ihe niile, nke ụdị òké enweghị ụkọ GHSR na-egosipụtakwa mbelata ịdị arọ ahụ mgbe ikpughe na nri chow ọkọlọtọ.6, 9, 31). N'ụzọ na-akpali mmasị, n'otu nnyocha, ebe mkpochapụ mkpụrụ ndụ ihe nketa nke ghrelin ma ọ bụ GHSR naanị arụpụtaghị mgbanwe ọ bụla na ịdị arọ nke ahụ mgbe ikpughe na ọkọlọtọ chow, mkpochapụ mkpụrụ ndụ ihe nketa nke abụọ mere ka ịdị arọ ahụ belata, na-atụ aro ịdị adị nke ihe ndị ọzọ molekụla nke ghrelin signaling system.9).

Ghrelin dịkwa mkpa maka nhazi oke ahụ mmadụ (32). Nlekọta Ghrelin na-abawanye oriri n'ime ndị nwere ahụike, yana a na-ahụta pre-prandial ghrelin ugboro ugboro kwa ụbọchị ka a na-enye ndị ekpughere n'usoro nhazi nri.8, 17). Na mgbakwunye, ghrelin dị mkpa maka ụfọdụ ụdị oke ibu mmadụ (32). Ọkwa Ghrelin na-ebili na ndị mmadụ n'otu n'otu mgbe oke ibu na-ebute site na iri nri, na nke a nwere ike itinye aka na nkwụghachi ibu ibu a na-ahụkarị na ndị na-eri nri.33). Ọzọkwa, ọtụtụ ndị na-eche na a ga-akwalite oke ibu ahụ akara na ogologo ogologo nke ịwa ahụ Roux-en-Y gastric bypass (RYGB) kpatara site na mbelata ga-agafe na ghrelin na-ekesa. Dị ka 1st kọrọ na 2002, 24-hr ghrelin profaịlụ nke isiokwu RYGB bụ>70% dị ala karịa nke njikwa oke ibu (33). Ọtụtụ ule RYGB sochirinụ ekwenyela na nke a bụ ụkọ ghrelin, na-emegide ịrị elu ghrelin na-eri nri ma ọ bụ ihe atụ ndị ọzọ nke enweghị ike (ike).34-36). Ọ bụ ezie na ọtụtụ ndị buru oke ibu ebelatala ọkwa mmalite nke ghrelin na-ekesa ma e jiri ya tụnyere isiokwu nkịtị (32), na Prader-Willi Syndrome, ọkwa ghrelin dị elu dị ma ụfọdụ biputere ya ka ọ nye aka na hyperphagia na-adịghị akwụsị akwụsị na uru bara uru nke ụdị oke ibu nke syndromic a.37, 38).

Nchọpụta ndị a akwadola echiche na igbochi ghrelin omume nwere ike ịbụ atụmatụ dị irè iji belata ibu ahụ ma ọ bụ gbochie mmepe nke oke ibu (39). N'ezie, mbelata nke bioavailable ghrelin ma ọ bụ nchịkwa kwa ụbọchị nke ndị na-emegide GHSR na oke oke ibu na-akpata nri na-ebelata ibu ahụ ma belata oriri.39-42). N'otu aka ahụ, nchịkwa nye ụmụ oke nke onye na-emegide ghrelin O-acyltransferase, nke na-eme ka mgbanwe mgbanwe dị mkpa gachara nke ghrelin, na-ebelata oke ibu na nzaghachi nri nke nwere triglycerides nke ọkara.43).

N'akụkụ nke ọzọ nke ụdịdị ahụ, òké na / ma ọ bụ ụmụ mmadụ nwere cachexia nke etiologies dị iche iche na anorexia nervosa nwere nnukwu ghrelin na-ekesa (19, 22). Anyị na-eche na elu ghrelin endogenous jikọtara ya na cachexia na anorexia nervosa na-arụ ọrụ nchebe megide ihe ọzọ ga-abụ phenotype siri ike karị. N'akụkụ dị otú ahụ, ghrelin ga na-arụ ọrụ nchebe yiri nke ahụ dị ka etinyere n'oge nrụgide psychosocial; ya bụ, ghrelin dị elu nke nrụgide na-akpata na-enyere aka ibelata àgwà ịda mbà n'obi metụtara nchekasị (lee n'okpuru maka mkparịta ụka ọzọ) (44). N'ezie, ọ bụ ezie na elu ghrelin na-emekarị na ọnọdụ nke cachexia, dịka ọmụmaatụ, site na nchịkwa nke onye na-ahụ maka chemotherapeutic cisplatin na oke ma ọ bụ itinye sarcomas n'ime oke, na-ebuli ọkwa ghrelin n'ụdị ndị a ọbụna na-eme ka ahụ dịkwuo mma. na-abawanye oriri oriri (22, 45). Ya mere, mgbanwe na usoro ghrelin na-egosi na ọ dị mkpa maka oke ahụ dị iche iche, na ọgwụgwọ n'ọdịnihu maka nsogbu dị iche iche nke ịdị arọ ahụ nwere ike ịgụnye ndị na-ezubere àgwà iri nri dabere na ghrelin.

Mmetụta Grelin na akụkụ hedonic nke iri nri

Usoro nke ghrelin na-akwalite oriri nri nwere ọtụtụ akụkụ, yana ọ bụghị naanị na-akpali akpali oriri site na usoro homeostatic, kamakwa ịkwalite akụrụngwa na-akwụghachi ụgwọ nke ụfọdụ nri nke onye ọbịa na-etinyekwu mgbalị iji nweta nri na-atọ ụtọ nke ọma.27, 46-51). Dị ka a tụlere n'okpuru, okwu GHSR na mmekọrịta ghrelin na ọtụtụ mpaghara ụbụrụ na-etinye aka na nhazi ụgwọ ọrụ na-akwado echiche nke ghrelin na-achịkwa akụkụ ndị a na-eri nri.12, 52). Nleba anya usoro okwu ndị a emeela ka ndị nyocha mara nsonaazụ ghrelin nke ọma na omume ụgwọ ọrụ nri.

Ọtụtụ ọmụmụ enyochala ọrụ maka ghrelin n'ịkọwa mmasị nri. Ghrelin na-atụgharị mmasị nri gaa na nri nwere abụba bara ụba (25, 49). N'otu aka ahụ, ghrelin na-abawanye oriri nke saccharin na-atọ ụtọ ma na-abawanye mmasị maka nri nwere ụtọ saccharin n'ụdị anụ ọhịa mana ọ bụghị ụmụ oke na-enweghị GHSR.47). Na-ewusi nchoputa ndị a ike, ụmụ oke na-enweghị GHSR na oke GHSR na-emegide ndị na-emegide GHSR na-eri obere peanut butter na Ensure® mana anaghị ebelata oriri nke chow mgbe niile na usoro nhọrọ nnwere onwe.48). N'otu aka ahụ, GHSR antagonist nwa oge wee họrọ mbelata oriri site oke nke 5% sucrose ngwọta na sucrose vs. mmiri abụọ-ụra mmanya-ụba mmanya (ụtụ mmanya).53). GHSR antagonist na-akpachapụkwa anya saccharin ngwọta nchịkwa onwe ya site na ụmụ oke (53).

Na mgbakwunye na ịkwalite mmasị maka nri dị ụtọ na abụba abụba, ghrelin na-edozi ihe mgbagwoju anya, omume iri nri dabere na ụgwọ ọrụ. Dịka ọmụmaatụ, n'ule nleba anya nri ọnọdụ ọnọdụ nri (CPP), oge ụmụ anụmanụ na-anọ na gburugburu ebe ha nwere ọnọdụ iji chọta nri na-atọ ụtọ ka atụnyere oge a na-etinye na gburugburu ebe dị iche iche jikọtara ya na ịcha mgbe niile ma ọ bụ enweghị nri. . Nlekọta ọgwụ nke ghrelin na mmụba endogenous na ghrelin kpatara site na mmachi caloric na-enyere aka inweta CPP maka HFD (27, 46, 50). N'aka nke ọzọ, ụdị oke anụ ọhịa ejiri GHSR antagonist emeso ya n'oge oge oyi na ụmụ oke GHSR-null ha abụọ egosighi CPP maka HFD a na-ahụkarị n'okpuru mmachi calorie (27). GHSR antagonist na-egbochikwa CPP maka pellets chocolate n'ime oke oke juru (48).

A na-enyochakwa mmetụta Ghrelin na omume iri nri dabere na iji operant lever-pressing ma ọ bụ operant imi, nke na-elekwasị anya n'akụkụ mkpali nke ụgwọ ọrụ.27, 51, 54). Ghrelin na-abawanye operant lever-pịa maka sucrose, sucrose na-esi ísì ụtọ nke ahụekere, yana pellets HFD n'ime òké.27, 51, 55, 56). N'aka nke ọzọ, GHSR antagonist na-ebelata ịzaghachi onye ọrụ maka 5% sucrose solution (53). N'ịmara, oke ibu nri kpatara na-ebelata onye na-arụ ọrụ na-akpali ghrelin na-aza maka ụgwọ ọrụ nri (51). N'akụkụ dị otú ahụ, mmetụta na-adịghị mma nke oke oke nri na-akpata na mgbasa ozi ghrelin nke omume ụgwọ ọrụ nri yiri nguzogide omume orexigenic nke ghrelin hụrụ na oke oke nri na-akpata.57, 58).

Omume Ghrelin na ụgwọ ọrụ nri dịkwa mkpa n'ime mmadụ. Karịsịa, nchịkwa ghrelin na ndị mmadụ n'oge onyonyo resonance magnet na-arụ ọrụ na-abawanye nzaghachi akwara ozi na foto nri n'ọtụtụ mpaghara ụbụrụ metụtara nri hedonic, gụnyere amygdala, orbitofrontal cortex, hippocampus, striatum, na mpaghara ventral tegmental (VTA).59, 60).

Mkpụrụ akwara na sekit na-agbazi omume ghrelin na ụgwọ ọrụ nri

N'ime afọ iri gara aga, ọtụtụ ndị ọrụ nyocha arụ ọrụ iji chọpụta ọnụọgụ neuronal na cascades intracellular na-ahụ maka ịhazigharị omume ghrelin na iri nri homeostatic, mwepụta homonụ na-eto eto na glucose homeostasis [dị ka enyocha ya na (2, 61)). A na-amalite ịkọwapụta ihe ndị neuronal substrates na sekit na-eme ka omume ụgwọ ọrụ nri ghrelin butere, a ga-atụlekwa ya ebe a (Nyocha 1).

Nyocha 1 Faịlị mpụga na-ejide eserese, ihe atụ, wdg. Aha ebumnuche bụ nihms360457f1.jpg

Ihe nlere nke ghrelin na-arụ ọrụ na sekit ụgwọ ọrụ mesolimbic na ụbụrụ òké

dopamine

Dopaminergic neurons na-esite na VTA oru ngo na nucleus accumbens (NAc), amygdala, prefrontal cortex na hippocampus.11, 15). Ntụle ndị a nwere ụzọ mesolimbic ma na-akpachapụ anya omume ụgwọ ọrụ nke ụdị dị iche iche. Dị mkpa, GHSR na-egosipụta nke ọma na VTA, gụnyere dopaminergic VTA neurons (12, 52). N'okpuru nchịkwa ghrelin, oke nwere VTA na-eri nri obere obere peanut mana na-eri nha nha nha anya, ma e jiri ya tụnyere anụmanụ ndị nwere mmerụ ahụ.48). Oke ndị nwere VTA na-anọ obere oge karịa oke ndị nwere mmerụ ahụ na-enyocha tubes nwere bọta ahụekere na nzaghachi na nchịkwa ghrelin intracerebroventricular (48). Nhọrọ nhọrọ nke okwu GHSR na oke transgenic na-ekwupụta transcript GHSR antisense na tyrosine hydroxylase nwere sel (nke gụnyere dopaminergic VTA neurons) na-ebelata oriri.62). Ọzọkwa, nchịkwa ghrelin na-adịghị ala ala na-emetụta mkpụrụ ndụ ihe nketa nke ọtụtụ ndị na-anabata dopamine n'ime sekit VTA-NAc.63).

Ghrelin nwere ike imetụta ọrụ dopaminergic VTA neuronal ozugbo.12, 52). Dịka ọmụmaatụ, exogenous ghrelin na-ebute ntọhapụ dopamine site na VTA neurons nke na-arụ ọrụ na NAc, na ghrelin na-abawanye ugboro ole omume na neurons ndị a.5, 12, 14, 64, 65). Ọzọkwa, nchịkwa intra-VTA nke ghrelin na/ma ọ bụ ndị na-emegide GHSR na-agbanwe oriri nke chaw mgbe niile, mmasị nri, omume ụgwọ ọrụ nri na-akpali akpali, na omume ndị ọzọ gụnyere locomotion. Dị ka nke a, ghrelin microinjection n'ime VTA na-abawanye ụbara oriri nke dị n'efu, ebe VTA microinjection nke onye na-emegide GHSR na-ebelata oriri oriri na nzaghachi na ghrelin dị n'akụkụ.12, 13). Nlekọta ghrelin na-adịghị ala ala n'ime VTA dose-dabere na-abawanye oriri nke ịhịa aka n'ahụ mgbe niile ma na-abawanye ibu ahụ.66). Direct ghrelin microinjection n'ime VTA na-abawanye oriri nke peanut bọta n'oge ịhịa aka n'ahụ.48). N'otu aka ahụ, nchịkwa intra-VTA nke onye na-emegide GHSR na-ahọrọ nke ọma na-ebelata oriri nke HFD, ọ nweghịkwa mmetụta na oriri nke protein-ọgaranya ma ọ bụ nke nwere carbohydrate na-amasịghị ya, nke ha nwere ohere nhata.66). VTA microinjection nke ghrelin na-abawanye operant lever-pịa maka ụgwọ ọrụ sucrose na pellet nwere ụtọ banana (12, 13, 48, 55, 56, 67), ebe VTA microinjection nke GHSR antagonist na-ebelata onye ọrụ na-azaghachi maka sucrose nke na-ebutekarị ngwa ngwa abalị (12, 55). A na-ahụ mmetụta ihe atụ na oke nri amachibidoro, nke nnyefe intra-VTA ghrelin na-adịghị ala ala na-abawanye ebe nnyefe intra-VTA GHSR na-adịghị ala ala na-eme ka onye na-arụ ọrụ na-azaghachi pellet nwere chọkọletị.66). Ọzọkwa, striatal dopamine depletion, dị ka nke a na-ebute site na nnyefe VTA na-adịghị n'otu nke neurotoxin 6-hydroxydopamine, na-ebelata mmetụta ghrelin intra-VTA na-achịkwa na operant lever-pịa maka ụgwọ ọrụ nri.67). A na-egbochikwa mmetụta mkpali locomotor nke ghrelin na nchịkwa intra-VTA GHSR.68).

N'ime ọmụmụ iji nyochaa ọrụ nke ghrelin ozugbo na VTA, anyị gafere ụmụ oke GHSR-null, nke nwere cassette na-egbochi ederede loxP nke etinyere n'ime mkpụrụ ndụ GHSR, na ụmụ oke nke onye na-akwalite tyrosine hydroxylase na-ebugharị Cre recombinase. (50). Ụmụ oke nwere nnomi abụọ nke GHSR-null allele na otu oyiri nke Cre transgene na-egosipụta GHSR na-ahọrọ n'ime sel ndị nwere tyrosine hydroxylase na-emekarị ka ha gosipụta ma GHSR na tyrosine hydroxylase. Ndị a gụnyere, ọ bụ ezie na ejedebeghị na, akụkụ nke VTA dopaminergic neurons. Ghrelin na-egosi kpọmkwem na neurons ndị a na-ahụkarị dopaminergic ọ bụghị naanị ndị mgbasa ozi na-enye ike ghrelin iji kpalite oriri nke chaw mgbe niile, kamakwa zuru ezu iji dozie omume ya na CPP maka HFD.50). N'ozuzu, ọtụtụ ọmụmụ ihe ndị a na-atụ aro ọrụ dị oke egwu nke GHSR nwere dopaminergic VTA neurons maka omume ghrelin na oriri nri na ụgwọ ọrụ nri.

Opioids

Opioids nwere ike rụọ ọrụ nchịkwa ama ama maka neurons VTA dopaminergic na-anabata ghrelin. Tupu nchịkwa intracerebroventricular nke μ-opioid receptor antagonist, naltrexone, na-egbochi ndị na-arụ ọrụ na-azaghachi pellet sucrose site na oke nyere ghrelin intracerebroventricularly.56). Kpọmkwem, infusion nke ghrelin etiti na-abawanye okwu mRNA μ-opioid receptor n'ime VTA.56). Ọzọkwa, onye ọrụ na-azaghachi maka sucrose nke sitere na VTA microinjection nke ghrelin na-egbochi tupu VTA microinjection nke naltrexone.56). N'ụzọ na-akpali mmasị, ebe ịba ụba nke ghrelin na-akpata chow nke dị n'efu na-egbochikwa naltrexone mgbe a na-elekọta ogige abụọ ahụ intracerebroventricularly, a naghị ahụ nke a n'elu VTA microinjection nke ogige ahụ.56). Dị ka ndị dị otú a, opioids dị oke egwu na omume ghrelin na ma nri nri na ụgwọ ọrụ nri, mana ebe anatomic nke sekit na-achịkwa usoro ndị a nwere ike ọ dịkarịa ala iche.

NPY

Neurons VTA na-anabata Ghrelin nwekwara ike imetụta site na neurons hypothalamic neuropeptide Y (NPY). Dị ka ọmụmụ naltrexone ahụ a kpọtụrụ aha n'elu, NPY-Y1 antagonist LY1229U91 (LY) na-egbochi onye na-arụ ọrụ ghrelin na-aza maka sucrose pellets mgbe a na-enye LY na ghrelin intracerebroventricularly, ọ bụ ezie na LY adịghị arụ ọrụ na-arụ ọrụ n'ime ya na n'ime ya.56). N'adịghị ka naltrexone, LY blunts ghrelin-kpaliri oriri nke chow a na-enweta n'efu ma a na-agbanye ha abụọ intracerebroventricularly ma ọ bụ intra-VTA.56). Ya mere, dị ka a na-ahụ maka opioids, NPY nrịbama dị mkpa maka omume orexigenic nke ghrelin na omume ya na ụgwọ ọrụ nri, n'agbanyeghị na sekit na-achịkwa usoro ndị a bụ ma ọ dịkarịa ala akụkụ dị iche iche.

Orexins

Ihe ọzọ nwere ike itinye n'ime sekit ghrelin-VTA bụ orexins (hypocretins). Orexins bụ ndị e ji mara neuropeptide nke ọma na omume na-akwụghachi ụgwọ. Omume Ghrelin na ụgwọ ọrụ nri chọrọ akara ngosi site na orexin, dị ka egosipụtara site na ọdịda nke oke orexin-knockout ma ọ bụ oke anụ ọhịa nyere orexin receptor 1 antagonist SB-334867 intraperitoneally iji nweta CPP maka HFD na nzaghachi ọgwụgwọ ghrelin (27). Na-egosipụtakwa mgbagwoju anya nke sekit akwara ndị a, SB-334867-pretreated ụmụ oke na oke oke orexin na-egosipụta nzaghachi orexigenic zuru oke na ghrelin.27).

nAChR

Ihe mgbaàmà cholinergic na-emetụtakwa omume Ghrelin na ụgwọ ọrụ nri. Nlekọta intraperitoneal nke ndị anaghị ahọpụta, nicotine acetylcholine receptor (nAchR) antagonist mecamylamine na-ebelata oriri na-ebu ọnụ n'ime òké ma na-ebelata ikike nke ụgwọ ọrụ nri chọkọleti iji dozie ọnọdụ mmasị (nAchR).69). Kpọmkwem, ịgba ọgwụ intraperitoneal nke mecamylamine na-ebelata oriri intracerebroventricular nke ghrelin na-ebute oke na oke.69). Nlekọta intraperitoneal nke mecamylamine ma ọ bụ 18-methoxycoronaridine, onye na-emegide ndị na-anabata α3β4 nicotinic, na-ebelata dopamine intracerebroventricular ghrelin na-ebufe na NAc.5), intra-VTA na-achịkwa ghrelin na-akpata dopamine na-ejupụta na NAc (64), na/ma ọ bụ intra-VTA-nri nri ghrelin na-ebute (69). Ọzọkwa, intracerebroventricular ghrelin na-adịghị ala ala na-agbanwe okwu nAChRb2 na nAChRa3 n'ime ụzọ mesolimbic.63). Ihe akaebe kacha pụta ìhè nke mmetụta cholinergic na mgbagha ghrelin nke nri nri sitere na ọmụmụ nke mecamylamine na-eme ka ghrelin nweta nri CPP (nri).47), na nke ọzọ nke nchịkwa mpaghara nke 18-methoxycoronaridine gbochiri intra-VTA ghrelin na-ebute mmụba na 5% sucrose ngwọta oriri n'oge usoro ohere oghere oghere abụọ.64).

Nnyocha na ọrụ nke nAChR nrịbama na ghrelin action ekpughere ebe ọzọ nwere ike ime ya kpọmkwem - mpaghara laterododorsal tegmental (LDTg) -maka mmetụta ghrelin na ụgwọ ọrụ nri. LDTg bụ saịtị ama ama nke okwu GHSR (52, 69, 70), ebe GHSR mRNA jikọtara ya na choline acetyltransferase mRNA (69). Intra-VTA nchịkwa nke nAChR antagonist, α-conotoxin MII, na-egbochi NAc dopamine njupụta nke LDTg na-achịkwa ghrelin.65). Ya mere, maka opekata mpe ụfọdụ mmetụta ya, ghrelin nwere ike ime ihe ozugbo na LDTg cholinergic neurons nke na-arụ ọrụ na VTA.

Glutamate

Mbelata ọgwụ ọgwụ nke akara glutamatergic, dị ka a na-enweta site na nchịkwa intra-VTA nke N-methyl-D-aspartic acid antagonist AP5, na-egbochi ghrelin na-akpata dopamine na-ejupụta na NAc na mkpali locomotor na-ebute ghrelin.68). Yabụ na ọ nwere ike na ntinye glutamatergic na VTA na-emetụtakwa ike ghrelin iji gbanwee omume ụgwọ ọrụ nri.

Endocannabinoids

Endocannabinoids na-abawanye oriri na mkpali iji rie nri dị ụtọ (71). Ngwunye etiti nke ghrelin na endocannabinoid ụdị 1 knockout ụmụ oke anaghị abawanye oriri nri, na-atụ aro na usoro akara ngosi endocannabinoid dị mkpa maka mmetụta orexigenic nke ghrelin yana nwekwara ike mebie omume hedonic nke ghrelin.72).

Ọrụ ghrelin dị ka onye ogbugbo nke omume iri ihe mgbagwoju anya na-akpata

Mmetụta physiologic mmetụta ghrelin na ụgwọ ọrụ nri yiri ka ọ pụtara ìhè n'oge ọnọdụ nke plasma ghrelin na-ebuli elu, dị ka oge ụkọ ike (oge adịghị ike).73, 74). Dịka ọmụmaatụ, CPP maka HFD na-adọta n'ime ụdị oke ọhịa site na mmachi caloric ogologo oge (27, 54), ebe nchịkwa GHSR antagonist na oke ụdị anụ ọhịa ma ọ bụ ọzọ, mkpochapụ mkpụrụ ndụ ihe nketa nke GHSRs, na-egbochi omume ụgwọ ọrụ nri metụtara mmachi caloric (27, 54). Nlekọta GHSR antagonist na-egbochikwa caloric mmachi operant lever ịpị maka sucrose na oke (63). Otu nwere ike na-arụ ụka na usoro ghrelin etolitela iji nyere ụmụ anụmanụ aka ịnagide ọnọdụ nke enweghị ume site n'ịkwado nri sitere na nri ndị nwere calorie na-atọ ụtọ.

A na-ahụkwa mmụba nke ghrelin n'elu nrụgide (ntụgharị uche).44, 75-81). Dịka ọmụmaatụ, mmụba na mkpụrụ ndụ ihe nketa ghrelin gastric na plasma ghrelin na-eme na nzaghachi anụ ahụ na nrụgide ọdụ ọdụ yana nrụgide na-ezere mmiri.75, 76). Plasma ghrelin na-ebuli elu na-apụtakwa na òké na-emesi ike site na ikpughe n'ọnụ ụlọ idei mmiri na-aga n'ihu ma ọ bụ na gburugburu ebe oyi.44, 50, 77, 82). Usoro mgbakasị mmekọrịta ọha na eze na-adịghị ala ala (CSDS), nke na-edobe ụmụ oke ka ọ bụrụ onye na-edo onwe ya n'okpuru ọha ugboro ugboro site n'aka onye agadi na onye na-eme ihe ike ka ukwuu, na-eduga n'ịdị elu plasma ghrelin.44, 50, 83). N'otu aka ahụ, ikpughe ụmụ oke na usoro nrụgide na-adịghị ala ala nke ụbọchị 14 na-ebuli plasma ghrelin.81). Ụmụ mmadụ dabara nke ọma na nrụgide psychosocial ma ọ bụ na-anwale ule nrụgide mmekọrịta ọha na eze na-egosipụtakwa mmụba plasma ghrelin.78, 80). Ekpebibeghị usoro ndị na-akpata mmụba a metụtara nrụgide na-ekesa ghrelin mana enwere ike ịgbazi ya site na nzaghachi sympathoadrenal, dị ka a tụrụ aro site na nyocha na-ejikọ ịgbalite sistemu ụjọ ahụ na / ma ọ bụ ntọhapụ nke catecholamines na nzuzo ghrelin na nke a na-ahazi. mmeghachi omume nrụgide omume (84-86).

Ihe ka ọtụtụ ná ndị mmadụ na-enwe nchekasị na-akọ mgbanwe na àgwà iri nri ha - na ụfọdụ na-eri nri na ụfọdụ na-eri ihe na-erughị tupu nrụgide ahụ (87, 88). Ọzọkwa, ahụmihe ụmụ mmadụ na-abawanye na iri nri na-atọ ụtọ nke ukwuu na-adabereghị na nzaghachi nri ha n'ozuzu na nrụgide ahụ (87, 88). Àgwà iri nri dị mgbagwoju anya nke jikọtara ya na nrụgide nwere ike na-enye aka na mmụba nke oke ibu na oke ibu n'etiti ndị mmadụ na-enwe nrụgide. N'ụzọ na-akpali mmasị, mmụba na-akpata nrụgide na plasma ghrelin dị na "ndị na-eri mmetụta uche dị elu" - nke a na-akpọ n'ihi agụụ nri ha nwere ahụmahụ na ụbara oriri nke nwere carbohydrates na abụba na nzaghachi mmetụta uche na nrụgide na-adịghị mma - ada ada nke ukwuu ịgbaso nri. oriri (80). Nke a adịghị ka nzaghachi ghrelin hụrụ n'oge nri nri na ndị mmadụ na-akọ obere mgbanwe n'omume iri nri ha na nrụgide.80), ma si otú a na-atụ aro ọrụ maka ghrelin na omume iri nri dabere na nrụgide.

Anyị ejirila CSDS nyochaa kpọmkwem ọrụ ghrelin na mgbanwe nrụgide na-akpata na omume ụgwọ ọrụ nri. CSDS, nke dị ka ekwuru n'elu na-ebuli ghrelin na-ekesa, na-ejikọta ya na hyperphagia nke a na-enweta ya mgbe niile ma n'ime ma ọ dịkarịa ala otu ọnwa mgbe oge mmeri gasịrị (44, 89, 90). Hyperphagia a, nke a na-ahụghị na ụmụ oke na-enweghị GHSR, nwere ike inye aka na uru ahụ dị elu nke a na-ahụ na ụdị oke ọhịa nke CSDS.44, 89, 90). Ọ bụghị naanị na CSDS na-ebute nzaghachi hyperphagic na ụdị oke oke ọhịa, mana ọ na-abawanye CPP maka HFD (50). Nzaghachi nri nri na-akpata nrụgide na-adabere na nrịbama ghrelin, ebe a naghị ahụ CPP maka HFD n'ime oke GHSR-null CSDS kpughere (CSDS).50). Ọzọkwa, nkwupụta nke GHSR na-ahọrọ na tyrosine hydroxylase nwere neurons (nke, dị ka akọwara n'elu, gụnyere dopaminergic VTA neurons) na-enye ohere maka ịmalite omume iri nri hedonic site na CSDS protocol.50). Ọ ga-ekwe omume na glucocorticoids na-arụ ọrụ nkwado na mgbasa ozi ghrelin nke nri na-akpata nrụgide na-akpata ụgwọ ọrụ, ebe a na-ahụ ọkwa corticosterone dị elu n'ụdị oke ọhịa nke ekpughere na CSDS karịa nke a na-emeso GHSR-null littermates. Nke a dị ka ọ dabara na ọdịiche dị na nrụgide metụtara nchekasị, nri na-akwụghachi ụgwọ na-ahụ n'ụdị anụ ọhịa na GHSR-null littermates ebe ọ bụ na nzuzo glucocorticoid na-abawanye omume mkpali ma na-abawanye oriri nke ukwuu.88).

Nchọpụta CSDS dị n'elu n'ụdị anụ ọhịa na anụ ọhịa GHSR-null dị iche na nke a hụrụ n'ụdị òké nrụgide na-adịghị ala ala nke nrụgide na-adịghị ala ala (81). Ọ bụ ezie na CSDS na nrụgide na-adịghị ala ala na-enweghị atụ ma na-ebuli plasma ghrelin, nchekasị na-adịghị ala ala nke ekpughere ụdị oke oke anụ ọhịa na-ebelata iri nri na uru ahụ n'ime oge ọgwụgwọ ahụ, ebe GHSR-na-adịghị ike ụmụ oke na-enweghị mgbanwe na usoro ndị a.81). A chọrọ ọrụ ọzọ iji dokwuo anya ike dị iche iche nke ghrelin na nri nri, ụgwọ ọrụ nri na ịdị arọ ahụ n'etiti ụdị anụ ọhịa dị iche iche nke iri nri dabere na nrụgide.91-96) na n'etiti ụmụ mmadụ nwere mmeghachi omume omume iri dị iche na nrụgide.

Mkpebi na echiche

Nnyocha e mere n'oge na-adịbeghị anya ekpughere ọtụtụ mgbagwoju anya gbasara ọrụ ghrelin na mgbanwe nke oriri nri yana uru na-akwụghachi ụgwọ nke nri dị ụtọ. Ọtụtụ na-egosipụta mkpa nke ụzọ mesolimbic na mmetụta ndị a. N'ụzọ na-akpali mmasị, mmetụta nke ghrelin na usoro mesolimbic na-agbatịkwa n'omume ọgwụ na ịṅụ mmanya na-aba n'anya, na-atụ aro na ghrelin nwere ike ịbụ njikọ dị n'etiti ụkọ nri na / ma ọ bụ nrụgide na mmụba na uru hedonic nke ụgwọ ọrụ dịgasị iche iche [dị ka enyocha ya. na (97-99)). A maara Ghrelin n'onwe ya ka ọ na-akwụghachi ụgwọ n'onwe ya (100). Ụzọ Mesolimbic dịkwa mkpa maka mmetụta ghrelin na ọnọdụ. Karịsịa, iji ụdị òké, anyị egosila na ịbawanye ọkwa ghrelin na-ekesa site na ụbọchị 10 nke mmachi kalori ma ọ bụ site na nnukwu injection subcutaneous na-emepụta nzaghachi antidepressant na ule igwu mmiri amanye.44). Agbanyeghị, mmachi caloric anaghịzi ebute nzaghachi a na ụmụ oke na-enweghị GHSRs, na-atụ aro na nnyonye anya na akara ghrelin na-egbochi omume antidepressant-dị ka nke jikọtara ya na mmachi calorie (44). Ọzọkwa, mgbe ikpughe na CSDS, ụmụ oke GHSR-null na-egosipụta oke mmekọrịta ọha na eze (ihe akara ọzọ nke ịda mbà n'obi-dị ka omume) karịa ụdị anụ ọhịa.44). Ya mere, anyị na-atụ aro na ịgbalite ụzọ mgbaàmà ghrelin na nzaghachi nke nrụgide na-adịghị ala ala nwere ike ịbụ mmegharị homeostatic nke na-enyere ndị mmadụ aka ịnagide nrụgide. Na mgbakwunye na usoro ndị ọzọ anyị nwere ike ịkọwa na ghrelin na-anabata catecholaminergic neurons, akara ghrelin kpọmkwem site na GHSRs na mpaghara catecholaminergic neurons (gụnyere ndị ahụ e kwuru n'elu VTA dopaminergic neurons) ezukwara maka nzaghachi ọnọdụ ọnọdụ na-esote nrụgide na-adịghị ala ala.50).

Nyere ọtụtụ omume ghrelin ndị a na sekit neuronal na-agafe agafe, mmadụ nwere ike chepụta ihe atụ nke nchịkwa ghrelin mimetic nye ndị mmadụ nwere anorexia nervosa na-enweta ọgwụgwọ nri ọzọ ga-egbochi ọdịda ikwu na ikesa ghrelin. Ụda na-esote na sekit na-etinye aka na ghrelin ga-enye aka kpalie oriri nri, belata ihe nwere ike ịka njọ ịda mbà n'obi (ọnọdụ na-akpatakarị ọrịa n'etiti ndị na-arịa ọrịa anorexia nervosa), ma na-eduga n'echiche nke ịdị mma (n'ihi Njirimara bara uru nke ghrelin).

N'aka nke ọzọ, ụzọ mesolimbic na-achịkwa ma ọ dịkarịa ala ụfọdụ mmetụta ghrelin na iri nri homeostatic, iri hedonic, na ọnọdụ nwere ike belata ịdị irè ya dị ka ebumnuche ọgwụ na-efunahụ ibu. Ọdịdị jikọtara ọnụ nke ụzọ neuronal na-eme ka nzaghachi nrụgide omume na-ahazi nwere ike ịkọ otu akara aka dị ka ọgwụ mgbochi oke ibu Rimonabant, nke na-enwetaghị nkwado FDA n'ihi ụbara akụkọ nke ịda mbà n'obi siri ike, maka ndị ọzọ na-eme ihe mgbochi oke ibu. Àgwà omume ndị dị otú ahụ yiri njikọ chiri anya na-egosipụta ọbụna n'ihu mkpa ọmụmụ ihe iji gbasaa ụzọ neuroanatomical na-achịkwa omume ghrelin na omume iri nri jikọtara ya na homeostasis arọ ahụ, ụgwọ ọrụ, nchekasị na ọnọdụ. N'agbanyeghị ihe ndọghachi azụ a, anyị kwenyere na data niile dị na-ejikọta ghrelin na omume ụgwọ ọrụ nri na-akwadosi echiche nke ịchebe usoro ghrelin dị ka atụmatụ dabara adaba iji gwọọ na / ma ọ bụ gbochie mmepe nke oke ahụ.

Nkweta

Ndị ode akwụkwọ ga-achọ ịnakwere enyemaka nke Dr. Michael Lutter maka ọtụtụ okwu na-enyere aka n'oge nkwadebe nke ihe odide a. Ndị Florencio Fiorini Foundation, International Brain Research Organisation na PICT2010-1954 nyere MP kwadoro ọmụmụ ihe a yana R01DA024680 na R01MH085298 NIH nyere JMZ.

Ihe odide ala

Nkọwapụta ego

Ndị na-ede akwụkwọ ekwupụtaghị ọdịmma ego ma ọ bụ nsogbu ndị nwere mmasị.

Nkwupụta Nkwupụta Onye Nkwusa: Nke a bụ faịlụ PDF nke ihe odide a na-akwadoghị nke akwadora maka mbipụta. Dịka ọrụ nke ndị ahịa anyị, anyị na-enye nsụgharị mbụ nke ihe odide ahụ. Ihe odide a ga-enwe ngbanwe, nhazi, na nyochaa ihe kpatara ya tupu e bipụ ya na nke ikpeazụ ya. Biko rịba ama na n'oge mmepụta usoro njehie nwere ike ịchọta nke nwere ike imetụta ọdịnaya ahụ, ihe niile gbasara iwu na-emetụta akwụkwọ akụkọ ahụ.

References

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